>> WELCOME TO THE FOURTH SESSION
OF THE 21st YEAR OF THE
COURSE, DEMYSTIFYING MEDICINE.
THE OVERALL GOAL IS TO BRIDGE
EXCITING DEVELOPMENTS IN BIOLOGY
AND ENGINEERING WITH MEDICINE.
THIS IS THE LOGO OF
THE COURSE, THE BROOKLYN BRIDGE,
MANY OF US THINK OF IT AS THE
MOST FAMOUS BRIDGE IN HISTORY.
AND WE ARE LIKE THE INDIVIDUALS
ON THE CATWALK, TAKING ADVANTAGE
OF HEARING EXPERT IDEAS AND
OPINIONS AND INFORMATION FROM
INDIVIDUALS WHO REPRESENT TWO
VERY DIFFERENT DISCIPLINES, BUT
DEALING WITH A MAJOR DISEASE
PROBLEM.
THE TWO SPECIFIC BRIDGES BEING
CROSSED TODAY IN COMMUNICATION
ARE, ONE, THE 19th CENTURY
DISCOVERY BY ELIE METCHNIKOFF
AND SECONDLY HOW MEDICAL HISTORY
RESULTS IN RECENT RESURRECTING A
DISCARDED DISCOVERY IN THE TIME
OF COVID PANDEMIC.
140 YEARS AGO METCHNIKOFF, A
RUSSIAN-BORN NATURALIST, NOT A
PHYSICIAN, STUDIED THE STARFISH
AND DISCOVERED WHAT HE CULLED
THE CALLED THE CELL EATING,
PHAGOCYTIC IMMUNE SYSTEM, BURIED
FOR YEARS.
BOTH AMERICAN RECEIVED PRIZE FOR
STUDIES ON IMMUNOLOGY.
OVER THE NEXT CENTURY THERE WERE
TEN NOBEL PRIZES GIVEN FOR
RESEARCH DEALING WITH ADAPTIVE
SYSTEM.
BUT IT WASN'T UNTIL 2013 THAT
THE AWARD WAS GIVEN TO BOYDLER
AND HOFFMAN FOR DISCOVERY OF
TOLL RECEPTORS FOR MACROPHAGES,
THE FIRST AWARD GIVEN FOR ANY
STUDIES DEALING WITH THE INNATE
IMMUNE SYSTEM.
METCHNIKOFF STUDIED THE
MICROBIOME ALONG THE WAY AND
PROPOSED ITS ROLE IN HEALTH,
DISEASE, EVEN AGING.
OUR FIRST SPEAKER TODAY, NEXT
SLIDE PLEASE, IS LUBA VIKHANSKI,
SHE'S A NOTED SCIENCE WRITER OF
ARTICLES AND BOOKS AND WORKS AT
THE WEIZMANN INSTITUTE IN
ISRAEL.
SHE OBTAINED ACCESS TO
PREVIOUSLY UNAVAILABLE
INFORMATION FROM THE PASTEUR
INSTITUTE WHERE METCHNIKOFF WAS
A DIRECTOR AND WROTE A BOOK, HOW
ELIE METCHNIKOFF CHANGED THE
COURSE OF MODERN MEDICINE.
THE TITLE OF HER TALK IS 19th
CENTURY INNATE IMMUNITY, ELIE
METCHNIKOFF AND THE IMMUNITY
WAR.
OUR SECOND SPEAKER IS BOB GALLO,
WHO RECEIVED HIS MEDICAL DEGREE,
TRAINED IN IMMUNOLOGY AT YALE,
IN CHICAGO, SPENT 30 YEARS AT
THE NIH, NATIONAL CANCER
INSTITUTE, WHERE HE WAS HEAD OF
THE LABORATORY OF TUMOR CELL
BIOLOGY.
PRIOR TO THE AIDS PANDEMIC, BOB
WAS THE FIRST TO IDENTIFY A
HUMAN RETROVIRUS, HTLV-1, AS
CAUSING A HUMAN CANCER.
AND IN 1982, I HEARD HIM PRESENT
AT A COLD SPRING HARBOR MEETING,
THE CONCEPT, HIS IDEA, THAT AIDS
WAS CAUSED BY A RETROVIRUS.
IN 1984, HE CO-DISCOVERED HIV AS
THE CAUSE OF AIDS, AND HIS
RESEARCH BROUGHT HONORS FROM
COUNTRIES AROUND THE WORLD,
ELECTION TO THE NATIONAL ACADEMY
OF SCIENCES, INSTITUTE OF
MEDICINE, ABOUT 35 HONORARY
DOCTORATES, AND IN 1980s AND
'90s HE WAS THE MOST
REFERENCED SCIENTIST IN THE
WORLD.
AND MOST REMARKABLY, HAD THE
UNIQUE DISTINCTION WINNING
AMERICA'S MOST PRESTIGIOUS
SCIENTIFIC AWARD, THE LASKER
AWARD IN MEDICINE.
HIS DISCOVERIES LED TO
DIAGNOSTIC AND THERAPEUTIC
ADVANCES IN CANCER, AIDS, AND
OTHER VIRAL DISORDERS.
AND TODAY, HIS WORK CONTINUES AT
THE UNIVERSITY OF MARYLAND WHERE
HE'S THE GUDELSKY DISTINGUISHED
PROFESSOR OF MEDICINE,
CO-FOUNDER AND DIRECTOR OF THE
INSTITUTE OF HUMAN BIOLOGY, AND
CO-FOUNDER AND SCIENTIFIC
ADVISER TO THE GLOBAL VIRUS
NETWORK.
RECENTLY, HE HAS TURNED HIS
ATTENTION TO THE INNATE IMMUNE
SYSTEM, AS IT APPLIES TO
COVID-19 AND OTHER VIRAL
DISEASES.
AND THE TITLE OF BOB'S TALK IS
REFLECTION ON SARS-COV-2
PANDEMIC AND INNATE IMMUNITY.
SO, WE WILL BEGIN WITH LUBA
VIKHANSKI.
IT'S A PLEASURE TO HAVE YOU WITH US
THANK YOU VERY MUCH FOR THIS
OPPORTUNITY TO TALK.
I WANT TO SAY A WORD ABOUT MY
VIRTUAL BACKGROUND.
THIS IS THE LIBRARY OF THE
PASTEUR INSTITUTE IN PARIS, AND
IN THIS INSTITUTE, METCHNIKOFF
WORKED FOR THE SECOND HALF OF
HIS LIFE AND WAGED TWO MAJOR
BATTLES IN HIS LIFE.
ONE WAS TO ADVANCE HIS THEORY OF
IMMUNITY, AND THE OTHER WAS TO
DEFEAT AGING.
AND WHEN HE DIED IN 1916, IT
SEEMED HE LOST BOTH HIS BATTLES.
BUT TODAY WE CONSIDER HIM A
WINNER, AND I WILL TELL YOU HOW
THIS HAPPENED.
AND IN THE PROCESS I HOPE TO
GIVE YOU INSIGHT TO THE ORIGINS
OF THE
INNATE IMMUNITY RESEARCH.
LET ME INVITE YOU TO PARIS AT
THE HEIGHT OF THE PERIOD THAT
BECAME KNOWN AS THE BELLE EPOCH,
A SPLURGE OF CREATIVITY IN THE
CITY, THESE ARE ICONIC WORKS OF
HEARTS AROUND THAT TIME, THE
EIFFEL TOWER IS ALMOST FINISHED
FOR THE UPCOMING WORLD FAIR.
AND THE SAME YEAR, 1888, A NEW
INSTITUTION OPENS IN PARIS, FOR
DIFFERENT SORT OF CREATIVITY, IN
SCIENCE AND MEDICINE.
IT IS THE PASTEUR INSTITUTE, AND
THE VERY FIRST SCIENTIST TO MOVE
INTO THIS BUILDING IS THE
RUSSIAN ZOOLOGIST, ELIE
METCHNIKOFF, HE CHANGES HIS
FIRST NAME TO ELI WHEN HE COMES
TO FRANCE, FROM ODESSA, IN ORDER
TO DEFEND HIS THEORY OF
IMMUNITY, WHICH IS IN TROUBLE.
WHO WAS METCHNIKOFF?
HERE HE IS AS AN ANGRY YOUNG
MAN, BORN IN UKRAINE, WHICH WAS
THEN PART OF THE RUSSIAN EMPIRE.
HIS FATHER CAME FROM MOLDAVIAN
NOBILITY, MOTHER'S JEWISH
PARENTS CONVERTED TO
CHRISTIANITY, GRADUATED FROM
UNIVERSITY AT 19, LOOKING FOR AN
INTERESTING RESEARCH TOPIC.
AT THE TIME, ONE OF THE CENTRAL
QUESTIONS IN BIOLOGY WAS HOW ARE
DIFFERENT TYPES OF ANIMALS
RELATED TO ONE MOTHER.
METCHNIKOFF WAS BLOWN AWAY BY
"THE ORIGIN OF SPECIES"
PUBLISHED RECENTLY BY DARWIN.
THEN THERE WAS THE IDEA THAT
PERHAPS DARWIN'S EVOLUTION WAS
STILL VERY CONTROVERSIAL, AND
THERE WAS THE IDEA THAT PERHAPS
IT COULD BE FIGURED OUT THROUGH
EMBRYOLOGY.
BUT EMBRYOLOGY IN VERTEBRATES
WAS NOT MUCH STUDIED, AND IN
GENERAL THEY WERE SO DIVERSE
PEOPLE THOUGHT THAT THERE IS NO
WAY THAT THEY COULD HAVE ALL
COME FROM A COMMON ANCESTOR LIKE
DARWIN HAD SUGGESTED.
HE BEGAN TO STUDY EMBRYO, THEY
WERE MADE UP OF GERM LAYERS,
FROM WHICH DIFFERENT ORGANISMS
GERMINATED IN THE SAME WAY AS
VERTEBRATES.
HE IN FACT CREATED ONE OF THE
FIRST LINKS BETWEEN THE TWO
TYPES OF ANIMALS, OTHER PEOPLE
WERE STUDYING MORPHOLOGY AND IT
WAS JUST TOO DISSIMILAR.
BUT THROUGH STUDYING DEVELOPMENT
THE WAY HE DID, HE SHOWED A
UNITY HERE, TWO EXAMPLES, TWO
PAPERS, ONE IN SQUID, ONE IN
SCORPIONS.
AT A YOUNG AGE BECAME A
CO-FOUNDER OF A NEW BRANCH OF
SCIENCE, COMPARATIVE EMBRYOLOGY
OF INVERTEBRATES, PARTICULARLY
FASCINATED BY THE MIDDLE GERM
LAYER, MESODERM, SOMETIMES
EMBRYOS HAD ONLY TWO LAYERS, AND
THIS MESODERM CONTAINED A MOBILE
CELL THAT SOMETIMES THEY STAYED
ON IN THE ADULT ANIMAL, AND
THESE CELLS PERFORMED A
PRIMITIVE FORM OF DIGESTION IN
ANIMALS THAT DIDN'T HAVE A
PROPER DIGESTIVE SYSTEM.
SO, HE CONDUCTED STUDIES OF THE
DIGESTION.
THESE ARE SOME OF THE DRAWINGS
FROM HIS PAPERS.
AND THESE ARE PICTURES I FOUND
ON THE INTERNET OF THE RELEVANT
SPECIES AND FIGURED OUT WITH
DYES ORGANELLES WHICH DIGESTION
TOOK PLACE THE CONTENT OF THE
ORGANELLES WAS ACIDIC, STUDIES
MOBILE CELLS IN EVERY
TRANSPARENT ANIMAL HE COULD LAY
HIS HANDS ON, THIS IS A PARTIAL
LIST FROM ONE PAPER.
AND THEN HE WROTE A REVIEW ABOUT
THIS.
HE WASN'T THE FIRST SCIENTIST TO
STUDY INTRACELLULAR DIGESTION
BUT CONDUCTED EXPANSIVE STUDIES
AND SYSTEMATIC ONES AND COULD
DRAW GENERALIZED CONCLUSIONS,
FOR EXAMPLE THIS WAS AN ACTIVE
PROCESS, NOT MERELY
DISINTEGRATION.
WHEN METCHNIKOFF WAS IN HIS LATE
30s, HIS WIFE OLGA INHERITED A
LARGE ESTATE.
AND THIS CAME IN HANDY BECAUSE
HE HAD QUARRELED WITH
ADMINISTRATION AT ODESSA
UNIVERSITY.
HE WAS A PROFESSOR OF ZOOLOGY.
NOW THE ESTATE HIS WIFE
INHERITED BROUGHT IN THREE TIMES
A PROFESSOR'S SALARY.
SO HE NO LONGER HAD TO WORRY
ABOUT MAKING A LIVING, AND HE
COULD DEVOTE HIMSELF ENTIRELY TO
SCIENCE, AND WITH OLGA TRAVELED
TO SICILY TO THE PORT OF
MESSINA, WHERE HE WANTED TO
STUDY MARINE ANIMALS, AND ONE OF
THE SPECIES THAT HE STUDIED WAS
THE STARFISH.
THIS IS A LARVA OF A STARFISH,
VERY PLEASED TO FIND THIS IMAGE,
JUST THE SPECIES METCHNIKOFF
WORKED ON, INTERESTED IN THE
CELLS IN THE LARVA, THAT
PERFORMED DIGESTION, AND THERE
HAD AN IDEA FOR AN EXPERIMENT
THAT BECAME REALLY HIS MOST
FAMOUS EXPERIMENT.
AND WHEN HE LATER WON THE NOBEL
PRIZE FOR THIS WORK, HE WROTE AN
ESSAY ABOUT HIS STAY IN SICILY,
AND IN THAT ESSAY HE TOLD THE
STORY OF HOW HE SUDDENLY HAD
THIS IDEA THAT PERHAPS THE SAME
MOBILE CELLS IN THE LARVA
PERFORM NOT ONLY DIGESTION BUT
MAYBE SERVE THE ORGANISM IN
RESISTANCE AGAINST HARMFUL
AGENTS.
SO, HE RAN INTO THE GARDEN AND
BROUGHT BACK SOME THORNS FROM A
ROSE BUSH AND HE INSERTED THEM
UNDER THE SKIN OF THE
TRANSPARENT LARVA, THE FOLLOWING
DAY IN THE MORNING HE SAW THAT
THE EXPERIMENT HAD BEEN A
SUCCESS.
THAT THE MOBILE CELLS INDEED
GANGED UP ON THE THORNS,
OBVIOUSLY IN ORDER TO PROTECT
THE LARVA, AND FROM THIS HE DREW
THE CONCLUSION THAT MAYBE THE
HYPOTHESIS THAT PERHAPS THE SAME
CELLS IN THE HUMAN BODY ALSO
PLAY A PRODUCTIVE ROLE.
IT WAS MOST UNUSUAL AT THE TIME
TO MAKE THIS CONCLUSION FROM AN
INVERTEBRATE TO THE HUMAN BODY.
BUT METCHNIKOFF WAS A CURIOUS
MAN AND HE HAD ATTENDED COURSES
IN PATHOLOGY AND HE KNEW THAT
SOMETIMES LEUKOCYTES WERE FOUND
AT THE SITE OF INFECTION AND
THAT SOMETIMES THEY ALSO
CONTAINED MICROBES, SO THAT WAS
HOW HE REALLY MADE THIS JUMP FRP
STARFISH TO HUMANS, HE SAID HE
SUDDENLY BECAME A PATHOLOGIST.
HE WRITES AT A EUREKA MOMENT BUT
WE HAVE SEEN THIS WAS PRECEDED
BY YEARS AND YEARS OF STUDIES,
AND THIS WAS HOW THE FIRST
MODERN THEORY OF IMMUNITY WAS
BORN.
JUST TO GIVE YOU SOME HISTORIC
CONTEXT, AT THE TIME THERE WAS
NOTHING KNOWN ABOUT IMMUNITY.
IT WAS ALREADY SOME PROGRESS IN
UNDERSTANDING DISEASES, LOUIS
PASTEUR STARTED CREATING THE
FIRST VACCINES, BUT NO ONE HAD A
CLUE HOW VACCINES WORKED.
AND A FEW MONTHS EARLIER ROBERT
KOCH DISCOVERED THE BACILLI
CAUSING TUBERCULOSIS BUT NO ONE
NEW WHY SOME PEOPLE RECOVERED
FROM TB.
THE HUMAN BODY WAS SEEN AS A
VESSEL, PEOPLE THOUGHT IF
SOMEBODY RECOVERED IT WAS SIMPLY
BECAUSE THE GERMS DIED IN AND OF
THEMSELVES.
SO WHEN METCHNIKOFF PUBLISHED
HIS FINDINGS FROM SICILY, IN
1883, THESE ARE THE DRAWINGS OF
THE STARFISH LARVA AND THE
THORNS AND HOW THE CELLS PROTECT
THE LARVA.
HE WAS VERY CAREFUL AND AT THE
END MADE A CAUTIOUS STATEMENT
THAT MAYBE THE SAME DIGESTION
PLAYS A PROTECTIVE ROLE IN
PROTECTING THE ORGANISM AGAINST
HARMFUL BODIES FROM THE OUTSIDE.
BUT ALREADY IN THAT PAPER, HE
COINED NEW NAMES FOR THESE
CELLS, CALLED THEM PHAGOCYTES,
FROM GREEK WORDS FOR EATING AND
CELLS, THE PROCESS BECAME
PHAGOCYTOSIS AND LATER ON IN
ANOTHER PAPER HE COINED THE TERM
MACROPHAGES FOR BIG EATERS AND
MICROPHAGEES, NEUTROPHILS, TERMS
NO LONGER USED, SMALLER AND MORE
MOBILE PHAGOCYTES.
HE CONTINUED TO STUDY PHAGOCYTES
IN DIFFERENT ANIMALS AND SHOWED
THAT THEY ALSO PLAY A ROLE IN
MAINTENANCE, HOMEOSTASIS, IN
CONSUMING ATROPHIED FISHES,
NEXT? E. FOR EXAMPLE WHEN A
TADPOLE TURNS INTO A FROG, THESE
ARE DRAWINGS OF PROGRESSION OF
ATROPHY, AND MADE
MODERN-SOUNDING GUESSES ABOUT
THE ORIGINS OF PHAGOCYTES, THE
ONES IN TISSUES AND BLOOD MUST
COME FROM THE SAME SOURCE.
BUT UNTIL THEN, HIS THINKING
ABOUT PHAGOCYTES AS A FORCED
IMMUNITY WAS A BRILLIANT GUESS,
BASED ON INTUITION.
HE HADN'T SEEN EVIDENCE OF THAT.
AND THEN HE FOUND EVIDENCE IN
MOST UNLIKELY PLACE, IN A FRIEND
IN ODESSA, HE SAW THE LITTLE
CREATURES, NICKNAMED WATER
FLEAS, AND THEY WERE INFECTED BY
A FUNGUS.
HE LOOKED IN THE MICROSCOPE AND
SAW THIS CORRECTION OF
PHAGOCYTES IN THE ABDOMEN --
COLLECTION OF PHAGOCYTES IN THE
ABDOMEN THAT TRIED TO STOP,
CONSUME THE FUNGI.
WHEN THEY MANAGED IN THE
DARKNESS, SURVIVED, WHEN THEY
DIDN'T THE CREATURES DIED.
HE LATER WROTE A HISTORIC ESSAY
ABOUT THE HISTORY OF THE
PHAGOCYTE THEORY SOME 30 YEARS
LATER AND WROTE THAT WHEN THE
THEORY WAS ATTACKED FROM ALL
SIDES, AND HE ASKED, IF HAD HE
GOTTEN ON THE WRONG TRACK, ALL
HE HAD TO DO WAS RECALL FUNGAL
DISEASE OF THE DAPHNIA TO KNOW
HE WAS A FIRM GROUND.
INDEED WHEN HE STARTED
PUBLISHING HIS STUDIES ON
PHAGOCYTOSIS AND IMMUNITY, HE
WAS REALLY ATTACKED FROM ALL
SIDES.
HIS IDEAS RAN COUNTER TO
EVERYTHING THAT PHYSICIANS
BELIEVED.
PATHOLOGISTS HAD SEEN MICROBES
INSIDE CELLS BUT BELIEVED THE
CELLS SPREAD DISEASE, CERTAINLY
DIDN'T FIGHT THEM.
SOME OF THE RESPONSES AND
OBJECTIONS TO METCHNIKOFF'S
THEORIES WERE INSULTING.
PERHAPS THE WORST ONE CAME FROM
THIS RESPECTABLE FRENCH
PHYSICIAN WHO SAID THAT
PHAGOCYTE THEORY IS AN ORIENTAL
FAIRY TALE BORN IN THE HEAD OF A
COSSACK AND I WONDERED WERE
THESE ATTACKS SO VICIOUS.
I THINK IT'S BECAUSE MEDICINE
ARE RECENTLY BECOME A PROPER
SCIENCE AND PHYSICIANS WERE
PROUD OF THAT, AND EVERYTHING
HAD TO BE BASED ON THE MATERIAL
EVIDENCE.
HERE HIS IDEAS OF CELLS THAT EAT
MICROBES, THEY JUST SOUNDED SO
WEIRD, IT SMACKED OF MYSTICISM,
VITALISM, ALL THESE DISCREDITED
SERIES, AND HE WASN'T EVEN A
PHYSICIAN.
HE WAS A ZOOLOGIST.
HE WAS AN OUTSIDER, A RUSSIAN.
SO, THEY DIDN'T WANT THE
DISCIPLINE TO BE DISCREDITED.
SO METCHNIKOFF FELT HE HAD TO
FIGHT BACK AND THAT WAS WHEN HE
MOVED TO THE PASTEUR INSTITUTE
IN PARIS, IN ORDER TO PROPERLY
DEFEND HIS THEORY.
THEN AT THE TIME IN GERMANY,
SCIENTISTS DEVELOPED A RIVAL
THEORY OF IMMUNITY.
THEY SAID IMMUNITY DID NOT
DEPEND ON CELLS BUT RATHER ON
THE BODY FLUIDS, THE ARCHAIC
NAME WAS HUMOROUS, THIS THEORY
BECAME KNOWN AS THE HUMORAL
THEORY, ONE OF THE MOST
PROMINENT PROPONENTS OF THIS WAS
EMIL BEHRING, IN ONE HIS FIRST
PAPERS CHALLENGED METCHNIKOFF
AND SAID HE WANTS TO HIGHLIGHT
EXPERIMENTS THAT SHOW PURELY
CHEMICAL VIEWPOINT FOR IMMUNITY.
SO WHAT HAPPENED LATER ON
METCHNIKOFF CALLED THE ATTACKS
ON HIS THEORY A WAR.
THAT'S WHY I CALLED IT IMMUNITY
WAR IN MY BOOK.
AND IN FACT, THERE WAS A GREAT
HOSTILITY AT THE TIME BETWEEN
FRANCE AND GERMANY, IT ALL WENT
BACK TO THE WAR BETWEEN FRANCE
AND RUSSIA A FEW YEARS BEFORE
THAT.
SO, AS SOON AS METCHNIKOFF
ALIGNED HIMSELF WITH PASTEUR IT
GAME A MATTER OF HONOR FOR
GERMAN SCIENTISTS TO PROVE HIM
WRONG IN ORDER TO SHOW WHO WAS
SUPERIOR IN SCIENCE AND
MEDICINE, WHO WAS THE TRUE RULER
OF EUROPE.
SO, POOR METCHNIKOFF HAD TO
FIGHT HIS IMMUNITY WAR AGAINST
THE BACK DROP OF A REAL WAR,
THIS POLITICAL HOSTILITY
CERTAINLY ADDED FUEL TO THE
FIRE.
SO THERE WERE NOW TWO REALLY
CAMPS OF IMMUNITY.
METCHNIKOFF WITH HIS CELLULAR
IMMUNITY IN FRANCE, AND THE
GERMAN SCIENTISTS WITH THEIR
HUMORAL IMMUNITY.
AND IN FACT METCHNIKOFF WAS AT A
DISADVANTAGE FROM THE START
BECAUSE HUMORAL IMMUNITY VERY
SOON PROVED VERY USEFUL.
NOW IN RETROSPECT, WE SAY THAT
BEHRING DISCOVERED ANTIBODIES.
AT THE TIME, AT THE BEGINNING
SCIENTISTS DID KNOW WHAT WAS IN
THE BODY FLUIDS, THEY KNEW THERE
WAS SOME BIOLOGICAL CHEMICALS
THERE, BUT EVEN BEFORE THAT WAS
COMPLETELY AND FULLY FIGURED OUT
BEHRING STARTED USING BODY
FLUIDS IN TREATING CHILDREN FOR
DIPHTHERIA.
THIS WAS THERAPY, IMMUNIZED
HORSES AND OTHER LARGE ANIMALS
AGAINST DIPHTHERIA AND DREW THE
BLOOD AND WITH THE SERUM THEY
TREATED CHILDREN, FOR
DIPHTHERIA, ADULTS AS WELL,
QUITE SUCCESSFULLY.
THERE WAS TREMENDOUS EXCITEMENT
OVER THAT.
SOMETIMES WE THINK BACK ABOUT
ANTIBIOTICS AS THE FIRST
SUCCESSFUL THERAPY AGAINST
INFECTION, BUT IN FACT IT WAS
SERUM THERAPY THAT WAS THERE
FIRST.
AND WHEN THE NOBEL PRIZES WERE
AWARDED FOR THE FIRST TIME IN
1901, THE FIRST PRIZE IN
MEDICINE WENT TO BEHRING FOR HIS
SERUM THERAPY.
BUT METCHNIKOFF WAS NOT
DISCOURAGED BY THE FACT THAT HIS
STATUS WAS NOT PRACTICAL.
ON THE CONTRARY, HE WAS
ENERGIZED BY THIS CONFRONTATION.
HE LAUNCHED A LARGE PROGRAM OF
STUDIES AT THE PASTEUR
INSTITUTE, A WHOLE SERIES OF
STUDIES HAD TO DO WITH
PHAGOCYTES AND INFLAMMATION.
HE DELIVERED 12 LECTURES AT THE
PASTEUR INSTITUTE, THEY WERE
LATER -- THEY CAME OUT AT A
BOOK, TRANSLATED INTO ENGLISH
NOW CONSIDERED A CLASSIC BECAUSE
HE LAID FOUNDATIONS FOR THE
MODERN UNDERSTANDING OF
INFLAMMATION.
AT THE TIME, SCIENTISTS THOUGHT
THAT INFLAMMATION WAS PASSIVE
AND HARMFUL.
THAT LEUKOCYTES THROUGH BLOOD
VESSELS, CAUSED NOTHING BY HARM.
METCHNIKOFF ARGUED IT WAS
ACTUALLY ACTIVE AND HEALING.
AND HE WROTE, FOR EXAMPLE, THAT
BY THE BLOOD CURRENT ORGANISM
CAN AT ANY GIVEN MOMENT SEND A
CONSIDERABLE NUMBER OF
LEUKOCYTES TO AVERT EVIL.
BUT THE MAJOR POINT OF
CONTENTION BETWEEN THE TWO CAMPS
WAS WHETHER PHAGOCYTES CAN OR
CANNOT KILL THE GERMS.
OF COURSE THE GERMAN SCIENTISTS
BELIEVED THAT THEY DIDN'T KILL
THEM, THEY SIMPLY PICKED UP DEAD
BACTERIA.
FOR EXAMPLE, ONE PROMINENT
BACTERIALOLOGYIST WROTE IN ONE
GERMAN JOURNAL THAT I PICKED
THIS QUOTE, I LIKE IT BECAUSE
IT'S VERY POETIC, PHAGOCYTES ARE
EITHER VICTIMS OF BACTERIA THAT
CONTINUE VICTORIOUS MARCH OR ARE
GRAVES SCATTERED OUTSIDE THE
BATTLEFIELD, MEANING THEY
CONTAIN DEAD BODIES OF THE
BACTERIA AFTER THE FIGHTING IS
OVER.
SO METCHNIKOFF HAD TO PROVE THAT
PHAGOCYTE KILLED BACTERIA,
INFECTED PIGEONS WITH ANTHRAX,
REMOVED PHAGOCYTES FILLED WITH
ANTHRAX GERMS AND APPLIED A
SOLUTION TO KILL THE CELL.
A FEW HOURS LATER LOOKED AND SAW
BACTERIA CONTINUED TO GROW.
HE WROTE THAT USING THIS METHOD
SIMPLE AND DEMONSTRATIVE HE WAS
ABLE TO SHOW THAT PHAGOCYTES
CAPTURE THE BACTERIA LIVE.
BUT OF COURSE HIS OPPONENTS WERE
NOT CONVINCED AND CONTINUED TO
SHOW THAT FLUIDS COULD KILL
BODY -- BODY FLUIDS COULD KILL
BACTERIA WITHOUT ANY HELP FROM
CELLS, AND THEN CAME THE MAJOR
OPPONENT, THE FINAL ONE, THIS
GERMAN JEWISH SCIENTIST, PALMER
LICK WHO DEVELOPED THE NOTION OF
RECEPTORS, CALLED THEM SIDE
CHAINS, ANTIBODIES CAN
NEUTRALIZE PATHOGENS THROUGH THE
PRECISE FIT, HE BORROWED A
METAPHOR FROM ORGANIC CHEMISTRY,
LOCK AND KEY.
AND THIS BECAME HUGE BECAUSE IT
SORT OF LAID THE FOUNDATIONS FOR
THE ENTIRE PHARMACEUTICAL
INDUSTRY OF THE FOLLOWING
20th, AND PALMER LICK STARTED
DEVELOPING DRUGS, YOU CALLED
THEM MAGIC BULLETS, A MOVIE WAS
MADE IN HOLLYWOOD, DR. EHRLICH'S
MAGIC BULLET.
NOW, METCHNIKOFF TRIED TO ARGUE
THERE WAS NO CONTRADICTION
BETWEEN PHAGOCYTES AND
RECEPTORS.
BUT EHRLICH WOULD HEAR NONE OF
THAT.
THEY KNEW EACH OTHER AND
ACTUALLY PERSONALLY EHRLICH
LIKED METCHNIKOFF BUT HE
BELIEVED ONLY IN CHEMISTRY, ALL
THIS TALK ABOUT EATING CELLS,
RUSSIAN MYSTICISM TO HIM, AND
EVEN ONCE WROTE TO A FRIEND IN
DENMARK THAT HE HAD GREAT
ADMIRATION FOR THE HEAD OF THE
PASTEUR INSTITUTE AND WROTE IT
WAS SUCH A SHAME THAT HE SHOULD
STRAYED SO DEEPLY INTO MYSTICISM
AND RUSSIAN FOG.
AND OF COURSE MEANING THAT
METCHNIKOFF HAD TOO MUCH
INFLUENCE OVER HIM.
SO, MANY BELIEVED IN
PHAGOCYTOSIS, THAT IT WAS REAL,
BUT IT WAS CONSIDERED USELESS,
NOBODY WORKED ON THAT, AND THE
FUTURE OF MEDICINE SEEMED TO
BELONG TO ANTIBODIES, NEW
VACCINES, NEW THERAPIES, AND SO
THE WORST BLOW TO METCHNIKOFF
WAS WHEN THE ENEMY ABANDONED
HIM, GERMAN SCIENTISTS STOPPED
FIGHTING FROM HIM AND WITHOUT
OPPOSITION HE LOST STEAM.
ON HE STOPPED WORKING ON
IMMUNITY.
HE WROTE IN 1901, THESE ARE
DRAWINGS FROM THE BOOK, AND THEN
IT SEEMED LIKE THIS WAS IT FOR
THE PHAGOCYTES THEORY.
A FEW YEARS LATER, WHEN KNOW
COMMITTEE DECIDED TO AWARD NOBEL
PRIZE FOR COMMUNITY, METCHNIKOFF
WAS HONORED EVEN THOUGH IT
SEEMED THE HUMORAL CAMP HAD WON,
HE HAD BEEN THE FIRST TO TALK
ABOUT, YOU KNOW, THE IMMUNITY
THAT BROUGHT HEALING POWERS OF
THE BODY AND EXPLAINED WHAT
LEUKOCYTES DO WHICH IS HUGE AND
HE CONDUCTED LOTS AND LOTS OF
VALUABLE STUDIES.
BUT THE CATCH WAS THAT THE PRIZE
WAS SHARED BETWEEN HIM, HAD HE
TO SHARE THE PRIZE WITH EHRLICH.
THE NOBEL COMMITTEE WROTE THAT
BY DIVIDING THE PRIZE BETWEEN
THEM, THEY DIDN'T HAVE TO TAKE
SIDES IN THIS IMMUNITY DEBATE.
AND OF COURSE IN RETROSPECT,
THEY WERE ABSOLUTELY RIGHT.
THEY CONSIDERED ONE OF THE MOST
WORTHY AND MOST WELL AWARDED
NOBEL PRIZES.
BUT BOTH METCHNIKOFF AND EHRLICH
WERE UNHAPPY.
EHRLICH BELIEVED HE DESERVED THE
PRIZE ON HIS OWN AND METCHNIKOFF
DIDN'T GO TO THER CEREMONY IN
STOCKHOLM, WROTE HE WAS BUSY
TEACHING AT THE PASTEUR
INSTITUTE BUT MORE LIKELY IT WAS
AN EXCUSE AND HE JUST DIDN'T
WANT TO PLAY SECOND FIDDLE TO
EHRLICH IN STOCKHOLM.
AND ALSO BY THEN ONCE HE WROTE
HIS MAJOR WORK ON IMMUNITY, HE
WAS IN HIS MID-50s, HE WAS 56.
AND HE STARTED TO WORRY ABOUT
AGING.
HE SWITCHED, BY NOW HE HAD
COMPLETELY NEW DIRECTION OF
STUDIES.
HE DEVELOPED THIS THEORY THAT IT
WAS THE CONTENT OF THE MICROBES
IN THE INTESTINES, TODAY WE CALL
THE MICROBIOME, RESPONSIBLE FOR
AGING, THAT THEY RELEASED
POISONS THAT SOMEHOW IMPROPERLY
STIMULATED PHAGOCYTES AND THAT'S
WHAT CAUSED THE PROPER -- THE
ATROPHY OF TISSUES.
HE STARTED STUDYING OLD ANIMALS.
THIS IS A STUDY OF PARROTS,
LONG-LIVED BIRDS.
THIS IS A COMPARISON BETWEEN THE
BRAIN OF A YOUNG PARROT AND OLD
PARROT, WHICH HAS NEURONS THAT
WERE SWALLOWED BY PHAGOCYTES.
HE ALSO STARTED WRITING
PHILOSOPHICAL BOOKS ABOUT THIS,
AND THIS IS THE FIRST ONE.
THIS IS CALLED "THE NATURE OF
MAN," AND IN THIS BOOK HE COINED
A NEW TERM, GERONTOLOGY, AND HE
CALLED ON OTHER SCIENTISTS TO
STUDY AGING IN A SYSTEMATIC WAY.
SO FOR THE THIRD TIME IN HIS
LIFE BECAME A FOUNDER OF A NEW
SCIENCE.
THEN HE WROTE IN BROAD TERMS,
WHAT HE SAW AT DISHARMONY OF
HUMAN NATURE.
THE WORD HARMONY WAS BETWEEN THE
SHORTEST OF LIFE AND THE
INFIRMITIES OF OLD AGE AND THE
STRONG WILL TO LIVE THAT PEOPLE
CONTINUED TO EXPERIENCE.
HE THOUGHT THIS WAS THE GREATEST
DISHARMONY OF ALL.
BUT NOTE THE SUBTITLE, STUDIES
OF OPTIMISTIC PHILOSOPHY.
AND WHEN METCHNIKOFF WAS AWARDED
THE NOBEL PRIZE, THE "NEW YORK
TIMES" RAN THE VERY LONG
INTERVIEW WITH HIM THAT ALSO WAS
SUBTITLED, THE APOSTLE OF
OPTIMISM, AND A BUNCH OF
INTELLECTUALS IN PARIS CREATED A
CLUB TO PROMOTE OPTIMISM, THEY
INVITED HIM.
HE BELIEVED HUMAN LIFE SHOULD
BE.
SHOULD BE MUCH LONGER, NORMAL
CYCLE OF LIFE SHOULD BE PERHAPS
SOMETHING LIKE 150 YEARS AND
BELIEVED THAT IF PEOPLE LIVED
THROUGH WHAT HE CALLED THE FULL
AND NORMAL CYCLE, THEY WILL LOSE
THE LIFE INSTINCT AND DEVELOP A
DEATH INSTINCT AND THEY WILL DIE
WILLINGLY.
HE WROTE ANOTHER PHILOSOPHICAL
BOOK, THE PROLONGATION OF LIFE,
OPTIMISTIC STUDIES, AND I WANTED
TO KNOW WHY DID OPTIMISM, THE
WORD ON THE -- THE WORD
OPTIMISM, THE CONCEPT CAME UP SO
MUCH.
AT THE TURN OF THE 20th
CENTURY PESSIMISM AND OPTIMISM
WERE MORE VIEWED AS
PHILOSOPHICAL OUTLOOKS RATHER
THAN STATES OF MIND, THE WAY WE
VIEW THEM TODAY.
AND IN FACT, THE DICHOTOMY
BETWEEN PESSIMISM AND OPTIMISM
WAS KIND OF CENTRAL TO
INTELLECTUAL LIFE IN EUROPE.
SO IT WAS ONLY NATURAL FOR
METCHNIKOFF TO DEFINE WHERE HE
STOOD ON THIS ISSUE.
BUT HE WASN'T AN EXTREME
OPTIMIST.
PEOPLE WERE AGAIN ASKING THE
SAME WAY AS WE DO NOW, IS THE
WORLD GETTING BETTER?
AND EXTREME OPTIMIST WOULD SAY
SURELY IT IS BUT METCHNIKOFF
DIDN'T THINK THE WORLD WAS
GETTING BETTER ON ITS OWN.
BUT HE DID THINK THAT IT COULD
BE IMPROVED WITH THE HELP OF
SCIENCE.
HUMAN CONSTITUTION IS NOTABLE
AND CAN BE ALTERED TO BENEFIT
HUMANITY, THAT'S WHY HE DEFINED
HIMSELF AS AN OPTIMIST.
AT THE TIME PESSIMISM WAS A MUCH
MORE POPULAR PHILOSOPHY.
SO HERE AGAIN HE WAS GOING
AGAINST THE GENERAL TYPE.
HE WAS AT THE SAME TIME AS BEING
A VISIONARY WAS A VERY PRACTICAL
MAN.
SO, HE CAME UP WITH A SOLUTION
TO AGING, AT LEAST A WAY TO
DELAY IT, AS HE HOPED.
BELIEVE IT OR NOT THIS IS
PROBIOTIC YOGURT, WHAT YOU BUY
TODAY IN THE SUPERMARKET.
THESE ARE PILLS OF LACTIC ACID
BACTERIA, METCHNIKOFF CAME UP
WITH THIS IDEA THAT YOGURT COULD
DELAY AGING BECAUSE IT CONTAINS
THE BACTERIA THAT TURN MILK
SUGARS INTO ACID AND THIS ACID
IN THE TEST TUBE KILLED OTHER
BACTERIA.
SO HE THOUGHT THAT IF THE SAME
THING HAPPENS IN INTESTINES, IF
BACTERIA KILL THE HARMFUL ONES
PERHAPS AGING COULD BE DELAYED.
THIS STARTED YOGURT CRAZE ALL
OVER THE WORLD, AND METCHNIKOFF
HIMSELF WAS EATING YOGURT THREE
TIMES A DAY.
AND HE ALSO TRIED TO PREVENT
GERMS FROM GETTING INTO THE
BODY.
HE ATE EVERYTHING BOILED AND HE
STERILIZED UTENSILS IN
RESTAURANTS BEFORE EATING, AND
FOR HIS GUESTS, AND PEOPLE WERE
ALL OVER THE WORLD BUYING YOGURT
AND THESE PILLS.
THESE PILLS HAVE HIS NAME ON
THEM, HE ALLOWED ONE COMPANY TO
USE THE -- TO PROMOTE HIM USING
HIS NAME AND HE BECAME WHAT
TODAY WE WOULD CALL A MEDIA
PERSONALITY, ALREADY FAMOUS BY
THEN BUT YOGURT REALLY MADE HIM,
YOU KNOW, SORT OF A HOUSEHOLD
NAME.
AND THIS STARTED THE MODERN
YOGURT INDUSTRY.
UNTIL THEN YOGURT WAS THIS
OBSCURE ETHNIC FOOD.
THIS IS A CARTOON OF METCHNIKOFF
SHOWING HIM TURNING OUT
CENTENARIANS.
AND THEN IN THE MIDDLE OF ALL
THIS OPTIMISM AND HOPE FOR LONG
LIFE, ALL THESE STUDIES, WORLD
WAR I BROKE OUT.
AND IN THE WAY, IT KILLED
METCHNIKOFF BECAUSE HE SO
BELIEVED IN RATIONAL THINKING
AND PROGRESS, AND SCIENCE, AND
SO THE SENSELESS KILLING,
MASSIVE KILLING JUST DEVASTATED
HIM.
AND HE DEVELOPED SEVERE HEART
TROUBLE, HEART FAILURE.
HE DIED AT THE AGE OF 71.
AND SO HIS THEORIES OF AGING
WERE NOT ACCEPTED ANYWAY IN THE
SCIENTIFIC COMMUNITY AND WHEN HE
HIMSELF DIED NOT EVEN HALFWAY TO
HIS GOAL OF 150, SO THAT WAS
PRETTY MUCH IT FOR THOSE IDEAS.
AND NO ONE WAS WORKING ON THE
PHAGOCYTE THEORY BY THEN.
SO IT REALLY SEEMED HE LOST ON
BOTH FRONTS.
BUT TODAY IN RETROSPECT, WE --
HE'S CONSIDERED THE FOUNDING
FATHER OF INNATE IMMUNITY
RESEARCH, AND EARLY FOUNDER OF
ADAPTIVE IMMUNITY RESEARCH.
AND I'M SURE MANY OF OF YOU KNOW
ABOUT FRIENDLY COLLABORATIONS
BETWEEN SCIENTISTS WHO WORK ON
THESE TWO ARMS OF THE IMMUNE
SYSTEM, BUT PERHAPS IF YOU --
WHEN YOU THINK BACK, YOU KNOW,
IT WASN'T ALWAYS AS FRIENDLY AT
ALL.
SO MAYBE WE CAN APPRECIATE MORE
THE COLLABORATIONS THAT EXIST
TODAY.
AND WHAT HAPPENED IN THE PAST
FEW YEARS ALSO THAT MICROBIOME
BECAME TOTALLY LEGITIMATE TOPIC
IN AGING RESEARCH, AND PROBABLY
PLAYS A ROLE IN THE AGING
PROCESS.
SO, ABOUT A CENTURY AFTER
METCHNIKOFF DIED, I CONDUCTED A
SEARCH IN PubMed TO SEE WHAT
HAPPENED WITH PHAGOCYTE
RESEARCH.
A NUMBER OF STUDIES PER YEAR.
LIKE DR. ARIS, IT WAS FORGOTTEN,
AND THIS SURGE OF STUDIES.
THE SAME THING YOU SEE, SAME
GRAPH YOU SEE WHEN YOU DO A
SEARCH FOR MACROPHAGE, AND I'M
SURE THIS WOULD HAVE BEEN A
GREAT SOURCE OF OPTIMISM FOR
METCHNIKOFF AND IN FACT IT PUTS
HIS OPTIMISTIC PHILOSOPHY IN A
NEW LIGHT IN THE SENSE THAT, YOU
KNOW, THE OPTIMISM THAT CAN COME
FROM -- FOR ADVANCES IN SCIENCE
AND MEDICINE THAT CAN COME FROM
THIS SURGE OF STUDIES IN INNATE
IMMUNITY.
AND THESE ARE SOME OF THE RECENT
COVERS OF JOURNALS WITH
METCHNIKOFF'S PICTURES ON THE
COVER.
SO, I WOULD LIKE TO END WITH A
QUOTE THAT I USE IN MY BOOK,
FROM LOUIS PASTEUR, THE
SCIENTIST MUST CONCERN HIMSELF
WITH WHAT ONE WILL SAY ABOUT HIM
IN A CENTURY RATHER THAN WITH
CURRENT INSULTS OR COMPLIMENTS.
THANK YOU VERY MUCH.
>> THANK YOU VERY MUCH, LUBA,
FOR A WONDERFUL PRESENTATION.
AND OF THE GREAT DEBT THAT WE
HAVE TO A SCIENTIST WHO CAN BE
MORE CONCERNED ABOUT THE FUTURE
THAN ABOUT THE CURRENT STATE OF
TURMOIL.
SO NOW WE'LL PROCEED TO BOB
GALLO, WHO IS GOING TO TALK MORE
ABOUT INNATE IMMUNITY NOW.
>>THANK YOU FOR
INVITING ME AND I THANK THE
PEOPLE ATTENDING.
IN CONTRAST TO LUBA'S TALK, SHE
MENTIONED THE BEGINNING OF
INNATE IMMUNITY, THE FOCUS ON
MACROPHAGE AND SOMETIMES
GRANULOCYTES.
BUT THE INNATE IMMUNITY I'M
TALKING ABOUT IS NOT GUARDING
AGAINST LARGER ORGANISMS BUT
RATHER AGAINST VIRUSES SO I
WON'T TALK ABOUT THOSE CELLS
GENERALLY AS FAR AS WE KNOW NOT
SO IMPORTANT FOR VIRUSES.
BUT THINGS LIKE WHAT WE CALL
TODAY IN THE IMMUNE SYSTEM
NATURAL KILLER CELLS, NK CELLS,
THINGS LIKE MOLECULES, INSTEAD
OF THE ANTIBODIES, WE'LL BE
TALKING ABOUT INNATE IMMUNE
MOLECULE.
INTERFERON.
THE VARIOUS INTERFERENCE.
BUT BEFORE I GET TO THAT, I WANT
TO LOOK AT THE FIRST PART OF MY
TALK IS ON SUMMARY FLEXION --
SOME REFLECTIONS ABOUT THE
PANDEMIC.
THE OUTLINE IS HERE.
A
A FEW LESSONS FROM HIV AND AIDS,
THE LAST PANDEMIC UNTIL THIS
ONE.
NO WAY TO PREPARE FOR HIV/AIDS,
WE CAN PREPARE FOR PANDEMICS,
CERTAINLY NO WAY TO PREPARE FOR
HIV AND AIDS.
ALTHOUGH PUBLIC HEALTH THINGS
ARE IN COMMON, YOU CAN DO
CERTAIN PUBLIC HEALTH THEMES ONE
PANDEMIC TO ANOTHER OR EPIDEMIC
TO ANOTHER, MICROBES CAN DIFFER.
VIRUSES CAN DIFFER SO MUCH.
IT'S HARD TO DRAW LESSONS ALL
THE TIME, ONE FROM ANOTHER.
THEN I WOULD LIKE TO MORE INTO
SARS-COV-2 COMPLETELY AND POINT
OUT SOME ASPECTS THAT I BELIEVE
STRONGLY, PAN MEANS ALL, THIS
MUST INVOLVE THE WHOLE WORLD.
BOTH IN TAKING CARE OF THE WHOLE
WORLD, NOT JUST OURSELVES, IT
WILL BE IN OUR INTEREST NOT JUST
DOING THE RIGHT THING, BUT ALSO
WE NEED THE COOPERATION OF
MEDICAL SCIENCE DOCTORS
EVERYWHERE.
THE COMPLEXITIES OF THERAPY I
DON'T THINK I'LL HAVE TIME TO
GET TO AND SHOULD WE BE SO
WORRIED ABOUT WHETHER THIS THING
ORIGINATED AND HOW, I THINK NOT,
BUT THAT'S MY OPINION.
THE VACCINES ARE TERRIFIC BUT
NOT LONG LASTING AND THAT WAS
PREDICTABLE.
THEY ARE STILL UNAVAILABLE FOR
MANY PEOPLE.
THE MECHANISMS, WELL, THEY ARE
NOT REALLY CERTAIN.
WE BELIEVE IT'S NEUTRALIZING
ANTIBODIES ATTACKING THE SPIKE
BUT THERE'S LITTLE PROOF.
THERE'S SOME SUGGESTION OF OTHER
THINGS GOING ON.
IT'S LIKELY THAT IT PLAYS A
SUBSTANTIAL ROLE BUT MAYBE NOT
THE ONLY ROLE.
AND THEN FINALLY BUT TAKING UP
AT LEAST A THIRD OF THE TALK
I'LL FOCUS ON INNATE IMMUNE
STIMULATION.
I HAVE TO TALK ABOUT INNATE
IMMUNITY AND SHOULD WE STIMULATE
DELIBERATELY BY REPURPOSING SOME
OLD VACCINES THAT CAN BE BROADLY
ACTIVE, THAT EVEN THOUGH THEY
ARE MADE AGAINST SOME OTHER
MICROBE, SOME OTHER VIRUS, COULD
WORK AGAINST SARS TOO, AGAINST
RESPIRATORY VIRUSES IN GENERAL.
AND THERE'S A LOT OF EVIDENCE
FOR THIS.
I WANT TO MAKE A STATEMENT FROM
THE START.
I CONTRIBUTED NOTHING TO INNATE
IMMUNITY ADVANCES.
I WORKED A LITTLE BIT ON
INTERFERON'S BASIC MECHANISMS OF
HOW THEY BLOCKED RETROVIRUSES
BUT THAT WAS IN THE '70s AND I
DIDN'T PROBABLY EVEN RECOGNIZE I
WAS WORKING ON INNATE IMMUNITY
REALLY.
WHAT I HAVE BEEN IS IMPACTED BY
IT THINKING HOW WE COULD HAVE
TAKEN ADVANTAGE OF IT AND SHOULD
HAVE, AND SHOULD FOR THE FUTURE,
IN THIS REGARD FROM NEW
EPIDEMICS OR PANDEMICS.
HAVE THERE HAVE BEEN SIX IN THE
PAST HUNDRED YEARS, THESE ARE
WIDELY APART EXCEPT FOR NUNS,
THAT RECURS, IF YOU GET THE
WRONG FLU VIRUS WELL ANOTHER
EPI, SOMETIMES REAL PANDEMIC.
WE DO HAVE THE FLU OF 1918, THE
GREAT KILLER, SPANISH FLU, THE
RUSSIAN FLU OF 1977, SWINE FLU
OF 2008, WHICH IS ALMOST THE
PANDEMIC.
SO FLU IS THE BIG PROBLEM.
OF THE GREAT PANDEMICS, FOUR --
RATHER, YEAH, FOUR, ARE
RESPIRATORY, UNDERLYING, THE
THREE FLUS, AND CURRENT SARS.
THERE ARE DIFFERENT KINDS OF
VIRUSES, FOUR, 30 YEARS APART.
IF WE SAY FLU, USE THE GREAT
FLU, THE REAL BIG PANDEMIC, WE
JUMP TO POLIO, HIV, LATE 70s
30 YEARS LATER AND THEN SARS, 30
YEARS LATER.
HIV AND SARS STILL CONTINUE.
IN MY MIND LESSONS OF EACH ARE
FORGOTTEN BY THE NEXT, IF YOU
READ ABOUT POLIO, LESSONS THE
GREAT FLU ARE FORGOTTEN.
WE FORGOT THE LESSONS AND
LESSONS OF HIV WERE FORGOTTEN AS
WELL.
SO, I'LL COME BACK TO THAT POINT
ABOUT HOW WE REMEMBER OR DON'T
REMEMBER.
SO AS I ALREADY SAID, THE
PANDEMICS, EXCEPTING FLU, HAVE
BEEN A GENERATION APART, 25 TO
30 YEARS, MANY EPIDEMICS IN
BETWEEN, CONCURRENTLY LIKE
DENGUE, FIRST SARS, MERS, OTHER
INFLUENZA STRAINS, CHIKUNGUNYA,
WEST NILE, EBOLA, ZIKA AND
OTHERS, RNA VIRUSES, MOST
RESPIRATORY.
THEY ALL REPRODUCE AT HIGH
RATES, I DON'T CONSIDER FINDING
A RESPIRATORY VIRUS AS REALLY A
DISCOVERY BECAUSE THEY ARE
USUALLY DRIPPING OFF THE TONGUE
OR THE MOUTH.
IT'S OBVIOUS THAT THEY ARE THE
CAUSE OF THE DISEASE AND OBVIOUS
YOU CAN ISOLATE THEM EASILY.
RNA VIRUSES ALL HAVE HIGH
MUTATION RATES, WE DON'T HAVE
TIME TO GET INTO WHY THIS IS
TRUE BUT THEY MUTATE.
THIS IS NOTHING NEW WITH
SARS-COV-2.
CURRENT PANDEMIC PEOPLE THINK
THIS IS UNIQUE SOMETIMES AND OF
COURSE ALL RNA VIRUSES HAVE THIS
KIND OF MUTABILITY.
EXCEPT FOR HIV, EXCEPT FOR HIV,
THEY ARE EASILY TRANSMISSIBLE
AND EASY TO FIND.
THIS IS MY VIEWPOINT, IT'S AN
OPINION, ANY PANDEMIC CAN BE
DESCRIBED IN ONE WORD.
CHANGE, THE WORD IS CHANGE.
THAT CAN BE CHANGE IN A VIRUS OR
CHANGE IN SOCIETY OR BOTH.
FOR SARS-COV-2, WE DO NOT KNOW
THE IDENTITY OF THE CHANGE BUT
LIKELY INVOLVED GENETIC CHANGES
IN PREVIOUSLY EXISTING
CORONAVIRUS, IN THE SPIKED
REGION IN PARTICULAR, BUT WAS
THERE A SOCIAL CHANGE?
IF SO, WE HAVEN'T IDENTIFIED IT.
WAS THERE A SOCIAL CHANGE IN THE
WUHAN REGION?
LET'S CONSIDER SOME PAST
PANDEMICS AND EPIDEMICS.
POLIO, WHAT WAS THE CHANGE?
IT APPEARS POLIO VIRUS WAS A
CHANGE NOT BY SOCIETY AS MUCH BY
THE VIRUS, GENETIC CHANGE, IT
WAS AND IS AN ENTEROVIRUS,
GASTROINTESTINAL TRACT, WE WON'T
GO INTO CLASSIFICATION, AN RNA
VIRUS, WE JUST DISCUSSED THAT.
FROM A RELATIVELY HARMLESS VIRUS
OF THE GASTROINTESTINAL TRACT
MUTATED TO CHANGE ITS TROPISM,
THAT IS, WHAT IT TARGETS, WHAT
ITS RECEPTOR IS AND BECAME
NEUROTROPIC, TARGETING THE CELLS
OF THE CENTRAL NERVOUS SYSTEM
CAUSING THE DISEASE WE CALL
POLIO MYELITIS.
WHAT ABOUT CHANGES IN ANCIENT
TIME?
WE HAVE CHANGES IN SOCIETY WHEN
ROMANS WENT TO THE EASTERN
MEDITERRANEAN, NEW EPIDEMICS AND
PANDEMIC FOLLOWED.
CHANGES WHEN THE NEW WORLD WAS
DISCOVERED, EUROPEANS CAME HERE,
ON BOTH SIDES OF THE SEA.
WE HAVE A MINOR SCALE NON-VIRAL
DISEASE LIKE LET'S SAY LYME
DISEASE, IN OUR AREA WE HAVE
DEER IN OUR BACK YARD, DEERS
HAVE DEAR TICKS THAT CARRY THE
LYME AGENT, AND WE GET PANDEMICS
BUT LOCAL EPIDEMICS,
LEGIONNAIRES DISEASE WITH
REFRIGERATION AND AIR
CONDITIONING, THAT'S A CHANGE.
WHAT HAPPENED WITH HIV?
WITH HIV, WE HAVE VIRUS RESPECT
IN THE RAINFOREST GOING FROM ONE
PRIMATE TO MAN PERIODICALLY, WHY
DID THIS BECOME EPIDEMIC AND
THEN PANDEMIC?
WE ASSUMED THERE WAS A GENETIC
CHANGE IN ONE OF THE MONKEY
VIRUSES KNOWN AS SIMIAN
IMMUNODEFICIENCY VIRUS, SIV, BUT
COLONIAL POWERS LEFT AFRICA AND
PEOPLE MOVED FROM RAIN FORESTS
IT TOWNS, THIS IS NOT SCIENCE
NOW BUT SOCIAL HISTORY, THERE
WAS INCREASE IN PROSTITUTION,
VIRUS CONCENTRATED, AND THEN
WHAT WAS LOCAL BECAME GLOBAL BY
POST WORLD WAR CHANGES WE CAN
DESCRIBE AS THE AIRPLANE,
TOURISM, INCREASED SEXUAL
PROMISCUITY, BLOOD GOING FROM
ONE NATION TO ANOTHER, FOR
EXAMPLE, JAPAN DOESN'T USE ITS
OWN BLOOD, USES BLOOD FROM
AMERICA AND EUROPE.
AND THE INSANE INTRAVENOUS DRUG
ABUSE BECOMING ALMOST GLOBAL,
COULD LEAD TO A FLUID BORNE
INFECTION RATHER HARD TO
TRANSMIT, BECOMING COMMONPLACE.
THAT'S IN ANY CASE HOW I WOULD
VIEW IT.
DOES THE ORIGIN MATTER THAT
MUCH?
NORMALLY WE'RE CURIOUS, WE WANT
TO KNOW.
I'M ALL FOR IT.
BUT I THINK WE'VE GONE A LITTLE
FAR WITH THIS AND WE'VE PUSHED A
BIT.
I DON'T THINK IT MATTERS THAT
MUCH.
IT MATTERS A BIT BUT NOT MUCH.
LET'S TAKE SARS-COV-2.
WHAT IF IT WAS BORN IN THE
MARKET?
WE PROVED THAT.
IT INVOLVED MAMMALIAN
INTERMEDIATE, WE PROVED THAT.
LET'S SAY IT WASN'T THE MARKET
BUT DIRECTLY CAME FROM BAT TO
MAN, OR BAT TO ANOTHER MAMMAL TO
MAN.
WELL, THAT WOULD BE USEFUL TO
KNOWING WHAT MAMMAL BUT WE WOULD
ALREADY KNOW WHAT TO DO ABOUT
THE MARKETS, WE COULD ACT ON
THAT NOW.
AND WHAT IF IT'S A LAB LEAK?
WE HAVE GOOD EVIDENCE, I WOULD
SAY NOW, MOST SCIENTIFIC
COMMUNITY WOULD AGREE, THIS IS
NOT A LABORATORY-CREATED VIRUS.
COULD IT BE A LAB LEAK?
WE CAN ALMOST NEVER RULE THAT
OUT FROM ANY VIROLOGY LAB WITH
ANY VIRUS.
DO WE KNOW WHAT TO DO WITHOUT
PROVING IT?
WE DO.
WE COULD, FOR EXAMPLE, HAVE
GREATER PRECAUTION ON WHO WORKS
ON THESE THINGS, REQUIRE SPECIAL
TRAINING.
FOR EXAMPLE, GAIN OF FUNCTION
RESEARCH IN WHICH YOU
DELIBERATELY MANIPULATE VIRAL
GENES SO THEY INFECT HUMAN CELLS
BETTER SO THAT WE CAN BE BETTER
PREPARED FOR EPIDEMIC OR
PANDEMIC BY SUCH A VIRUS IF IT
MUTATES IN THAT DIRECTION WE
COULD HAVE GREATER REVIEWS.
RYE
VIROLOGISTS ARE PRONE TO WANT TO
GET FUNDED, YOU WANT ANSWERS,
YOU WANT SCIENCE TO GO FORWARD.
WE STILL DO.
BUT WE MIGHT TAKE A LESSON FROM
THE PAGES OF MOLECULAR BIOLOGY
WHERE WHEN GENE CLONING CAME TO
THE FOREFRONT THEY HAD MEETINGS
IN CALIFORNIA CALLED ASILOMAR
CONFERENCES WHICH LED TO HAVING
REVIEWS FOR GENE CLONING OF WHAT
WAS ETHICALLY ADVISABLE, WHAT
WAS THE RISK/BENEFIT VALUE HERE,
OR RATIO.
AND THEY USED INTELLIGENT
LAYPEOPLE TO BE ON SOME OF THE
REVIEW BODIES.
WE COULD DO THAT NOW IN VIROLOGY
SO YOU DON'T JUST HAVE
VIROLOGISTS' OPINION.
MY VIEW IN THE END IS IT IS
REALLY NOT WORTH PUSHING CHINA
IN THIS, IN THE END WE'LL ONLY
SUCCEED IN PUSHING THEM FROM
AWAY FROM COLLABORATION.
I DON'T SEE WHAT THERE IS THEY
ARE REALLY GETTING.
THIS IS ANOTHER GENERAL COMMENT
THAT I'D LIKE TO MAKE.
I WANT TO PICK UP WHAT ARE
CONTROVERSIAL THINGS IN MY MIND
IN A I DON'T AGREE WITH.
I FREQUENTLY HEAR COMMENTATORS
SAY WE'LL NEVER FORGET.
WE WILL FORGET.
THE LESSONS OF PRIOR VIRUS
PANDEMICS SHOWED TO ME THAT
ROUGHLY AFTER A GENERATION OR SO
FROM THE TIME OF THE END OF THE
PANDEMIC, END OF A PROBLEM, WE
FORGET IN EVERY SINGLE CASE.
I DON'T THINK THIS WILL BE ANY
DIFFERENT.
IN THIS STORY OF HIV, IT'S
PARTICULARLY RELEVANT.
ACTUALLY IT'S NOT EVEN NOW OFTEN
CURRENTLY LISTED AS ONE OF THE
RECENT PANDEMICS BELIEVE IT OR
NOT.
IT'S STILL ONGOING.
BUT IT'S SOMETIMES FORGOTTEN, TO
BE LISTED AS ONE OF THE PREVIOUS
PANDEMICS.
I'M GOING TO SHOW A COUPLE
SLIDES ON HIV.
LESSONS FROM HIV ARE -- IT'S A
VERY DIFFERENT KIND OF VIRUS,
BUT LET ME SAY THAT THE SLIDE
BEGINS BY SAYING REMARKABLY BIAS
OF RECENT PAST IN THE '70s, I
CAME TO THE NATIONAL INSTITUTES
OF HEALTH IN THE '60s, IN MY
MIND FROM WHERE I SAT THERE WAS
A STRONG RESPECT FOR VIROLOGY,
VIRUSES CAUSING SERIOUS DISEASE,
FOR THE POSSIBILITY OF EPI AND
PANDEMICS BUT BY 1970s, VERY
DIFFERENT.
I HEARD STATEMENTS LIKE LISTED
ON THE TOP HERE, SERIOUS
EPIDEMIC INFECTIOUS DISEASES ARE
OVER IN THE INDUSTRIALIZED
WORLD.
THEREFORE WE CAN FORGET ABOUT
IT.
IT WAS SOMETHING YOU WOULDN'T
SAY TODAY BECAUSE INDEED WE AT
LEAST ARE SUPPOSED TO CARE ABOUT
OTHER NATIONS AND OTHER PARTS OF
THE WORLD.
BUT ALSO IT'S IN OUR INTEREST TO
CARE, ISN'T IT?
SO IT WAS SAID, OH, THOSE ARE
PROBLEMS FOR THE TROPICAL
DISEASE INSTITUTES ONLY AND
FUNDING SHOULD GO TO
DEGENERATIVE DISEASES.
HAVING NOT THE WISDOM TO THINK
IT THROUGH SOMETIMES THE
DEGENERATIVE DISEASES ARE CAUSED
BY A MORE LET'S CALL THEM SLOW
VIRUS, DIFFICULT TO FIND,
DIFFICULT TO PROVE, LIKE THE
RECENT EVIDENCE THAT A COMMON
INFECTION OF HUMANKIND
EPSTEIN-BARR OR HERPES VIRUS
ABOUT 95% OF US HAVE MAY IN SOME
PEOPLE BE THE CAUSE OF MULTIPLE
SCLEROSIS.
WE NEED TO UNDERSTAND WHY IT'S
SO LIMITED IN ITS HIT TO CAUSE
THE DISEASE.
THAT'S WHERE WE ARE.
THE SECOND WAS THAT A CERTAIN
CATEGORY OF VIRUSES LIKE WHAT IS
THE AIDS VIRUS, RETROVIRUS,
DON'T INFECT HUMANS.
THERE WERE MANY REASONS.
THIS WAS THE '70s, NOT A GOOD
TIME FOR SOME OF US TO BE
WORKING AND LOOKING FOR HUMAN
RETROVIRUSES, AND THERE'S
STRONG -- WELL, PROOF, NOT
STRONG EVIDENCE, PROOF FOR THE
STATEMENT THAT IT WAS FELT THAT
NO VIRUSES CAUSED CANCER, NO
INFECTION CAUSES CANCER, OR
PLAYS A ROLE IN CANCER IN MAN.
IT WAS A RATHER FORMAL
CONCLUSION IN A 1974 MEETING ON
THE ORIGINS OF HUMAN CANCER AT
COLD SPRING HARBOR LABORATORIES.
BY THE EARLY '80s, THESE
PREJUDICES WERE OVERCOME.
VIRUSES ARE NOW KNOWN TO BE
INVOLVED IN THE CAUSE OR AT
LEAST STAGE OF THE ORIGIN OF A
BIT OVER 20% OF HUMAN CANCERS.
RETROVIRUSES WERE INDEED
DISCOVERED IN MAN AND SHOWN TO
CAUSE SERIOUS DISEASE, LOOK AT
BULLET 3, AIDS APPEARED CAUSED
BY ANOTHER RETROVIRUS, NOW
ORIGINALLY I WAS THINKING OF
TALKING ABOUT HOW THESE ADVANCES
OCCURRED.
BUT THERE IS NOT TIME FOR THAT.
SO I'M GOING TO GO JUST USE THIS
AS WHAT'S CALLED SEDGEWAY.
THE BLOOD TEST WAS A KEY ADVANCE
PREVENTING BLOOD TRANSFUSION
INFECTION AND CONSEQUENT
INFECTIONS, ALLOWED EPIDEMIC TO
BE FOLLOWED BECAUSE WE HAD A
TEST, YOU DIDN'T HAVE TO WAIT
FOR TEN YEARS OR FIVE YEARS OR
EIGHT YEARS FOR THE PERSON TO
DEVELOP AIDS, TO KNOW HOW THIS
THING WAS SPREADING.
WE COULD TELL WITHIN TWO WEEKS
WHEN ANTIBODIES WOULD APPEAR.
CELL CULTURE SYSTEM ALLOWED
SCREENING, WHEN THERAPY BECAME
AVAILABLE BY THE BLOOD TEST WE
COULD DETERMINE WHO TO TREATMENT
AS WELL AS BLOCK MOTHER-TO-CHILD
TRANSMISSION.
IT WAS ALSO CRITICAL FOR MY
COLLEAGUES AND MYSELF TO VERIFY
HIV IS THE CAUSE OF AIDS BECAUSE
VIRUS ISOLATION WAS VERY TRICKY,
VERY DIFFICULT, PATIENTS HAD
HAVE YOU OF FEW T CELLS FROM
WHICH THE VIRUS HAD TO BE
OBTAINED.
IT WAS A REAL KIND OF NIGHTMARE.
BLOOD TEST ALLOWED VERIFICATION,
PEOPLE COULD TEST ALL OVER THE
WORLD AND VERIFICATION CAME
RATHER EASILY.
SO WE SWITCHED BACK TO
SARS-COV-2, COVID, AROUND I
WOULD SAY WE'RE GOING TO AGAIN
IT MUST INVOLVE THE WORLD,
COMPLEXITIES OF THERAPY, BECAUSE
UNLIKE AIDS VIRUS ALSO STAY
AROUND GIVING YOU OPPORTUNITY TO
HAVE DRUG THERAPY THAT TARGETS
THE VIRUS.
QUICK IN THE EARLY PHASE WHEN
YOU NEED ANTI-VIRAL THERAPY.
YOU CAN DO IT RAPIDLY.
WE HAVE PRETTY SUBSTANTIAL MAJOR
VACCINES BUT THEY ARE NOT
AVAILABLE FOR EVERYBODY.
ALSO IT'S IMPORTANT TO EMPHASIZE
THAT THEY DON'T LAST LONG.
FIVE TO SIX MONTHS.
YOU HAVE TO REMEMBER THAT.
THAT'S KEY POINT.
THEY DON'T LAST LONG.
AND THAT WAS KINDLY PREDICTABLE
FROM THE GENOME PUBLISHED IN
2020, JANUARY 10, BY THE
CHINESE.
YOU COULD PREDICT THIS WOULD BE
THE CASE.
THAT'S A PROBLEM YOU GOT TO KEEP
BOOSTING.
IS THERE A ROLE FOR INNATE
IMMUNE STIMULATION?
BY REPURPOSING OLD VACCINES THAT
ARE BROADLY REACTIVE AND MIGHT
HELP?
IT'S TIME TO FOCUS IN THAT WAY
FOR A MINUTE BUT FIRST WHAT
HAPPENED TO DIAGNOSTICS?
ACCURATE AND SENSITIVE
DIAGNOSTICS ARE KEY TOO ANY
PANDEMIC OR EPIDEMIC, THE
REASONS ARE OBVIOUS, OFTEN
UNDERAPPRECIATED, AND WE DID
RATHER POORLY IN THE EARLY DAYS
OF THE CURRENT SARS CORONAVIRUS
PANDEMIC.
WHY?
WELL, NUMBER ONE, THERE WASN'T
ANY RESPONSIBLE GROUP OR GROUPS.
IT HAS BEEN SAID THIS WAS A
PROBLEM FOR CDC TO SOLVE.
BUT THAT'S REALLY NOT TRUE.
IT'S NOT IN CDC'S ORDERS TO GO
GET BLOOD TESTS OR PARTICULAR
TESTS THOUGH THEY ARE INTERESTED
EVERY TIME AND TRY.
THE HIV TEST WAS NOT DEVELOPED
AT CDC BUT IS DEVELOPED IN MY
LAB AT NIH.
SO NIH SOMETIMES CONTRIBUTES TO
TESTING.
I THINK WE JUST DIDN'T GET
INVOLVED BECAUSE PEOPLE THOUGHT
IT WAS EASY.
THERE'S A LOT OF VIRUS, IT'S
OBVIOUS.
YOU CAN MAKE DIAGNOSTIC TEST
PRETTY FAST.
SO I THINK IT WAS A FAILURE OF
ALL OF US THAT WE DIDN'T GET
INVOLVED.
MY INSTITUTE DIDN'T GET
INVOLVED.
THERE'S ALSO CROSS-REACTIONS
WITH RATHER HARMLESS SEASONAL
CORONAVIRUSES THAT MADE IT MORE
DIFFICULT AT THE BEGINNING.
THERE'S INSUFFICIENT GLOBAL
COOPERATION.
PERHAPS, PERHAPS, THERE WAS ALSO
SOME FEAR OF THIS VIRUS LEADING
PEOPLE, SCIENTISTS, MEDICAL
SCIENTISTS, MAYBE, AT THE
BEGINNING, TO STAY AWAY.
SO, HERE ARE SOME SPECIFICS, I
WANT TO BE SURE THAT I LEAVE YOU
WITH BEFORE WE GO FURTHER TO
INNATE IMMUNITY.
THIS IS A VIRUS AREAS TO FIND,
SELF-EVIDENT, NEEDS TO INVOLVE
THE WORLD.
IT'S ESSENTIAL IN MY MIND FOR
CHINA, U.S. AND EUROPE, I
INCLUDE RUSSIA, TO HAVE CLOSE
COLLABORATION.
KNOWING THE ORIGIN IS NOT
CRITICAL AND CAN BE HARMFUL TO
PUSH IT TOO FAR.
WE DISCUSSED DIAGNOSTICS
ALREADY, COMPLEXITY OF THERAPY,
THE VACCINES, VARIANTS.
THEY ARE LIKELY TO BE COVERED,
MOST VARIANTS ARE LIKELY TO BE
COVERED BY CURRENT VACCINE BUT
THE LIMITED AVAILABILITY EVEN
NOW FOR THE WORLD.
NOW WE COME TO IS THERE A ROLE
FOR STIMULATING INNATE IMMUNITY?
WHAT ARE ITS BENEFITS?
WHAT ARE ITS LIMITS?
HOW CAN WE STIMULATE IT?
WE MIGHT FIND DRUGS TO DO IT,
THAT'S PROBABLY GOING TO BE MORE
ACCEPTABLE.
LET'S SAY THE U.S. ARMY TO HAVE
A PILL IN THE POCKET OF A
SOLDIER GOING TO A NEW AREA, WE
KNOW HOW TO DO IT NOW WITH OLD
VACCINES.
MEASLES, MUMPS, RUBELLA, ORAL
POLIO, NOT THE DEAD ONE OF SALK,
DOESN'T WORK WELL.
LIVE SHINGLES,IVE , INTRANASAL,
THEY WILL ALL WORK, NOT TO THE
EXTENT THE LIVES ONES DO.
YELLOW FEVER, ROTAVIRUSES, BCG,
WHICH IS FOR TUBERCULOSIS, BUT
REPURPOSED FOR NEW RESPIRATORY
EPIDEMIC, OR PANDEMIC.
WHAT'S THE IMPORTANCE OF INNATE
IMMUNITY IN CONTROLLING SARS
CORONAVIRUS 2?
IT'S IMPORTANT, PERIOD, AS
YOU'LL SEE IN A MOMENT FROM MY
SLIDE, 95% OF ALL -- WELL, ALL
CREATURES HAVE INNATE IMMUNITY,
AND 95% HAVE ONLY INNATE
IMMUNITY.
IT'S ONLY WE VERTEBRATES THAT
EVOLVE ADAPTIVE IMMUNE RESPONSE.
95% OF LIVING ORGANISMS HAVE
INNATE MECHANISMS AND GET
PROTECTED.
LET'S THINK HOW MANY, IF YOU'RE
OVER 20 OR 30 YEARS OLD, YOU
KNOW YOU'VE HAD INFECTIONS THAT
WENT NOWHERE.
ONE DAY YOU WOKE UP, WITH A
SMALL HEADACHE, MAYBE FATIGUE.
OR MAYBE JUST HAD A CHILL OR
TWO.
AND POSSIBLY A LOW GRADE FEVER,
USUALLY NOT.
NEXT DAY YOU WERE BETTER.
YOU WERE INFECTED BY A VIRUS.
HOW DID IT GET BETTER?
DID THE VIRUS RUN OUT OF CELLS
TO INFECT?
OF COURSE NOT.
THE VIRUS DECIDED TO GO AWAY?
OF COURSE NOT.
IT'S YOUR INNATE IMMUNE SYSTEM.
IT TOOK IT AWAY.
THAT HAS HAPPENED TO YOU OVER
AND OVER AND OVER AGAIN.
INNATE IMMUNITY DOESN'T PROTECT
AGAINST DISEASE SO MUCH, IT
PREVENTS COMPLETELY AGAINST
INFECTION.
I SAID I LIKE TO USE THE ANALOGY
OF THE END OF THE WESTERN ROMAN
EMPIRE.
IT WENT AROUND IN THE MID-400s
OR SO, ROMANS UNDER SIEGE, AT
THE GATE YOU HAD PREMIER
LEGIONNAIRES TO BLOCK ENTRY.
WHEN THEY BREAK THROUGH,
SECONDARY AUXILIARY AND OTHER
LEGIONNAIRES ARE GOING TO COME
INTO THE FRAY.
THAT'S THE ADAPTIVE IMMUNE
SYSTEM.
BUT AT THE BEGINNING IT'S ALL
THE INNATE IMMUNE SYSTEM THAT
BLOCKS INFECTION.
I WAS STRUCK BY SEVERAL THINGS
IN THE BEGINNING OF THE PANDEMIC
THAT SAID TO ME, IT'S EXTREMELY
IMPORTANT FOR THIS CORONAVIRUS.
FIRST OF ALL I BEGAN LEARNING
FROM MY COLLEAGUE AT THE FDA, A
RUSSIAN SCIENTIST, WHOSE PARENTS
WERE WELL KNOWN RUSSIAN
VIROLOGISTS, HIS NAME IS
CONSTANTINE SHUMIKO, HIS PARENTS
WORLD WITH ALBERT SABIN WITH THE
FIRST POLIO TRIALS OF THE LIVE
VACCINE IN RUSSIA.
THAT WAS THE '50s.
IN THE '70s, HIS MOTHER
OBSERVED IN ANALYZING DATA THAT
PARTICULAR YEAR THAT PEOPLE WHO
WERE JUST VACCINATED WITH THE
LIVE POLIO VIRUS WERE PROTECTED
AGAINST INFLUENZA AT LEAST
CORRELATING BETTER THAN WITH THE
FLU VACCINE.
SO THEY MADE NOTE AND THEY FOUND
OUT THERE'S INDEED A LITERATURE,
SCATTERED, NEVER ORGANIZED OR
FUNDED, UNDERSTUDIED, HEAVY IN
LITERATURE AND IT'S COME BACK
TODAY.
I WAS AWARE OF THAT.
I STARTED THINKING WITH THIS
PANDEMIC, BECAUSE I REALIZED AND
READ A BOOK ON THE IMMUNOLOGY.
BATS ARE HARBORING CORONAVIRUS,
THEY LIVE WITH IT, HOW DO THEY
HOLD IT IN CHECK?
NOT BY ANTIBODIES OR ADAPTIVE
IMMUNE SYSTEM.
THEY HAVE A CONSTANT WE CALL IT
CONSTITUATIVE LEVEL OF INNATE
IMMUNE RESPONSE.
BY HAVING THE NATURAL KILLER
CELLS ACTIVATED AT LOW LEVEL AND
PRESENT.
THIS IS PART OF THE INNATE
IMMUNE SYSTEM.
AS WELL AS MOLECULE INTERFERON,
PRESENT AT LOW LEVEL, TOO HIGH,
YOU'LL GET INFLAMMATION AND MANY
OTHER PROBLEMS.
IT'S A LOW LEVEL.
AND THAT LEADS THEM TO CONTROL.
THEN I NOTICED GENETIC
INFORMATION IN THE SARS
CORONAVIRUS IS OVERLY CHOCK FULL
OF GENETIC SEQUENCES THAT TARGET
SPECIFICALLY INNATE IMMUNITY.
WHAT WE CALL THE GENE
NON-STRUCTURAL PROTEIN 1,
NON-STRUCTURAL PROTEIN AND 14
HAVE THE CAPACITY OF INTERFERING
WITH INNATE IMMUNITY.
THAT SAID TO ME THIS VIRUS IS
VERY MUCH FRIGHTENED BY INNATE
IMMUNITY.
BUT IT'S GOT TO BE THERE IN
ADVANCE.
CLINICALLY, BEGINNING WITH THE
WORK AT STANFORD, THERE'S A
BETTER PROGNOSIS CORRELATES
MAINLY WITH INNATE IMMUNITY
PARAMETERS, THAT'S BEEN SEEN
OVER AND OVER.
NOW, DURABILITY IS SAID TO BE
THE MAIN ADVANTAGE OF THE
CONVENTIONAL ADAPTIVE IMMUNE
STIMULATING VACCINES, SPECIFIC
VACCINES LIKE MEASLES, POLIO,
CURRENT SARS-COV-2 MESSENGER RNA
VACCINES, ET CETERA.
CLASSICAL APPROACH WITH
SARS-COV-2 DOES NOT YIELD
ANTIBODIES THAT ARE DURABLE.
AND WHAT ABOUT THE DURABILITY OF
THE INNATE IMMUNE RESPONSE?
I HAVE TO TELL YOU I'LL COME
BACK IN THE NEXT SLIDE I THINK,
WE REALLY DON'T HAVE A LOT OF
DATA ON I AT LEAST A MONTH.
EVIDENCE FROM BCG FROM WORK OF A
ROMANIAN SCIENTISTS IN HOLLAND,
WITH BCG HE MEASURED IT LAST THE
SIX MONTHS.
YOU'LL NEVER GET LIFETIME LIKE
WITH POLIO OR SMALLPOX OR
MEASLES, ET CETERA.
BUT THERE ARE PLACES AND TIME AS
I'LL TRY TO ARGUE SOON.
THERE'S CLINICAL EVIDENCE HIGHER
LEVELS OF INTERFERON, IFN,
CORRELATE WITH BETTER PROGNOSIS.
NOW THERE ARE SEVERAL
CORRELATIVE POSITIVE CLINICAL
STUDIES, IN MAN, THAT ARE
SCATTERED HERE AND THERE,
RUSSIAN STUDY IN INDIA, IN
BRAZIL, MEXICO, ALSO ANIMAL
STUDIES, FOR EXAMPLE, AT NIH, BY
DR. SHEER AND COLLEAGUES WITH
VCG, A GROUP AT UCSF AND
STANFORD THAT PUBLISHED ON USING
ORAL POLIO VIRUS AGAIN, THIS
TIME A MUTATED FORM THAT THEY
GAVE A SPECIAL ABBREVIATION TO
SO IT ONLY INFECTS CELLS LIKE IN
THE GUT AND NOT ABLE TO INFECT
ANYMORE.
AND THEY SHOWED DRAMATIC
PROTECTION AGAINST SARS-COV-2,
AS WELL AS BEING ABLE TO USE IT
THERAPEUTICALLY.
SO, IF YOU USE IT EARLY ON.
SO, THESE STUDIES, TO ME, ARGUE
RATHER STRONGLY WE BETTER PAY
MORE ATTENTION TO INNATE
IMMUNITY.
LET'S LOOK AT SOME PROPERTIES OF
INNATE IMMUNITY CONTRASTED TO
THE ADAPTIVE IMMUNE SYSTEM.
I THINK IF YOU DROP DOWN TO THE
FIRST ONE IN RED, WHEN YOU
DEVELOP ANTIBODIES FOR THE FIRST
TIME WHEN YOU'RE EXPOSED TO A
NEW VACCINE, IT TAKES WEEKS TO
MAKE THE ANTIBODIES, TWO, THREE
WEEKS.
TO GET REAL IMMUNE RESPONSE,
IT'S WEEKS.
IT TAKES USUALLY MORE THAN THE
TWO YEARS IT TOOK THIS TIME TO
DEVELOP THE VACCINE.
IT AVERAGES MORE LIKE FOUR TO
FIVE YEARS.
AS YOU KNOW, IN SOME PARTS OF
THE WORLD WE STILL DON'T HAVE
IT.
SO, WHAT DO YOU DO?
INNATE IMMUNE VACCINES, INNATE
IMMUNE STIMULATION, OCCURS
WITHIN AN HOUR.
SO IF I GO TO MY DRUG STORE AND
GET MMR, MEASLES, MUMPS,
RUBELLA, ONE HOUR LATER I'LL
HAVE INNATE IMMUNE STIMULATION
LIKELY LASTING AT LEAST A MONTH.
AND IT WILL BE IN MY VIEW
EFFECTIVE.
THE ADAPTIVE IMMUNE SYSTEM COMES
FROM THE LYMPHOID SYSTEM.
IT INVOLVES CELLS WE CALL B
CELLS, B LYMPHOCYTES, T CELLS,
INCLUDES ANTIBODIES.
ANTIBODIES.
ALSO T CELLS THAT KILL
SPECIFICALLY.
SOMEBODY NEEDS TO TURN THEIR
MICROPHONE OFF BECAUSE YOU'RE
INTERFERING.
INNATE IMMUNITY IS COMING FROM
MYELOID CELLS, MYELOID CELLS
FROM THE BONE MARROW, AND LOCAL,
AND THEY LEAD TO MAINLY BUT NOT
SOLELY BY A LONG SHOT
INTERFERON, INTERFERONS, AND
NATURAL KILLER CELLS.
I'VE MENTIONED THAT THEY ARE
PRESENT IN THE ADAPTIVE IMMUNE
SYSTEM, IT'S ONLY IN
INVERTEBRATES 95% OF SPECIES
HAVE ONLY INNATE IMMUNITY.
AND WE TALKED ABOUT DURABILITY
ALREADY.
THE SAFETY OF A NEW VACCINE IS
USUALLY UNKNOWN AND VARIABLE, WE
ALREADY KNOW THE USE OF OLD
VACCINES, WE KNOW WHAT SAFETY
THEY HAVE.
COST, A NEW VACCINE IS
RELATIVELY COSTLY.
REPURPOSEING OLD VACCINES IS
VERY INEXPENSIVE.
ORAL POLIO 12 CENTS A PILL.
MIGHT NOT BE ABLE TO USE IT SO
IF YOU GO TO MMR PROBABLY A FEW
DOLLARS.
FUNDING FOR RESEARCH AND
DEVELOPMENT OF ADAPTIVE IS OF
IMMUNITY IS IN THE BILLIONS,
VERY POORLY STUDIED, THESE ARE
THE OPPORTUNITIES IN MY MIND FOR
USING BROAD STIMULATING INNATE
IMMUNE STIMULATING VACCINES.
AT THE BEGINNING OF ANY NEW
EPIDEMIC OR PANDEMIC, TO FILL IN
THE GAP OF TIME BETWEEN
APPEARANCE OF THE NEW EPIDEMIC
AND DEVELOPING DURABLE SPECIFIC
VACCINE.
FOR COUNTRIES THAT CANNOT GAIN
ACCESS FOR EVEN LONGER PERIODS
OF TIME, COSTS CAN BE LOW.
THIS IS SOMETHING TO THINK OF
NOW.
IF THERE'S A PROBLEM WITH
DURABILITY OF THE SPECIFIC
VACCINE, LIKE THIS ONE LASTS SIX
MONTHS, I WOULD SAY MAX, OR IF
THAT VACCINE IS UNABLE TO HANDLE
SOME VARIANTS THAT EMERGE, THINK
OF THIS APPROACH.
FINALLY, WHAT ABOUT PUTTING THEM
TOGETHER?
SOME PEOPLE THINK MAYBE THE
INNATE IMMUNE STIMULATION WOULD
INHIBIT DEVELOPMENT OF THE
SPECIFIC VACCINES WORKING AS
WELL.
THE OPPOSITE IS LIKELY TRUE,
NOTHING TO SUGGEST THE OPPOSITE.
YOU LIKELY MAKE THE CURRENT
VACCINES WORK EVEN BETTER.
THE PROBLEMS GOING FORWARD WITH
INNATE STIMULATING OLD VACCINES
I THINK MOST IMPORTANT IS THE
LACK OF UNDERSTANDING AMONG
POPULATION, EVEN SCIENTISTS.
INCLUDING UNTIL THIS EPIDEMIC
MYSELF.
VERY LITTLE RESEARCH SUPPORT.
TOO IS FEAR, THIS MAY CAUSE
CONFUSION IN THE PUBLIC, AND
THAT I UNDERSTAND.
AND LEAVE TO GREATER VACCINATION
RESISTANCE, LOOK WHAT'S GOING ON
NOW.
DURABILITY.
LIKELY A FEW MONTHS.
MAYBE BETTER THAN WE BELIEVE.
UNJUSTIFIED FEAR OF SIDE
EFFECTS, FIFTH IS CONCERNS THEY
MAY INTERFERE WITH SPECIFIC
VACCINES, AS I MENTIONED.
BUT THAT I THINK IS THE OPPOSITE
WOULD BE TRUE.
LAST, NO MARKET VALUE.
VERY INEXPENSIVE, YOU CAN'T
PATENT IT.
THAT'S ALL I WANTED TO SAY.
I THINK I -- I KNOW I FINISHED
IN TIME.
MAYBE TOO EARLY.
I DON'T KNOW IF YOU DIDN'T GET
YOUR MONEY'S WORTH, I BLAME MY
FRIEND WIN BECAUSE HE MADE ME
TAKE OUT A LOT OF SLIDES.
[LAUGHTER]
NO, I THINK IT WAS BETTER THIS
WAY, MORE TIME FOR DISCUSSION.
I WAS HAPPY TO FOLLOW LUBA.
I DIDN'T KNOW ALL THOSE DETAILS.
>> THERE WAS A QUESTION ABOUT
AUTOIMMUNITY.
QUESTION NUMBER ONE, DID
METCHNIKOFF HAVE IDEA OF IMMUNE
SYSTEM TURNING ON ITS HOST, I
HAVEN'T SEEN ANY MENTION IN HIS
WORK ABOUT AUTOIMMUNITY.
HE DID TALK ABOUT INAPPROPRIATE
ROLE OF PHAGOCYTES IN AGING BUT
THIS WAS -- YOU KNOW, HE
BELIEVED THEY CAUSED ATROPHY BUT
NOT AUTOIMMUNITY.
>> LUBA, THERE A QUESTION ASKED,
FROM THE MANY DISCOVERIES MADE
BY METCHNIKOFF, WHAT DO YOU
THINK WAS THE MOST EXCITING AND
IMPORTANT TO HIM?
>> OH, WELL, I THINK
PHAGOCYTOSIS WAS HIS BABY, FOR
SURE.
YOU KNOW, I THINK THE VERY FIRST
DISCOVERY, THE FACT THAT HE WON
THE NOBEL NOBEL PRIZE WROTE
ABOUT THE EXPECT WITH THE
STARFISH LARVA, MY GUESS IS THIS
WAS HIS FAVORITE.
>> IT WAS ASKED WHETHER -- I
GUESS YOU ANSWERED THIS PARTLY
BUT THE QUESTION WAS IS THE FACT
THAT METCHNIKOFF WAS A BIOLOGIST
AND DEALING WITH ORGANISMS
NON-VERTEBRATES IN WHICH THE
INNATE SYSTEM IS THE ONLY SYSTEM
THAT'S PRESENT, DID THAT PLAY A
PART IN HIS ATTITUDES TOWARD THE
SUGGESTION THAT THE ADAPTIVE
SYSTEM WASN'T RELEVANT OR WASN'T
IMPORTANT?
>> I THINK -- LOOK, I CAN ONLY
SAY WHAT I THINK.
I DON'T KNOW WHAT -- YOU KNOW,
HOW IT REALLY WAS BUT I THINK
THERE WAS A BIAS THERE,
ABSOLUTELY.
HE DID WORK WITH VERTEBRATES.
HE WORKED WITH RABBITS AND WITH
RATS AND BUT, FOR EXAMPLE, HE
WAS NEVER INTERESTED IN
LYMPHOCYTES, AND MAYBE THAT'S
BECAUSE, YOU KNOW, THE
VERTEBRATES, THE ORIGINAL
SPECIES HE WORKED WITH THAT
DON'T HAVE THEM.
BUT I THINK MORE THAN THAT, YOU
HE WASN'T WILLING TO REALLY
ADMIT THE DECISIVE ROLE OF
ANTIBODIES BECAUSE IT WAS AN
EITHER/OTHER, LIFE AND DEATH.
IF HE ACCEPTED THAT ANTIBODIES
WERE THE MAIN THING, THEN HIS
LIFE'S WORK WOULD GO DOWN THE
DRAIN.
HE DID ACCEPT THEIR FUNCTION
SORT OF A LITTLE BIT TOWARDS
THE END BUT THOUGHT IT WAS
SECONDARY AND PHAGOCYTES WERE
THE PREDOMINANT ONES.
>> DID METCHNIKOFF EVER CONSIDER
THE IDEA THE INNATE SYSTEM COULD
SORT OF TURN ON ITSELF AND
PRODUCE WHAT TODAY WE WOULD CALL
AUTOIMMUNITY?
>> I ANSWERED THAT BEFORE.
I READ THAT QUESTION FROM THE
PROMPT, THAT I HAVE IN THE CHAT.
NO, I DON'T -- I DIDN'T SEE ANY
EVIDENCE OF THAT, ONLY IN
ATROPHY AND OLD AGE.
BUT NOT IN AUTOIMMUNITY.
>> WHAT THAT IS AUTOPHAGY?
>> SORRY?
>> I SAID THEN WHAT IS
AUTOPHAGY, WHEN YOU'RE EATING,
IT'S NORMAL, PHYSIOLOGY, BUT YOU
EAT YOUR OWN JUNK, RIGHT?
>> YEAH, DEGRADATION.
WELL, BAD COMMENT.
IT WILL TAKE US AWAY FROM
REALITY.
>> SO, OKAY.
BOB?
THERE ARE A SERIES OF QUESTIONS,
QUITE A FEW.
I'M TRYING TO GET THEM
ORGANIZED.
ONE IS DO YOU THINK THE FLU
VACCINE ACTIVATES INNATE
IMMUNITY?
>> WHY NOT?
OF COURSE, YES.
LIVE ONE.
REMEMBER I SAID THERE'S
INTRANASAL AND INJECTABLE BUT
INTRANASAL FOR SURE, AND I WOULD
SAY EVEN THE DEAD ONE, SOME
INNATE IMMUNITY.
LOOK, IF YOU DON'T HAVE INNATE
IMMUNITY UP CAN'T MAKE
ANTIBODIES, YOU DON'T MAKE
ANTIBODIES, YOU DON'T GET THAT
RESPONSE.
MAYBE THE MEMORY AFTER BUT IN
ORDER TO BEGIN ANY VACCINATION,
YOU NEED INNATE IMMUNITY.
SO, YEAH, SURE.
DEAD VACCINES DON'T WORK AS
WELL, THAT SEEMS CLEAR, NOT AS
BIG A STIMULATION, OKAY?
BUT YEAH.
I THINK FLU VACCINE --
>> YEAH.
THERE'S A QUESTION RAISED ABOUT
THE ORAL POLIO VACCINE, WHICH
CLEARLY WAS ASSOCIATED VERY
INFREQUENTLY FORTUNATELY BUT WAS
ASSOCIATED WITH THE CLINICAL
DISEASE.
HOW DID YOU GET AROUND THAT
ISSUE?
>> I THINK IT'S RATHER SIMPLE,
I THINK.
FIRST OF ALL, IT'S ONE IN EVERY
FEW MILLION DOSES, IN AN
UNVACCINATED POPULATION.
IN THE UNITED STATES, WE TOOK IT
BETWEEN 1962 AND 2000, THE LIVE
ORAL POLIO.
THERE WASN'T A SINGLE CASE, MY
UNDERSTANDING, NOT A SINGLE
CASE, THE NUMBER OF DOSES WERE
BILLIONS, NOT A SINGLE SIDE
EFFECT MAJOR, NOT A SINGLE POLIO
CASE.
SO, IN A VACCINATED POPULATION
THERE IS NO PROBLEM.
IN OTHER POPULATIONS THEY ARE
DOING IT BECAUSE THEY HAVE TO
AND NEED IT BECAUSE THAT'S WHAT
THEY HAVE AND CAN AFFORD.
AND IT'S ABOUT 1 IN 2 MILLION.
IF YOU PLANNED IT, WE'RE
VACCINATED WITH IPV, IT WOULDN'T
BE A DANGER FOR US BUT IF YOU
WANT TO BE SURE, YOU USE
SOMETHING THAT CAN'T REVERT.
I MEAN, GATES -- I SHOULDN'T SAY
GATES, HIS FOUNDATION FUNDED
SOME PEOPLE TO MAKE A SEROTYPE
2 THAT CAN'T REVERT.
I DON'T THINK 1 AND 3 REVERT.
THERE'S EASY WAYS TO GET AROUND
IT.
THAT'S IT.
I THINK IT'S A MISTAKE TO AVOID
USING OPV.
FROM TALKING -- PEOPLE I KNOW
AND RESPECT THE MOST HAVE THE
SAME OPINION THAT ARE THE BEST
POLIO VIROLOGISTS, VIMMER IN NEW
YORK, EGGOL IN MOSCOW, AND MY
FRIEND CONSTANTINE CHERMIKOFF
WOULD ADVOCATE STOP THE
DISCUSSION OF NO MORE
VACCINATION WITH OPV AND TALK
ABOUT ERADICATING, BECAUSE IT'S
NOT GOING TO BE ERADICATED BUT
GET EVERYONE VACCINATED WHICH IS
STILL NOT THE CASE.
IT'S NOT INSURMOUNTABLE, IT'S
SURMOUNTABLE.
I DIDN'T SAY -- I THOUGHT OF OPV
BECAUSE OF THE LESSON IN THE
PAST BUT IT'S NOT LIMITED TO
OPV.
ROTAVIRUSES, INTRANASAL FLU,
BCG, THERE'S MEASLES, MUMPS,
RUBELLA.
I DON'T WANT TO PROMOTE THIS TOO
MUCH BUT MANY PEOPLE IN THE
GLOBAL VIRUS NETWORK THAT ARE
CENTER DIRECTORS, WE TAKE MMR
BEFORE THE VACCINE WAS
AVAILABLE, EVEN NOW, IN BETWEEN
BOOSTS.
FOR JUST BOOSTING INNATE
IMMUNITY WHEN WE KNOW WE'RE
GOING INTO A POPULATION-DENSE
AREA.
IF I'M GOING TO TRAVEL, IN A
POPULATION-DENSE AREA, I'D LIKE
FOR SEVERAL WEEKS TO HAVE MY
INNATE SYSTEM ALERTED.
BECAUSE THEY PROTECT AGAINST
INFECTION.
NOT AGAINST JUST DISEASE IN
ALLOWING INFECTION.
>> THAT'S OBVIOUSLY VERY
IMPORTANT.
AARON ASKS WHAT'S THE
POSSIBILITY THAT AN HIV-LIKE
RETROVIRUS THAT ATTACKS THE
IMMUNE SYSTEM CAN CHANGE ITS
TROPISM TO BECOME A RESPIRATORY
VIRUS?
>> MY BEST ANSWER IS IN 1988 I
WAS ASKED THAT, IN A PRESS
CONFERENCE IN WHICH IN THE NEXT
ROOM THERE WAS ANOTHER PRESS
CONFERENCE IN STOCKHOLM, THE
INTERNATIONAL AIDS SOCIETY
MEETING.
AND TWO SCIENTISTS, MYSELF AND
ANOTHER, FROM EUROPE, WERE PUT
IN OPPOSITE ROOMS AND ASKED THE
SAME QUESTION.
HE SAID THAT IT WAS A GOOD
POSSIBILITY WE COULD HAVE THE
SUPER VIRUS AND THAT MADE
HEADLINES.
AND MY ANSWER WOULD BE THE SAME
AS I SAID THEN.
IF A VIRUS CHANGES ITS TROPISM
TO TARGET T CELLS, IT'S GIVING
UP ITS TROPISM TO TARGET MY NOSE
AND MY MOUTH AND MY RESPIRATORY
TRACT.
IT CAN'T -- SECONDLY, HOW MANY
YEARS HAVE WE HAD HIV FLOATING
AROUND NOW?
IT'S ABOUT 42 YEARS, 43 YEARS,
45 YEARS.
THE WAY THIS VIRUS REPLICATES,
THE NUMBER OF PEOPLE INFECTED,
YOU KNOW, REALLY A LOT OF
MILLIONS OF PEOPLE.
DON'T YOU THINK IT WOULD HAVE
HAPPENED BY NOW?
SO, THE ANSWER IS I THINK
THAT'S -- WE GOT A LOT OF THINGS
TO WORRY ABOUT, THIS IS LIKE
WORRYING ABOUT TOMORROW, THE
MOON IS GOING TO HIT THE EARTH.
I DON'T THINK THAT'S GOING TO
HAPPEN AND THAT YOU HAVE TO
WORRY BIT.
THE TROPISM CHANGE WOULD DESTROY
ITS ABILITY TO TARGET T CELLS
RATHER SPECIFICALLY AND
MACROPHAGE, TO AN EXTENT.
>> WHAT IS THE MECHANISM WHEREBY
BCG AFFECTS BLADDER CANCER?
>> I ASSUME IT'S THE SAME BY
STIMULATING TOLL-LIKE RECEPTORS
THAT INDUCE A LOT OF INNATE
IMMUNITY WHICH IS OF COURSE USED
TO TREAT CANCERS, AND WAS PUSHED
IN GERMANY PRIOR TO CHEMOTHERAPY
AS YOU MAY KNOW, I DON'T HAVE
ANY EXPERIENCE WITH IT, NEVER
FOLLOWED IT THAT CAREFUL
CAREFULLY BUT ASSUME THE
MECHANISM IS THE SAME.
YOU DEVELOP A LOT OF INTERFERON,
DEVELOP NATURAL KILLERS CELLS,
WHICH CAN KILL CANCER CELLS,
THROUGH INNATE IMMUNITY, YEAH.
MANY PEOPLE STUDY INNATE
IMMUNITY IN TERMS OF CANCER, I'M
NOT EXPERT ON OR DON'T KNOW A
LOT ABOUT.
>> TODAY YOU REFERRED TO A
VARIETY OF EPIDEMIOLOGIC
STUDIES, NOT ALL LINKING THE
INNATE IMMUNE SYSTEM TO A
PROTECTIVE ROLE.
TWO QUESTIONS.
ONE, IS THERE RENEWED INTEREST
IN THE SCIENTIFIC WORLD THAT
PEOPLE MORE AND MORE ARE
STUDYING MECHANISM AND
OCCURRENCES AFOOT REGARDING
INNATE IMMUNE SYSTEM AND WHAT
WOULD YOU SUGGEST AS WAYS IN
WHICH SUCH RESEARCH COULD BE
STIMULATED?
>> FIRST ANSWER NO, SECOND
ANSWER, I DON'T KNOW.
YOU SAID BE BRIEF.
NO, I DON'T THINK THERE'S ANY
REAL INCREASE.
THERE'S A GROUP OF PEOPLE THAT
KEEP IN TOUCH WITH EACH OTHER.
THERE'S A LOT OF INTEREST, WE
TALK ABOUT IT A LOT, IT'S POORLY
FUNDED.
WELL, I'M TALKING -- WELL, I'M
TALKING TO MILITARY, BECAUSE THE
ARMY LOOKS FOR THAT.
WHEN THEY GO INTO LET'S SAY YOU
HAD TO SEND A LARGE NUMBER OF
SOLDIERS INTO FUNNY AREA NEAR
EGYPT, LET'S SAY THERE WAS A NEW
OUTBREAK OF A RESPIRATORY VIRUS,
IMAGINE YOU HAD A PILL IN YOUR
POCKET, FORGET MMR OR OBG.
THIS SHOULD BE ABLE TO BE
CONVERTED TO A PILL THAT REACTS
CAN THE SAME RECEPTORS WITH THE
SAME THING IN YOUR POCKET.
I THINK THAT DAY WILL COME.
I DON'T KNOW WHEN.
I HAVE A DISCUSSION NEXT WEEK
WITH SOME GROUP OF COLONELS IN
THE ARMY ABOUT THIS.
I MEAN I HOPE SOMEBODY WILL GET
INTERESTED IN COMING.
>> ARE THERE ANY, TO YOUR
KNOWLEDGE, CONTROLLED CLINICAL
TRIALS WITH BCG OR OTHER --
>> YES.
THERE WILL BE A RUSSIAN STUDY
PUBLISHED, AND PEOPLE WILL SAY
IT'S FROM RUSSIA, LIKE IT
DOESN'T MEAN -- YOU KNOW, BUT
THERE IS.
>> LIKE METCHNIKOFF, WHERE WE
STARTED.
>> HE ENDED UP MOVING TO PARIS.
TODAY MOVE HERE MAYBE, OR MAYBE
MOVE TO CHINA, I'M NOT SURE.
IN ANY CASE, YES.
THERE WILL BE A RUSSIAN STUDY
PUBLISHED, WITH OPV I GUESS.
THERE HAVE BEEN SMALL STUDIES
FROM INDIA, I THINK MEXICO, I
WOULD FOLLOW, THE BEST IN MY
FIELD IS A GUY, FOLLOW THE NAME
NETEA, A ROMANIAN, WORKING WHY
HOLLAND IN A UNIVERSITY, A
REALLY GOOD SCIENTIST.
AND HE'S THE ONE WHO DISCOVERED
TRAINED INNATE IMMUNITY FROM
MYELOID CELL INNATE IMMUNITY.
TRAINED, MEANING -- HE SHOWED IT
LASTED MUCH LONGER THAN WE
THOUGHT, WITH BCG HE SHOWED SIX
MONTHS, HE KNOWS THE MECHANISM,
HE'S WORKED OUT THE MECHANISMS,
HE GETS INVOLVED IN TRIALS, ALSO
MICHAEL AVIDAN AT WASHINGTON
UNIVERSITY, AND CHRIS STEIN
STABLE-BEN, AND HER COLLEAGUE
PETER AABBY, THEY DO CLINICAL
TRIALS.
YES, DO I KNOW THEM ALL, NO.
FOR THIS TALK I ASKED MY FRIEND
IF HE WOULD SEND A LIST OF ALL
SUCH PAPERS, HE DID THREE DAYS
AGO.
AND LET'S BE OPEN, I FORGOT TO
READ IT.
IF I READ IT, I'D KNOW THE
ANSWER BETTER.
BUT IT'S SOMEWHERE IN MY STACK
OF -- ON MY DESK.
>> IF YOU WOULD BE KIND ENOUGH
WHEN YOU GET TO IT --
>> I'LL SEND IT TO YOU.
>> WE'LL POST IT.
WE'LL POST THEM ON THE WEBSITE
BECAUSE I'M SURE ATTENDEES WOULD
BE VERY INTERESTED IN READING
SUCH --
>> LET'S REMEMBER THE ANIMAL
PAPERS THAT JUST CAME OUT.
TWO ANIMAL TRIALS JUST CAME OUT.
ONE, I THINK A VERY INTERESTING
STUDY BY ELLEN SCHERER OF NIH,
INTRAVENOUS BCG, PROTECTING MICE
AGAINST LETHAL CHALLENGES SARS
2.
ANOTHER COLLABORATING WITH A
GROUP AT STANFORD, SHOWING IN
ANIMAL MODEL, "CELL" PAPER,
WONDERFUL DATA OF PROTECTION,
ALSO USING THERAPEUTICALLY.
WHICH ONE HAS TO BE A LITTLE
CAREFUL ABOUT IF IT'S TOO FAR
INTO THE INFECTION PROCESS
BECAUSE YOU WANT TO TAKE CARE OF
THE VIRUS BUT DON'T WANT TO MAKE
INFLAMMATION AUGMENTED IN LATER
STAGES.
>> THERE WAS A QUESTION ON THAT
SCORE, WHETHER THE CYTOKINE
STORM THAT'S BEEN OBSERVED IN
SOME COVID PATIENTS COULD BE DUE
TO THE INNATE IMMUNITY.
>> NOT REALLY, NO.
I DON'T THINK SO.
I MEAN, I DON'T KNOW BUT I DON'T
THINK SO.
USING INNATE IMMUNITY IS
SOMETHING THAT OCCURS AT THE
BEGINNING, NOT LATE.
IN FACT CYTOKINES INVOKED WITH
THINGS LIKE IL6, NOT A BIG PART
OF INNATE IMMUNITY USUALLY.
SO I DON'T -- THIS IS COMPLEX
WHEN YOU GET LATE AND ALL THIS
INFLAMMATION.
YOU I DON'T WANT TO USE INNATE
STIMULATION LATE.
THAT'S FOR SURE.
THIS IS BEFOREHAND AND EARLY
PHASE.
IF YOU'RE REALLY SICK GETTING
INTO A CYTOKINE STORM, A
RESPIRATOR, YOU I DON'T WANT
ANYBODY STICKING YOU, CAUSING
ANYTHING THAT WOULD AUGMENT
INFLAMMATION.
>> IF YOU LOOK AT SYMPTOMOLOGY,
TYPICAL COVID CASE WHERE THERE
ARE SYMPTOMS, WHAT SYMPTOMS
WOULD YOU ASCRIBE LIKELY AS DUE
TO THE INNATE IMMUNE SYSTEM?
>> WELL, YOU KNOW, EVERY
TIME -- I MENTIONED THAT AT MY
AGE PROBABLY THERE'S BEEN 100,
200, HOW MANY TIMES WE'VE BEEN
INFECTED, THE NEXT DAY WE'RE
WELL, WHAT WERE YOUR SYMPTOMS?
THEY ARE EITHER NOTHING AND WHAT
ARE YOUR SYMPTOMS AFTER A
VACCINATION?
WHAT DO YOU THINK IT'S DUE TO?
INNATE IMMUNITY.
WHAT ARE THEY USUALLY?
NOTHING, MAYBE A LITTLE
HEADACHE, MAYBE A CHILL.
MAYBE A LOW GRADE FEVER.
THOSE ARE THE MAIN THINGS.
THOSE ARE INTERFERON SYMPTOMS
MAINLY.
I DON'T KNOW WHAT MORE I CAN
SAY.
I DON'T THINK IN LATE STAGE
YOU'RE TALKING ABOUT THAT.
YOU'RE TALKING ABOUT A GREAT
DEAL OF DESTRUCTION OF A LOT OF
VASCULAR DESTRUCTION, AND I
DON'T KNOW, I JUST READ SOMEBODY
WHO HAS A HYPOTHESIS ABOUT GRADY
KIEM CAUSING BULK OF
PATHOGENESIS.
I MEAN, THAT'S A MESS.
A LOT OF CELLS ARE -- I DON'T
KNOW HOW MUCH THE IMMUNE SYSTEM
HAS A ROLE.
A LOT OF IT IS DIRECT VIRAL.
WE DON'T KNOW SO-CALLED LATE
COVID, WE DON'T KNOW THAT IT'S
DUE TO IMMUNITY.
IT MAY BE WELL THAT VIRUS IS
STILL THERE.
WHO HAS PROVEN VIRUS IS NOT
STILL THERE, A YEAR LATER?
I JUST -- WIN KNOWS, I JUST HAD
KNEE SURGERY.
THE PERSON DOING MY PHYSICAL
THERAPY TOLD ME HER BROTHER IS A
YEAR OTHER TWO LATER STILL CAN'T
TASTE OR SMELL.
DO WE KNOW IT'S NOT VIRUS LEFT
SOMEWHERE BETWEEN HIS NASAL
PASSAGES, OLFACTORY NERVES OR
THE BRAIN ITSELF?
>> I GUESS WE STILL DON'T KNOW,
DO YOU KNOW?
WHAT DO WE KNOW IS THE MECHANISM
OF CHRONIC COVID?
>> I DON'T KNOW.
AND I BET YOU NOT TOO MANY
PEOPLE KNOW OR MAYBE NOBODY.
I DON'T KNOW.
YOU ASK A QUESTION THAT IS THE
MAIN SUBJECT OF OUR GLOBAL VIRUS
NETWORK MEETINGS NOW, RELATED TO
SARS 2.
SHOULD WE BE THINKING OF WHAT DO
WE KNOW, AND I THINK THIS IS NOT
GOING ANYWHERE.
WE NEED ALL OUR CLINICIANS
TOGETHER, WE'LL GET THE SAME
DESCRIPTION BUT I THINK WE KNOW
VERY ALSO. -- VERY LITTLE.
WE DON'T KNOW MUCH.
IT'S POSTMORTEM WE'LL HAVE TO
RELY ON, NOT MANY AVAILABLE FOR
DEEP DOWN STUDY BUT I THINK IT
WILL COME FROM POST MORT EM.
>> WE HAVE A SESSION IN THE
COURSE ON CHRONIC COVID.
ON MARCH 29.
WITH THE WALTER KOROSHETZ,
DIRECTOR OF NINDS.
AND JOSH GORDON, DIRECTOR OF OF
THE NATIONAL INSTITUTES OF
MENTAL HEALTH.
WE'LL SEE WHAT EMERGES AT THAT
POINT.
THERE'S A QUESTION AS TO WHETHER
ANTIGEN SPECIFICITY OF THE CD 8
T-CELL RECEPTOR CAN BE
DIFFERENT, IN DIFFERENT ORGANS,
PLAYING A ROLE IN WHAT ORGAN IS
AFFECTED, SAY THE ORAL MUCOSA
VERSUS -- OR THE ORAL PHARYNX
VERSUS THE LUNGS.
IS THERE ANY EVIDENCE FOR
ANTIGEN SPECIFICITY OF CD8
T-CELL RECEPTORS?
>> RIGHT, THE WORDS I SAY WE
DON'T USE ENOUGH, I DON'T KNOW.
I DON'T KNOW IF THERE'S ANYTHING
IN THE LITERATURE THAT DESCRIBES
THAT.
IT SEEMS REASONABLE THERE COULD
BE VARIATION, DIFFERENT ORGANS
HAVE DIFFERENT NUMBERS OF T
CELLS AND DIFFERENT -- SOMETIMES
THE MARKERS ARE VERY DIFFERENT.
DIFFERENT DEGREES OF ACTIVATION,
DIFFERENT DEGREES OF
DIFFERENTIATION.
SO WHY NOT?
I SUSPECT IT'S LIKELY TO BE THE
CASE.
BUT I CAN'T QUOTE LITERATURE
THAT KNOWS THAT.
THERE WAS ONE ABOUT WHETHER
OMICRON CAME FROM AN
HIV-INFECTED PERSON BECAUSE IT
CAME OUT OF SOUTH AFRICA.
REASONABLE, WE'VE CERTAINLY
THOUGHT ABOUT IT.
THERE'S NO PROOF OF IT.
>> ALL RIGHT.
I'M TRYING TO -- ALL RIGHT.
I'M HAVING SOME DIFFICULTY WITH
MY CHAT BOX HERE.
THERE ARE A COUPLE OF QUESTIONS
THAT JUST ARRIVED.
>> IF I SEE ONE THAT YOU HAVEN'T
SAID, DO YOU WANT ME TO READ IT?
>> SURE.
>> I SEE ONE THAT SAYS DO THE
CURRENT VACCINES FROM CHINA
STIMULATE INNATE IMMUNITY
EFFECTIVELY?
I DON'T THINK SO.
I DOUBT IT.
I MEAN, MOST OF THE ONES FROM
CHINA THAT I'M AWARE OF ARE
REALLY CARRYING A GENE, THAT
GENE BY A VECTOR, EXPRESSED THAT
PROTEIN, WOULDN'T BE NECESSARILY
VERY POWERFUL.
DEPENDS ON HOW MUCH REPLICATION
THERE IS.
I DON'T THINK IT WOULD BE LIKELY
TO BE POWERFUL IMMUNE
STIMULATORS.
I DON'T THINK ANY OF THEM VERY
MUCH ARE.
>> I'M SORRY.
>> THERE'S ANOTHER, ASKING HOW
DOES POLIO VACCINE LAST A
LIFETIME?
HOW DO ANY?
WHY POLIO?
YOU KNOW, JAY CHUNG, YOU ASKED
THAT QUESTION, WHY DO YOU ASK ME
ABOUT POLIO THAT YOU COULD ASK
ABOUT ANYTHING, WHY DOES
ANYTHING LAST A LIFETIME?
IT'S LUCKY THE RIGHT B CELL THAT
CONVERTS TO PLASMA CELLS THAT
ARE MATURE, THAT FIND THE RIGHT
MISSION IN THE BONE MARROW,
THAT'S WHAT WE KNOW.
THEY MAKE ANTIBODIES THAT GET TO
WHAT WE CALL THE GAMMA STAGE OF
THE IMMUNE RESPONSE OF AN
ANTIBODY, AND THOSE JUST GO ON
AND ON AND ON.
IT'S THE DIFFERENTIATION OF THE
B CELL TO THE RIGHT PLASMA CELL,
AND WHY SOME B CELLS DO IT AND
SOME DON'T.
POLIO AND MANY OF OUR VACCINES
THAT LAST LIFETIME, ALL VACCINES
THAT LAST A LIFETIME HAVE TO DO
THAT, HAVE TO STIMULATE NERVE B
B CELL THAT RESPOND TO EPITOPES.
WE'LL LOOK FOR B CELLS THAT
CONVERT WITH FAST ASSAYS THAT
WE'RE ABLE TO DO IN BLOOD RATHER
THAN BONE MARROW, TRYING TO
DEVELOP THAT ACTUALLY.
SUCH STUDIES.
>> BOB, WE HAVE A QUESTION FOR
YOU FROM JOHN GALLIN.
HE SAYS THANK YOU, BOB.
INNATE IMMUNITY, AS YOU SAID, IS
COMPLEX.
WE CAN LEARN FROM PATIENTS WITH
INBORN DEFECTS OF INNATE IMMUNE
SYSTEM, PATIENTS WITH CHRONIC
GRANULOMATOUS DISEASE RESPOND TO
VACCINES NORMALLY AND DO NOT
HAVE VIRAL INFECTIONS AS PART OF
THEIR CLINICAL PICTURE.
A PATIENT WE FOLLOW WITH OUR IK
4 DEFICIENCY OF THE TOLL
RECEPTOR PATHWAY ALSO DOES WELL.
DO YOU THINK STUDIES OF THE
GROUP OF PATIENTS WITH DEFECTIVE
INNATE IMMUNITY WOULD BE ONE
METHOD TO DISSECT THE IMPORTANCE
OF SPECIFIC COMPONENTS OF THE
INNATE IMMUNITY IN VIRAL
DISEASE?
>> YEAH, I DON'T KNOW ABOUT
THOSE PATIENTS.
IT'S A GOOD IDEA.
FRANKLY SPEAKING, MY BIAS WOULD
HAVE BEEN THAT IF YOU HAVE
SERIOUS MUTATIONS THAT AFFECT
INNATE IMMUNITY, YOU WON'T LIVE
PAST ONE YEAR.
I WOULDN'T HAVE THOUGHT IT
POSSIBLE.
BECAUSE WE GET SO MANY
INFECTIONS EARLY IN LIFE AND
EXPOSURE TO THINGS THAT YOU
WONDER HAD YOU THEY COULD
SURVIVE.
YES, IF YOU HAVE SUCH A PATIENT
POPULATION IT COULD BE
INVALUABLE.
>> ALL RIGHT.
LET'S SEE.
WAIT A MINUTE HERE.
WELL, ROB ASKED THE SAME
QUESTION THAT I FLOATED UP TO
YOU A LITTLE WHILE AGO.
WHY IS INNATE IMMUNITY STUDIED
SO LITTLE?
>> I WISH I WERE SMARTER.
I DON'T KNOW.
ONE POSSIBILITY IS THAT A LOT OF
VACCINE RESEARCH IS CERTAINLY
AND PROPERLY DRIVEN BY
PHARMACEUTICAL COMPANIES, RIGHT?
THE CONSEQUENCE OF THAT WOULD BE
THAT THAT'S NOT GOING TO BE ABLE
TO BE AFFORDABLE.
I MEAN, I DON'T CRITICIZE THE
PHARMACEUTICAL INDUSTRY.
THEY HAVE TO SURVIVE.
SOMEBODY HAS TO DEVELOP REGULAR
VACCINES.
SO I THINK THEY DON'T DRIVE IT
IN THIS DIRECTION SO THERE'S NOT
A LOT OF SPINOFF RESEARCH FROM
PEOPLE THAT INTERACT WITH THE
PHARMACEUTICAL INDUSTRY AND
COLLABORATE, IT'S UNDERSTUDIED.
THAT MAY BE ONE PART OF THE
REASON.
I THINK IN THIS CASE BECAUSE
IT'S NOT -- WE'RE NOT USED TO
THINKING ABOUT IT, I DON'T WANT
TO GO THROUGH THE PERSONAL
THINGS OF PEOPLE THAT I TALKED
WITH BUT IF YOU COULD SEE THAT
IF I WAS IGNORANT, WHEN I WAS
FIRST STARTING OUT, ABOUT THE
IMPORTANCE OF THIS AREA, I
DIDN'T FIND MANY PEOPLE WHO
AREN'T ALREADY IN THE PROBLEM,
ANY BETTER INFORMED.
IN FACT, A LOT WORSE INFORMED.
I WAS SURPRISED.
SO I THINK IT'S JUST
UNDERAPPRECIATED AREA OF
RESEARCH.
ONE OF THE AREAS THAT NEEDS TO
GET FILLED IN.
WE NEED CLINICAL TRIALS WITH IT.
WE NEED FUNDING.
IT'S NOT BEEN AN INTEREST TO
NIH.
I SEE A QUESTION, THE SAME EXACT
NAME AS MY COUSIN, A MUSICIAN.
[LAUGHTER]
I PLAYS IN A SYMPHONY, IT CAN'T
BE HIM, NO WAY HE WOULD BE
ASKING A SCIENCE QUESTION.
SAME EXACT NAME, RON CAPALEPI,
SAME NAME AS ROMEO AND JULIETTE,
YES, JULIET'S NAME.
CAPULETS, FROM VERONA.
>> YOUR COUSIN ASKS TO DISCUSS
WHAT EVIDENCE EXISTS ABOUT THE
EFFICACY OF INNATE IMMUNITY.
>> WELL, RON, YOU PROBABLY ARE
MY COUSIN TO ASK.
YOU WEREN'T PAYING ATTENTION TO
WHAT I SAID IN THE MIDDLE OF THE
TALK.
THERE'S A LOT OF EVIDENCE, TRIED
TO SUMMARIZE, BEGINNING FOR ME,
THE GROUP'S PAPER FROM STANFORD
SHOWING CORRELATES OF DOING WELL
BEFORE THE VACCINES WERE INNATE
IMMUNE CORRELATES.
THERE'S A HOST OF STUFF.
THE ANIMAL STUDIES THAT I JUST
MENTIONED, CLINICAL STUDIES I
MENTIONED, THE STUDIES WITH
INTERFERON AND CORRELATIONS THAT
I MENTIONED, THE EVIDENCE THAT
THIS VIRUS CARRIES AT LEAST
THREE GENES TO TRY TO AVOID
INNATE IMMUNITY.
WHY IS IT DOING THAT WHEN IT
DOESN'T HAVE MUCH GENETIC
INFORMATION TO SURVIVE THAT IT'S
SO WORRIED ABOUT IT?
SO I SHOULD SEND YOU MY SLIDES,
RON.
PLEASE LET ME KNOW IF YOU'RE MY
COUSIN, RON CAPALETTI.
>> LUBA, THERE'S A QUESTION,
WHAT DO YOU PLAN FOR YOUR NEXT
BOOK?
PERHAPS COVID?
>> NO, NO.
NO PLANS AT THE MOMENT.
>> ALL RIGHT.
WELL, LISTEN, ON BEHALF OF ALL
THE PEOPLE LISTENING AND FOR ALL
OF US, WE WANT TO THANK BOTH OF
YOU FOR TAKING THE TIME.
IT'S NOW ALMOST MIDNIGHT IN
ISRAEL, THANK YOU ESPECIALLY.
AND IT'S A PLEASURE TO MEET YOU
AT LAST, LUBA.
AND BOB, THANK YOU REALLY SO
MUCH FOR PROVOKING AND
STIMULATING AND PRESENTING A
VERY EXCITING PERCEPTIVE WAY OF
CAUSING US TO ALL, EVERYBODY, TO
TAKE A HARD LOOK AT WHERE WE
THINK WE ARE.
>> THANK YOU.
>> WE WANT TO JUST MENTION TWO
THINGS.
OUR ASSOCIATES IN THIS PROGRAM,
GOING TO CHAIR THE NEXT THREE
SESSIONS OF THIS COURSE, AS I
WILL BE IN A PART OF THE WORLD
WHERE WE'RE NOT SURE ABOUT HOW
RELIABLE THE CONNECTIONS ARE
GOING TO BE.
AND THE NEXT SESSION IS ON
FEBRUARY 1, AND SPEAKERS ARE
MIKE LEONARDO OF NIAID, AND
HELEN SU, DEFINING GENES
UNDERLYING MENDELIAN
IMMUNOLOGICAL DISORDERS, LEADS
TO PRECISION MEDICINE
INTERVENTIONS.
I'M SURE IT WILL BE A VERY
EXCITING PRESENTATION.
SO THANK YOU ALL VERY MUCH.
AND STAY WELL.
>> THANK YOU.