GOOD MORNING.
MY NAME IS JOSEPH BREEN.
I'M A PROGRAM OFFICIAL IN THE
NATIONAL INSTITUTES OF ALLERGY
AND INFECTIOUS DISEASE, AND I
WANT TO WELCOME YOU TO THE
ADVANCING ME/CFS RESEARCH,
IDENTIFYING TARGETS FOR
INTERVENTION AND LEARNING FROM
LONG COVID.
THIS MEETING, ONE VERY MUCH LIKE
IT, WAS STARTED IN 2019, AND WE
BROUGHT PEOPLE TOGETHER HERE IN
THE CLINICAL CENTER WITH THE
IDEA THAT WE WOULD TRY AND
ACCELERATE THE PROGRESS OF
RESEARCH FOR ME/CFS AND REALLY
START TO HIGHLIGHT SOME OF THE
COLLABORATIVE RESEARCH CENTERS
THAT WERE FUNDED OUT OF THE NIH
ME/CFS WORKING GROUP.
THINGS HAVE CHANGED SINCE 2019.
SO THIS MEETING IS REALLY A
LITTLE DIFFERENT.
I THINK WE'LL FIND THAT THE
SCIENCE HAS MOVED TO MUCH MORE
ABOUT MECHANISMS AND THE IDEA OF
THIS MEETING IS TO TRY AND
IDENTIFY PATHWAYS THAT WILL BE
TREATABLE AND DRUGGABLE, AND
REALLY MAKE AN IMPACT FOR
PATIENTS BASED ON THE THINGS
THAT WE'VE LEARNED OVER THE LAST
NUMBER OF YEARS, AND INCLUDING,
FORTUNATELY OR UNFORTUNATELY,
THE HUGE NUMBER OF PEOPLE WHO
ARE SUFFERING FROM LONG COVID,
WHERE THE SYMPTOMS OVERLAP SO
MUCH WITH THOSE THAT HAVE BEEN
SUFFERING FOR A LONG TIME WITH
ME/CFS.
BOTH SHORT TERM AND LONG TERM.
SO THE IDEA IS THAT WE'LL
LEVERAGE THE UNDERSTANDING FROM
LONG COVID AND TRY AND APPLY TO
ME/CFS TO REALLY BENEFIT PEOPLE
WHO ARE SUFFERING.
SO THAT'S WHAT WE'VE ASSEMBLED.
THE OTHER THING WE'VE DONE A
LITTLE BIT DIFFERENT IS TO
REALLY HELP US UNDERSTAND HOW
THIS IMPACTS LIVED EXPERIENCE
INDIVIDUALS, WE HAVE THROUGHOUT
THE CONFERENCE AND THE PROGRAM
LIVED EXPERIENCE FOLKS TO
PROVIDE THEIR PERSPECTIVE, AND
THEY'LL BE DIFFERENT, WHICH
REPRESENTS THE HETEROGENEOUS
NATURE OF ME/CFS.
MOST LIKELY, THE BIOLOGY DRIVING
IT AS WELL AS THE VARIED HOST
RESPONSE.
THIS EFFORT IS A TRANS-NIH
EFFORT LED BY DR. WALTER
KOROSHETZ AND VICKY WHITTEMORE
AND YOU'RE GOING TO HEAR FROM
THEM SHORTLY, AND HISTORICALLY
HAS BEEN SUPPORTED BY A NUMBER
OF INSTITUTES AT NIH, INCLUDING
MINE, NIAID, AND WE HAVE A NEW
DIRECTOR, WHO'S HERE TODAY TO
SHOW HER SUPPORT AND THE KIND OF
SUPPORT THAT WE'VE GIVEN FROM
NIAID OVER THE PAST AS WELL, DRL
COME UP AND SAY A FEW WORDS.
JEANNE?
>> THANKS SO MUCH, JOE.
IT'S A REAL HONOR TO BE HERE
TODAY.
I'VE BEEN AT NIH NOW AS DIRECTOR
OF NIAID FOR JUST A LITTLE OVER
TWO MONTHS, HAVING COME FROM THE
UNIVERSITY OF ALABAMA AT
BIRMINGHAM, WHERE I WAS,
INCIDENTALLY, THE CONTACT
PRINCIPAL INVESTIGATOR FOR THE
RECOVER STUDY THERE, SO I AM
FAMILIAR CERTAINLY WITH THAT
ASPECT OF LONG COVID RESEARCH.
A COUPLE OF THINGS I JUST WANTED
TO MEX BEFORE GETTING JOE BACK
TO INTRODUCE VICKY.
AS JOE MENTIONED, HE'S BEEN THE
POINT PERSON, HE DIDN'T SAY THAT
BUT HE HAS BEEN THE POINT PERSON
AND I WANT TO PUBLICLY THANK HIM
AS OUR NIAID STAFF WORK CLOSELY
WITH THE WORKING GROUP UNDER THE
LEADERSHIP OF DR. KOROSHETZ AND
VICKY WHITTEMORE, BOTH WHOM
YOU'RE GOING TO HEAR FROM IN A
MOMENT.
AND I THINK THE THING I WOULD
EMPHASIZE ABOUT NIAID'S
INVOLVEMENT IS THAT WE ARE
PARTICULARLY INTERESTED IN SOME
AREAS I KNOW THAT MANY
SCIENTISTS AND COMMUNITIES IN
THE ROOM AND ONLINE ARE VERY
FOCUSED ON, INCLUDING POST
INFECTIOUS DISEASE ETIOLOGIES,
HERPES VIRUSES IN PARTICULAR,
IMMUNE DYSREGULATION, BOTH
ADAPTIVE AND -- THAT CHANGE IN
THIS SYNDROME OR THESE SYNDROMES
AND IN GREAT INTEREST TO ME IN
PARTICULAR AS A MICROBIOME
ENTHUSIAST, THE GUT MICRO BUY
AM -- THE BOTTOM LINE IS THAT
THERE ARE I THINK INCREDIBLE
ADVANCES HAPPENING IN THIS
SPACE, AND WE ARE REALLY
THRILLED TO BE ABLE TO WORK WITH
NINDS TO SUPPORT THEM.
I WANT TO JUST QUOTE SOMETHING
VERY QUICKLY, I'M NOT SURE IF
EVERYBODY SAW ED YOUNG'S PIECE
IN THE "NEW YORK TIMES"
YESTERDAY ABOUT HOW REPORTING ON
LONG COVID, BUT ALSO ON THE
FIELD OF M.E. AND CFS MADE HIM A
BETTER REPORTER.
THERE ARE JUST A COUPLE OF
SENTENCES THAT I THOUGHT FOR ME
REALLY CAPTURED SO MUCH ABOUT
WHERE THIS MEETING IS GOING FROM
WHERE IT STARTED IN 2019, AND
WHAT HE SAYS IS, COVERING LONG
COVID SOLIDIFIED MY VIEW THAT
SCIENCE IS NOT THE OBJECTIVE
NEUTRAL FORCE, IT IS OFTEN
MISCOCONSTRUED AS.
IT IS INSTEAD A HUMAN ENDEAVOR
BUFFERED BY OUR CULTURE, VAL YOU
OOS AND POLITICS, AS ENERGY
DEPLETING ILLNESSES THAT
DISPROPORTIONATELY AFFECT WOMEN,
LONG COVID AND ME/CFS ARE EASILY
BELITTLED BY A SEXIST SOCIETY
THAT TRIVIALIZES WOMEN'S PAIN
AND A CAPITALIST ONE THAT VALUES
PEOPLE ACCORDING TO THEIR
PRODUCTIVITY.
SOCIETAL DISMISSAL LEADS TO
SCIENTIFIC NEGLECT AND A LACK OF
RESEARCH GU BECOMES FODDER FOR
FURTHER SKEPTICISM.
I THOUGHT THAT WAS A BEAUTIFUL
CAPSULISM ABOUT HOW PEOPLE'S
EXPERIENCES DOES LEAD TO
DISMISSAL WHICH THEN DOES
UNDERMINE THE ABILITIES TO DO
THE SCIENCE THAT WE NEED TO DO
TO UNDERSTAND WHAT WAS GOING ON
IN THE FIRST PLACE, AND I THINK
THIS MEETING IS A FANTASTIC
EXAMPLE OF NOW MOVING INTO THIS
AREA WHERE PROGRESS IS GOING TO
BE HIGHLIGHTED AND YOU'RE GOING
TO BE LOOKING AT POTENTIAL
AVENUES FOR DIAGNOSIS AND
TREATMENT.
SO I REALLY WANT TO THANK YOU
FOR THE OPPORTUNITY TO BE HERE
AND MORE IMPORTANTLY, THANK YOU
FOR YOUR DEDICATION TO THIS
WORK.
[APPLAUSE]
>> THANK YOU, DR. JEANNE
MARRAZZO.
BEFORE WE MOVE AHEAD I WANT TO
THANK THE ORGANIZING COMMITTEE
THAT PUT TOGETHER THE PROGRAM,
PARTICULARLY THE TWO CO-CHAIRS,
AND A GROUP OF FOLKS WHO INCL
INCLUDED SOME OF OUR PRIVATE
PARTNERS, AS WELL AS OTHER
RESEARCHERS WHO HELPED PUT
TOGETHER THE PROGRAM SO THANK
YOU FOR YOUR EFFORTS TO PUT
TOGETHER WHAT WE'RE GOING TO SEE
IN THE NEXT TWO DAYS.
IT'S MY PLEASURE TO INTRODUCE
DR. VICKY WHITTEMORE, WHO'S
REALLY BEEN A LEADER AT NIH IN
DRIVING A LOT OF WHAT HAPPENS
WITH THE NIH ME/CFS WORKING
GROUP AND I TELL THEM MY PARTNER
IN CRIME, GREAT COLLEAGUE.
VICKY?
[APPLAUSE]
>> THANK YOU, JOE.
IT'S MY PLEASURE TO WELCOME YOU
ALL TO NIH AND TO THE
CONFERENCE.
WE HAD AN ABSOLUTELY FANTASTIC
WORKSHOP YESTERDAY WITH ALL THE
YOUNG INVESTIGATORS, WITH
INDIVIDUALS FROM A HIGH SCHOOL
STUDENT ALL THE WAY UP THROUGH
TO JUNIOR FACULTY.
SO THANK YOU ALL FOR
PARTICIPATING IN THAT MEETING
THAT WE HAD A GREAT TIME AND
HOPE TO CONTINUE THAT NETWORKING
AND REALLY HELP TO FOSTER THOSE
YOUNG INVESTIGATORS TO BECOME
ESTABLISHED INVESTIGATORS IN
THIS FIELD.
I JUST WANT TO SAY THAT IT HAS
BEEN MY PLEASURE TO WORK WITH
DR. KOROSHETZ AND JOE TO REALLY
ADVANCE ME/CFS RESEARCH HERE AT
NIH, AS WELL AS TO WORK WITH THE
COMMUNITY, WITH INDIVIDUALS WITH
LIVED EXPERIENCE, WITH THE
NON-PROFIT ORGANIZATIONS TO
REALLY WORK TOGETHER TO MOVE THE
FIELD FORWARD.
SO I HOPE THAT YOU ENJOY THE
CONFERENCE, AND I REALLY THINK
THAT YOU'RE GOING TO HEAR SOME
GREAT SCIENCE.
SO IT'S MY PLEASURE TO INTRODUCE
MY BOSS, MY BOSS AT THE NIH, DRE
DIRECTOR OF NINDS, WHO IS BY FAR
ONE OF THE MOST STEADFAST
CHAMPIONS FOR RESEARCH ON ME/CFS
AND REALLY SUPPORTIVE OF
EVERYTHING THAT THE TRANS-NIH
ME/CFS WORKING GROUP HAS BEEN
ATTEMPTING TO DO TO REALLY
ADVANCE THE FIELD.
SO WELCOME, WALTER.
[APPLAUSE]
>> THANKS, AND THANKS, JEANNE.
IT WAS REALLY GOOD TO HAVE YOU
HERE, AND LOOKING FORWARD TO
WORKING TOGETHER.
NIAID AND NINDS HAVE BEEN GREAT
PARTNERS IN THIS, SO WELL, GOOD
MORNING, FOLKS.
HOW DO YOU FEEL?
HOW DO YOU KNOW HOW YOU FEEL?
SO START OFF WITH A LITTLE
HUMOR, BUT AN ACTUAL FACT, I
THINK THIS CUTS -- THE QUESTION
CUTS RIGHT TO THE ISSUE OF
ME/CFS.
EVERY DAY WE WAKE UP, WE FEEL
DIFFERENTLY.
THERE'S A REASON WHY WE FEEL
DIFFERENTLY.
WHEN WE GET AN INFECTION OR A
COLD, WE DON'T FEEL SO GOOD.
WHAT'S THAT ALL ABOUT?
IT COMES UNDER THE TERM OF
ENTEROSEPTION, WHICH IS HOW THE
BRAIN IS TAKING ALL THE INPUTS
FROM AROUND THE BODY AND
INPUTTING INTO WHATEVER THESE
MYSTERIOUS CENTERS ARE TO GIVE
US THIS PERCEPTION OF HOW WE
FEEL.
HOW MUCH ENERGY WE HAVE.
ARE WE IN A GOOD MOOD, ARE WE IN
A BAD MOOD, AND WE DON'T REALLY
UNDERSTAND EXACTLY HOW THAT IS
HAPPENING.
BUT WE DO KNOW THAT THERE'S SO
MANY DIFFERENT THINGS THAT
INFLUENCE HOW WE FEEL AND SO I
WOULD SAY THAT TH UNDERSTANDING
ME/CFS IS KIND OF ONE OF THE
LAST MEDICAL MYSTERIES THAT ARE
OUT THERE, BUT IT CUTS ACROSS SO
MUCH OF BASICALLY HEALTH, AND SO
I THINK IT'S INCREDIBLY -- AN
INCREDIBLY IMPORTANT FIELD,
THERE'S A LOT TO BE LEARNED,
WE'RE KIND OF -- WE'VE BEEN KIND
OF REACHING IN THE DARK BUT
THERE ARE SOME LITTLE BURSTS OF
LIGHT THAT I THINK WE CAN
FOLLOW, AND WE REALLY NEED TO
BUILD THE WORKFORCE TO GIVE THEM
THE TOOLS THAT THEY NEED, FEED
THEM WITH IDEAS THAT THEY CAN
FOLLOW UP ON, AND HOPEFULLY WE
CAN REALLY GET SOME ANSWERS THAT
ARE GOING TO LEAD TO TREATMENTS,
AS JOE SAID.
SO NIAID AND NINDS WERE KIND OF
INSTRUCTED BY DR. FRANCIS
COLLINS TO GET TOGETHER AND
REALLY TRY AND MAKE A DIFFERENCE
IN THIS FIELD A NUMBER OF YEARS
AGO.
AND WE'VE BEEN WORKING HARD
WITH, YOU KNOW, I WOULD SAY SOME
SUCCESS BUT CLEARLY NOT THE KIND
OF SUCCESS WE WANTED.
WE HAVE -- BECAUSE THE ISSUES OF
ME/CFS, THE SYMPTOMS ARE SO
BROAD AND ACROSS MULTIPLE
INSTITUTES, THERE'S INTEREST AND
NEED FROM EXPERT FROM MULTIPLE
DIFFERENT INSTITUTES TO BE
INVOLVED IN ME/CFS RESEARCH.
TAKE FOR EXAMPLE, TACHYCARDIA
SYNDROME, THAT'S CLEARLY IN THE
MISSION OF NHLBI, SO GETTING THE
EXPERTISE FROM THAT SPACE IS
ALSO IMPORTANT, BUT MANY OTHER
INSTITUTES AS WELL.
HAVE THESE
REALLY SEVERE PROBLEMS WHICH
LEAD TO CHRONIC FATIGUE IF NOT
ME/CFS ITSELF.
SO WE HAVE THIS WORKING GROUP OF
21 INSTITUTES THAT HAVE EQUITIES
IN THE SPACE AND WE TRY AND
COORDINATE A ACTIVITIES AMONG EH
OTHER AND GET EXPERTISE FROM
MULTIPLE DIFFERENT INSTITUTES TO
BEAR ON THIS PROBLEM.
WE ALSO HAVE BEEN WORKING WITH A
LOOSE INTERAGENCY GROUP OF OTHER
FEDERAL AGENCIES THAT HAVE
EQUITIES IN ME/CFS, PARTICULARLY
THE CDC, WHICH HAS LONG TERM
INTEREST.
WE'VE BEEN TRYING TO KIND OF
IMPROVE AND INCREASE THE AMOUNT
OF RESEARCH GOING ON IN THIS
SPACE WITH A NUMBER OF DIFFERENT
MECHANISMS, AND ALTHOUGH YOU CAN
SEE THERE'S BEEN SOME SUCCESS IN
TERMS OF THE NUMBERS GOING UP,
IF YOU THINK ABOUT THE SEVERITY
OF THE DISEASE AND THE NUMBER OF
PEOPLE AFFECTED, THERE'S A PAUL
TRI AMPALTRY AMOUNT OF FUNDING.
THIS IS OF COURSE WHAT WE GET
CRITICIZED FOR ALL THE TIME BY
THE PATIENTS WHO ARE SUFFERING
AND RIGHTLY SO.
I THINK THEY ARE VERY, VERY
FRUSTRATED, PARTICULARLY, YOU
KNOW, PEOPLE HAVE BEEN SUFFERING
FOR DECADES AND STILL NO ANSW
ANSWERS.
BUT TO MOVE THIS DIAL, WE REALLY
NEED THE SCIENCE TO KIND OF COME
IN AND COMPETE FOR NIH GRANTS
THAT ARE GOING TO MAKE A
DIFFERENCE IN THE FIELD.
SO I THINK THAT'S WHY WE REALLY
ARE VERY INTERESTED IN HEARING
FROM YOU, HAD A REALLY GREAT
SESSION YESTERDAY WITH EARLY
INVESTIGATORS, NEW INVESTIGATORS
TO THE FIELD, AND SO WE WILL DO
ANYTHING WE CAN TO TRY AND BUILD
THIS FIELD UP.
WE HAVE AN INTRAMURAL PROGRAM,
DR. AVI NATH TOOK THIS ON,
AGAIN, WHEN FRANCIS BROUGHT US
INTO THIS AREA, DEVELOPED AN
ME/CFS DEEP PHENOTYPING STUDY.
SOME OF THE RESULTS ARE STILL IN
PREPARATION FOR PUBLICATION
PHASE.
THERE'S THIS ONE ARTICLE THAT
CAME OUT LOOKING AT MUSCLE AND
FINDING WASF-3, A PROTEIN
INVOLVED IN ER STRESS AND
AUTOPHAGY AS POTENTIALLY
SOMETHING THAT IS PRESENT IN
PEOPLE WITH ME/CFS AS COMPARED
TO CONTROLS.
IN THESE FIELDS, THE MAIN
QUESTION IS GETTING TO
CAUSALITY.
THERE'S GOING TO BE LOTS OF
ABNORMALITIES, AND HERE AGAIN, I
THINK WE NEED FURTHER WORK TO
KNOW WHAT'S CAUSE AND EFFECT,
PARTICULARLY WE HAVE THIS ISSUE
OF DECONDITIONING, WHICH IS
GOING TO AFFECT MUSCLE, BUT WE
REALLY NEED TO FIND SOMETHING
THAT HAS -- IN A CONTROL GROUP
THAT'S DECONDITIONED, YOU'RE NOT
GOING TO SEE THE SAME THING.
BUT THIS IS SOMETHING TO FOLLOW
UP ON, AND MAY PROVE TO BE
SOMETHING SPECIFIC TO ME/CFS,
BUT TIME WILL TELL.
DR. NATH ALSO, WITH BRIAN
WALLEN, WHO HAS BEEN WORKING IN
THE ME/CFS FIELD A LONG TIME,
HAD A PROGRAM IN LONG COVID DEEP
PHENOTYPING, AND AGAIN, THEY
HAVE BASICALLY THE SAME
PROTOCOLS WITH ME/CFS, NOW
TRANSLATED TO COVID, SO THEY'LL
BE ABLE TO GET A COMPARISON TO
THE LONG COVID AND THE ME/CFS
GROUP THAT THEY HAVE BEEN
INVESTIGATING.
AND THEY'RE ALSO LOOKING AT
ANOTHER KIND OF MYSTERIOUS
ILLNESS THAT GULF WAR ILLNESS,
WHICH HAS SOME OVERLAP WITH
ME/CFS, SO THEY'RE GETTING THESE
GROUPS, DEEP PHENOTYPING THEM
AND ALLOWING COMPARISONS TO SEE
IF SOMETHING FALLS OUT FROM ALL
THREE.
WE HAVE, OVER THE YEARS NOW,
BEEN WORKING TO DEVELOP A
CONSORTIUM OF WHAT WE CALL
CENTERS OF EXCELLENCE FOR ME/CFS
RESEARCH.
THE IDEA THAT WE NEED CENTERS TO
FORM THAT CAN TRAIN NEW
INVESTIGATORS THROUGH RESEARCH,
BUT THE MAIN THING IS TO DO IT
IN A GROUP AND A TEAM SETTING AS
OPPOSED TO ONE-OFFS.
I THINK THE BANE OF A LOT OF
ME/CFS RESEARCH IN THE PAST HAS
BEEN A LOT OF PUBLICATIONS OF AN
ABNORMALITY BUT VERY FEW THAT
HAVE THEN BEEN REPRODUCED BY
ANOTHER GROUP, SO IT'S BEEN
REALLY HARD TO PUT YOUR HAND ON
SOMETHING THAT YOU CAN BE SURE
OF, BUT I THINK GROUPS WORKING
TOGETHER DOING THINGS SIMILARLY,
IF THEY'RE SEEING THE SAME THING
IN MULTIPLE DIFFERENT PATIENT
GROUPS, MORE LIKELY THIS IS
GOING TO BE SOMETHING WE CAN
SINK OUR TEETH INTO.
WE HAVE A NUMBER OF INVESTIGATOR
INITIATED RESEARCH PROGRAMS OUT
THERE FOR PEOPLE TO APPLY TOMENT
SOME OF THESE, THEY'RE ON FOR A
COUPLE YEARS BUT THE PLAN IS TO
REISSUE THEM.
SO SO PLEASE LOOK FORWARD TO
THOSE, TALK TO FOLKS THAT YOU
MIGHT BE INTERESTED IN THIS
FIELD EVEN IF THEY'RE IN ANOTHER
FIELD TO KIND OF TEAM UP WITH
YOU TO KIND OF LOOK AT A NEW AIR
PROACH TNEWAPPROACH TO SOME OF E
PROBLEMS.
THE ONE CENTER THAT STILL WAS
FUNDED IN THE GO-AROUND IS THE
CORNELL GROUP.
WE'RE HOPING -- AND YOU'LL
PROBABLY HEAR FROM THEM TODAY,
BUT WE'RE HOPING TO PUT THIS OUT
AND FUND MORE CENTERS AND GET
THAT TEAM APPROACH BACK, AND KEY
TO THIS IS THE FACT THAT WE HAVE
IN THE CENTER IDEA THE ABILITY
TO BRING SAMPLES IN SO THAT
OTHER INVESTIGATORS, EITHER
WITHIN THE GROUP CAN HAVE ACCESS
TO SAMPLES AND DO TESTS THAT
THEY FIND ABNORMAL IN THEIR
GROUP AND LOOK THE A SAMPLES
FROM ANOTHER GROUP, SEE IF THEY
CAN SEE THE SAME THING, AND ALSO
THE HOPE IS TO MAKE THIS
AVAILABLE TO INVESTIGATORS
ACROSS THE COUNTRY.
SO IF YOU'RE TRYING TO DO ME/CFS
RESEARCH AND YOU NEED FIVE YEARS
TO COLLECT SAMPLES, THAT'S BIG
DOWNTIME.
IF WE HAVE A REALLY GOOD, WELL
ANNOTATED SAMPLE BANK, PEOPLE
CAN TEST THEIR IDEAS POTENTIALLY
IN THOSE SAMPLES WITHIN A YEAR
AND GET ANSWERS.
SO WE HAVE A NUMBER OF AWARDS
AND I'LL JUST MENTION JUST THE
TITLES TO GIVE YOU A SENSE OF
WHAT THEY ARE.
BUT THE GROUP AT COLUMBIA
LOOKING IT THE NEUROLOGICAL POST
SEQUELAE OF SARS-COV-2.
A GROUP AT MASS GENERAL LOOKING
AT NEUTROPHIL FUNCTION AND
CYTOKINE PROFILES IN ME/CFS.
A GROUP AT FLORIDA ATLANTIC
LOOKING AT ENDOGENOUS
RETROVIRUSES IN ME/CFS.
A GROUP, AVIK ROY AND SIMMARON
RESEARCH LOOKING AT ATG13, A
FACTOR INVOLVED IN METABOLISM
THROUGH THE MTOR PATHWAY IN
ME/CFS.
AN ANIMAL MODEL THAT LOOKS
INTERESTING IN TERMS OF
DEVELOPING WHAT SOME IN THE
NEUROSCIENCE FIELD CALL SICKNESS
BEHAVIOR.
SO THE PEOPLE WHO ARE LOOKING AT
THE EQUIVALENT OF ME/CFS IN
ANIMALS ARE LOOKING IN THE
HYPOTHALAMUS, TRYING TO FIND
SOME EVIDENCE THAT THERE ARE
CENTERS THERE THAT, WHEN TURNED
ON BY WH WHATEVER, NOT CLEAR WHT
TURNS THEM ON YET, BUT THERE ARE
SEEMING LISTEN TERES THAT WILL
CHANGE THE ANIMAL'S BEHAVIOR TO
ONE THAT MIMICS WHAT HAPPENS
WHEN, QUOTE-UNQUOTE, THE ANIMAL
IS SICK.
SO THESE MIGHT BE GOOD WAYS OF
GETTING AT SOME MECHANISTIC
PRINCIPLES AND SEE IF THEY APPLY
TO THE HUMAN.
THERE'S ANOTHER GROUP AT MOUNT
SINAI LOOKING AT PROTEOMICS IN
ME/CFS, AND ANOTHER GROUP AT
MOUNT SINAI LOOKING AT HIGH
FIELD MRI, BOTH STRUCTURAL AND
LOOKING AT MR SPECTROSCOPY IN
PATIENTS WITH ME/CFS.
ANOTHER SET OF GRANTS LOOKING AT
SINGLE CELL IMMUNE CELLS FROM
RON DAVIS AT STANFORD.
LEONARD JASON HAS BEEN STUDYING
A LONG TIME PEOPLE WHO DEVELOP
MONO AND THEN HAVE ME/CFS
FOLLOWING MONO, WHICH WAS
PROBABLY THE BEST MODEL UNTIL
COVID CAME ALONG.
MAYBE IT'S STILL THE BEST MODEL
BUT WE'LL SEE.
STUDIES OF HUMAN HERPES VIRUS IN
ME/CFS, LOOKING AT
CARDIOVASCULAR CHARACTERISTICS
OF POST EXERTIONAL MALAISE,
LOOKING AT LONG COVID AS A
SUBTYPE OF CHRONIC FATIGUE
SYNDROME, A GROUP AT UMASS
LOOKING AT ALTERED T RESPONSES
IN ME/CFS, A GROUP AT CORNELL
LOOKING AT N ACETYLCYSTINE AS AN
ANTIOXIDANT TO IMPROVE
GLUTATHIONE LEVELS IN THE BRAIN,
MEASURED BY SP SPECTROSCOPY, AND
THEN ANOTHER ONE LOOKING AT
MAGNETIC RESONANCE SPECTROSCOPY
FOR SIGNS OF NEUROINFLAMMATION
IN ME/CFS.
AT NIH NOW, WE ARE INVOLVED IN
DEVELOPING A ROAD MAP FOR ME/CFS
RESEARCH.
WHAT THIS MEANS IS THAT NIH
CONVENES EXPERTS IN AN AREA IN
HERE WE'RE TALKING ABOUT ME/CFS
AND KIND OF DIVE DOWN INTO WHAT
IS KNOWN AND WHAT THE
OPPORTUNITIES ARE TO MOVE THE
FIELD FORWARD, AND SO THIS GROUP
HAS BEEN WORKING OVER THE YEAR,
AND THIS IS A WORKING GROUP OF
THE NINDS COUNCIL, AND A LOT OF
WORK GOING INTO THIS.
THEY HAVE GROUPS THAT ARE
LOOKING AT ALL THESE DIFFERENT
ASPECTS OF ME/CFS THAT YOU SEE
HERE IN THE BLUE.
THEY'RE HAVING MULTIPLE
WORKSHOPS, INCLUDING PEOPLE WITH
ME/CFS IN THE PLANNING AND THE
EVALUATION PROCESS, AND WILL PUT
TOGETHER A REPORT TO THE NINDS
ADVISORY COUNCIL, WHICH I HOPE
WILL BE ACCEPTED BY THE COUNCIL
AND THEN USEFUL TO NOT JUST NIH
BUT ALSO TO INVESTIGATORS AROUND
THE WORLD IN TERMS OF TRYING TO
MOVE THIS FIELD FORWARD, GETTING
A SENSE OF WHAT THE EXPERTS HAVE
SEEN AS THE MAJOR OPPORTUNITIES
GOING FORWARD.
THEN THE ELEPHANT IN THE ROOM,
OF COURSE, IS THE FACT THAT LONG
COVID HAS REALLY KIND OF
CHANGED, I THINK, THE SPECTRUM
FOR ME/CFS ON THE DOWNSIDE, YOU
KNOW, PROBABLY HUNDREDS OF
THOUSANDS OF PEOPLE NOW HAVE A
SYNDROME THAT IS PROBABLY
IDENTICAL TO ME/CFS.
IT IS MAYBE ME/CFS ITSELF.
AND IT CAME AFTER ACUTE COVID
INFECTION.
AND THAT PUTS THE PRIORITY FOR
FINDING TREATMENTS WAY UP HIGH
ON THE LIST, BECAUSE THE NUMBERS
ARE JUST ASTRONOMICAL.
IT WAS BAD BEFORE COVID, IT'S SO
MUCH WORSE NOW.
YOU CAN SEE HERE THE SYMPTOMS
THAT PEOPLE WITH LONG COVID HAVE
COMPLAINED OF AND YOU CAN
RECOGNIZE THAT MANY OF THESE ARE
ALSO VERY COMMON IN ME/CFS.
SO THE OVERLAP IS REALLY QUITE
STRIKING.
IN ADDITION, MANY PEOPLE --
ME/CFS OCCURS AFTER SOME KIND OF
STRESS, PARTICULARLY AN
INFECTIOUS CONDITION, BUT IN THE
PAST, PEOPLE WOULD SHOW UP YEARS
AFTER THEY'VE HAD TROUBLES AND
IT WAS VERY HARD TO UNDERSTAND
WHAT'S GOING ON, WHAT TRIGGERED
THIS IN THE BEGINNING, ALTHOUGH
THEY MIGHT HAVE TALKED ABOUT AN
INFECTIOUS ILLNESS, THE EPSTEIN
BARR VIRUS AND MONONUCLEOSIS WAS
KIND OF A GOOD WAY OF GOING
AFTER THAT, BUT THAT WAS
PROBABLY A MINORITY OF FOLKS.
SO -- BUT HERE WITH COVID, WE
KNOW EXACTLY WHAT THE INFECTION
IS, WE KNOW EXACTLY WHEN IT
OCCURRED, AND WITH THE RECOVER
PROGRAM, WE HAVE $1.15 BILLION
THAT WE PUT IN TO TRY AND
UNDERSTAND THIS PROCESS.
AND I THINK THERE'S HOPEFULLY
GOING TO BE SOME ANSWERS THAT
COME OUT OF THIS THAT ARE
RELEVANT NOT JUST TO LONG COVID
BUT TO ME/CFS IN GENERAL.
SO WE HAVE COHORTS AND WE HAVE
TO JUST BE SO GRATEFUL TO PEOPLE
WHO VOLUNTEERED TO BE POKED AND
TESTED.
WE HAVE -- I THINK IT'S UP TO
16,000 PEOPLE NOW HAVE ENROLLED
IN THE COHORT STUDY.
THIS INCLUDES PEOPLE WHO ARE
ACUTELY INFECTED, AND THEN WERE
RECRUITED INTO THE STUDY WITHIN
30 DAYS OF THEIR ACUTE
INFECTION.
SOME OF THOSE ARE GOING TO MAKE
A GOOD RECOVERY.
TURNS OUT FROM WHAT WE'VE HEARD,
ABOUT 70% OF THEM MAKE A GOOD
RECOVERY.
30% HAVE PERSISTENT SYMPTOMS AT
THREE MONTHS AFTER.
SO THIS IS NOT REPRESENTATIVE OF
THE INCIDENCE BECAUSE MY
SUSPICION IS THAT THE PEOPLE ARE
MORE LIKELY TO ENROLL IF THEY
WERE HAVING SYMPTOMS THREE OR
FOUR WEEKS LATER, SO I THINK WE
GOT AN ENRICHED POPULATION, BUT
THAT'S REALLY GREAT FOR THE
STUDY BECAUSE W WHAT WE REALLY
WANTED WAS A GROUP THAT WAS
ACUTELY INFECTED AT THE SAME
TIME, SOME OF WHICH GOT BETTER,
SOME OF WHICH DIDN'T.
SO WE CAN COMPARE THE TWO GROUPS
AND SEE WHAT HAPPENED OVER TIME.
IF WE GOT TO, SAY, 5% PEOPLE
DEVELOPING TROUBLE, WE WOULDN'T
REALLY HAVE A LOT TO COMPARE BUT
IT TURNS OUT THE STUDY IS ABOUT
30% OF THOSE ACUTELY ENROLLED
ARE CURRENTLY HAVING SYMPTOMS.
THEN THERE'S THOUSANDS OF PEOPLE
WHO HAVE HAD SYMPTOMS AND THEY
ARE ENROLLED ALONG WITH A
CONTROL GROUP, AND THIS ALLOWS
THESE CONSORTIA ACROSS THE
COUNTRY TO STUDY THIS IN LARGE
DETAIL, MULTIPLE PATIENTS,
DIFFERENT TIERS OF TESTS, AND
ALSO SAMPLES ARE BEING COLLECTED
AND STORED AT MAYO CLINIC SO
THAT WE'LL HAVE A GREAT
COLLECTION, IF WE DON'T FIGURE
THIS OUT IN THE SHORT TERM,
THOSE SAMPLES WILL BE AVAILABLE
FOR LONGER FUTURE STUDIES.
WE HAVE STUDIES GOING ON NOW TO
GET AT THE PATHOBIOLOGY OF THE
LONG COVID SITUATION IN PATIENTS
AND IN ANIMAL MODELS.
WE HAVE AUTOPSY STUDIES, WHICH
ARE LOOKING FOR EVIDENCE OF
TISSUE DAMAGE OR POTENTIALLY
PERSISTENT VIRUS OR IMMUNE
ABNORMALITIES IN DIFFERENT
IMMUNE AREAS OF THE BODY.
THIS IS SOMETHING THAT'S
TERRIBLY LACKING IN ME/CFS.
WHERE WE DON'T KNOW THAT THERE
COULD BE SOMETHING HIDING THERE
THAT NO ONE'S EVER SEEN BEFORE,
BECAUSE NO ONE HAS EVER DONE A
REALLY CAREFUL AUTOPSY STUDY IN
PEOPLE THAT HAVE DIED FROM
ME/CFS.
I THINK NOW THEY HAVE 120
AUTOPSIES IN THE LONG COVID
STUDY.
SOME OF THEM ARE CONTROLS, SOME
ACUTELY INFECTED AND SICK, AND
SOME OF THEM ARE PEOPLE WITH
PASC OUT PAST AN INFECTION, SOME
NORMALS OUT PAST INFECTION.
THIS IS JUST AN INTERESTING
POINT TO MAKE, IS THAT WHEN THE
GROUP LOOKED AT THESE THOUSANDS
OF PEOPLE IN THE COHORT STUDY,
THE QUESTION IS ALWAYS WHAT'S
THE DEFINITION, AND CERTAINLY
ME/CFS HAS BEEN, YOU KNOW,
INVOLVED IN TRYING TO DEFINE
WHAT IT IS FOR DECADES.
THIS IS BASICALLY A STATISTICAL
ANALYSIS, SO IT'S NOT REALLY --
IT'S NOT A CLINICALLY USEFUL
TOOL, BUT I THINK IT GIVES US
SOME LESSONS.
SO WHAT THEY DID IS, BECAUSE THE
SYMPTOMS ARE SO COMMON IN THE
NON-COVID POPULATION, IT'S
REALLY HARD TO KNOW WHAT IS
EXACTLY LONG COVID VERSUS THE
USUAL, YOU KNOW, FATIGUE,
EXERCISE INTOLERANCE, AND THAT
APPLIES TO ME/CFS AS WELL.
BUT STATISTICALLY, THEY LOOKED
AND THEY SAID, WELL, WHAT ARE
THE THINGS THAT REALLY TURN OUT
TO BE REALLY DIFFERENT, AND IT
TURNS OUT THAT THE NUMBER OF
SYMPTOMS AND THE TYPE OF
SYMPTOMS ARE THE ONES THAT RISE
TO THE TOP, AND AT THE TOP IS A
LOSS OF SMELL AND TASTE, AND OF
COURSE THAT'S RELATED TO COVID
SO TH THAT WAS BE EXPECTED
DIFFERENT FROM CONTROLS, BUT
POST EXERTIONAL MALAISE WAS
NUMBER TWO.
THAT WAS THE SECOND MOST
IMPORTANT DISTINGUISHING FACTOR,
AND OF COURSE THAT'S WHAT ONE OF
THE REAL SIGNATURES OF ME/CFS
ARE.
BRAIN FOG, FATIGUE ARE ON THAT
LIST.
FATIGUE IS SO COMMON, IT DOESN'T
DISTINGUISH AS WELL AS A SYMP
SYMPTOM.
THEN AS YOU CAN SEE, THE NUMBER
OF SYMPTOMS CORRELATES WITH A
DIFFERENCE FROM WHAT YOU WOULD
EXPECT IN NORMALS.
WE DON'T KNOW WHAT HAS CAUSED
LONG COVID.
WE WERE HOPING WE'D HAVE SOME
BETTER EVIDENCE BY NOW BUT WE
DON'T.
THERE'S A LOT OF PAPERS OUT
THERE TAUTING OR GOING AFTER
CERTAIN MECHANISMS, BUT NONE OF
THEM ARE TOTALLY NAILED DOWN.
BUT THESE ARE THE ONES THAT ARE
STICKING TO THE TOP AND WE HAVE
DEVELOPED CLINICAL TRIALS.
SOME OF THEM ARE TRYING TO GET
AT THE PATHOPHYSIOLOGY, SO FOR
INSTANCE, WE HAVE TRIALS TO
START USING IVIG IN PEOPLE WITH
AUTONOMIC DYSFUNCTION AFTER LONG
COVID.
POTS SYNDROME IS A REALLY
PROMINENT ONE, AND THEN WE HAVE
A PROLONGED ANTIVIRAL TREATMENT
ON THE IDEA THAT THERE COULD BE
PERSISTENT ACTIVE VIRUS IN
FOLKS, AND THEN WE HAVE A NUMBER
OF SYMPTOMATIC TRIALS LOOKING AT
SLEEP, LOOKING AT COGNITION, TO
TRY AND IMPROVE PATIENTS -- THE
SUFFERING THE PATIENTS ARE
UNDERGOING NOW.
SO I THINK THERE'S -- I THINK
WHAT COVID DID IS, I THINK IT
MADE ALL THE WORK THAT PEOPLE IN
ME/CFS HAVE BEEN DOING OVER THE
YEARS, KIND OF RAISED IT IN
PROMINENCE.
THE PROBLEM OF ME/CFS IS STILL
WITH US, THE PROBLEM OF LONG
COVID IS WITH US, BUT WE HAVE A
GREATER ARMY OF PEOPLE STUDYING
THIS WITH GREATER TOOLS,
HOPEFULLY GREATER SAMPLES, AND I
THINK WORKING TOGETHER IS OUR
BEST CHANCE AT REALLY DOING
SOMETHING THAT TURNED THE CORNER
AND GETS US TO IMPORTANT
TREATMENTS FOR PEOPLE WHO ARE
SUFFERING WITH ME/CFS.
SO REALLY APPRECIATE THE WORK
YOU'RE DOING.
NIH IS HERE TO KIND OF MOVE THIS
FORWARD AS BEST WE CAN, BUT THIS
IS A TOUGH PROBLEM, AND WE HAVE
TO BE CLEVER.
THANKS.
[APPLAUSE]
>> THANK YOU, DR. KOROSHETZ.
SO WE'RE GOING TO MOVE INTO OUR
FIRST SESSION, IMMUNOLOGY OF
ME/CFS AND LONG COVID.
WE HAVE THREE SPEAKERS IN THIS
SESSION.
BUT WE'RE GOING TO START WITH
LIVED EXPERIENCE SPEAKER VOX JO
HSU.
AND IT'S OUR PLEASURE TO
INTRODUCE YOU AND PLEASE COME UP
TO THE PODIUM.
>> CAN YOU HEAR ME OKAY?
FANTASTIC.
THANK YOU.
SO I APPRECIATE THE OPPORTUNITY
TO SPEAK WITH YOU TODAY.
I'LL JUST JUMP RIGHT INTO IT.
"TO HAVE PAIN IS TO HAVE
CERTAINTY.
TO HEAR ABOUT PAIN IS TO HAVE
DOUBT."
THIS IS THE WILD PART ABOUT
LIVING WITH A POORLY UNDERSTOOD
ILLNESS.
YOU WAKE EVERY DAY TO THE DREAD
OF SUFFERING WHILE STRUGGLING TO
PROVE TO OTHERS, WHILE MEDICAL
AUTHORITIES SPEND TIME, ENERGY
AND MONEY TRYING TO CONFIRM WHAT
YOU ALREADY KNOW TO BE TRUE.
SO I'M SPEAKING TO YOU AS A
PERSON WITH M.E., WHICH COLLIDED
WITH COVID-19 AND LONG COVID
LAST YEAR.
I'M ALSO SPEAKING TO YOU AS A
RESEARCHER.
I'M A PROFESSOR AT THE
UNIVERSITY OF TEXAS AT AUSTIN,
WHERE I STUDY THE POLITICAL
EMBODIED IMPACT OF STORYTELLING,
THE WAYS THAT NARRATIVE SHAPE
POLICY, SOCIAL NORMS AND
PERSONAL AND PUBLIC HEALTH.
AND WE TELL STORIES EVERYWHERE,
THROUGH NEWS MEDIA, POLITICAL
BRIEFINGS, AND SCIENTIFIC
STUDIES.
MORE RECENTLY, I FOCUSED ON HOW
DISCRIMINATORY STORIES
INFILTRATE MEDICAL RESEARCH AND
HOW THAT RESEARCH GETS TAKEN UP
TO DO FURTHER DAMAGE.
ALMOST EXACTLY A YEAR AGO,
NATALIE SHORE PUBLISHED AN
ARTICLE TITLED WE MIGHT HAVE
LONG COVID ALL WRONG.
IT OPENS WITH A STORY OF A WOMAN
WITH FUNCTIONAL NEUROLOGICAL
DISORDER WHICH WAS MISDIAGNOSED
AS DEGENERATIVE DEMENTIA.
SHE MIRACULOUSLY RECOVERS BY
RETRAINING HER THINKING.
SHORE DOES NOT DIRECTLY ACCUSE
LONG COVID OF BEING
PSYCHOSOMATIC.
INSTEAD SHE CITES AN NIH STUDY
THAT FOUND INCREASED RISK FOR
LONG COVID AMONG, QUOTE, WOMEN
AND THOSE WITH A HISTORY OF
ANXIETY DISORDER.
SHE EXPLAINS ANXIETY FREQUENTLY
CAUSES SYMPTOMS MOST PEOPLE
WOULD DESCRIBE AS PHYSICAL.
BY LAYERING THESE STORIES ON TOP
OF EACH OTHER, SHE'S BUILDING AN
ARGUMENT.
ANXIETY IS MISDIAGNOSED AS
BIOMEDICAL ILLNESS, LONG COVID
IS COMMONLY ASSOCIATED WITH
ANXIETY, ANXIETY CAN BE CURED
WITH THERAPY.
THIS IS A PARTICULAR SELECTION
OF EVENTS THAT SUGGESTS A COULD
CONCLUSION, THAT M.E. AND LONG
COVID COULD BE EFFECTIVE TREATED
WITH PSYCHOLOGICAL APPROACHES.
SHORE'S ARTICLE CLOSES WITH THE
WOMEN'S PSYCHIATRIC
REHABILITATION WHICH INVOLVES
STRESS MANAGEMENT AND HABIT
BUILDING.
OF COURSE MEDIA WRITEUPS LACK
THE NUANCE OF SCIENTIFIC
LITERATURE BUT SHORE'S FRAMING
PARALLELS THAT OF THE STUDY
WHICH IDENTIFIES FEMALE GENDER
AND ANXIETY AND DEPRESSION AS
RISK FACTORS FOR LONG COVID.
QUITE FRANKLY, IT DOESN'T MATTER
WHETHER SHORE OR ANY OF THE
RESEARCHERS WHOSE ARGUMENTS
SUPPORT HER ARGUMENT BELIEVE
THAT LONG COVID IS ALL IN ONE'SS
HEAD.
THEIR ARGUMENTS ENTER A CULTURAL
CONTEXT WHERE DISABLED PEOPLE
ARE ALREADY TREATED WITH
SUSPICION, WHERE PSYCHIATRIC
DIAGNOSES ARE ALREADY WEAPONIZED
TO INVALIDATE A PERSON'S
SELF-KNOWLEDGE.
LET ME BE CLEAR.
WHETHER OR NOT YOU ACTUALLY
BELIEVE A DISCRIMINATORY
NARRATIVE, YOUR WORDS CAN
ENDORSE IT.
WITH ALL THE AUTHORITY OF YOUR
POSITION.
STORIES ARE ALGORITHMIC.
THEY PROVIDE A SET OF RULES FOR
ANSWERING A QUESTION.
WHEN WE SEE A MARVEL MOVIE, WE
EXPECT FLASHY ACTION SEQUENCES.
WHEN WE SEROMID-ATLANTIC
COMEDIES WE ANTICIPATE HAPPILY
EVER AFTERS, WHEN WE ENCOUNTER A
PATIENT WITH ANXIETY, WE
PRESCRIBE PSYCHOTHERAPY AND
MAYBE EXERCISE AND SSRIs.
LIKE THE ALGORITHMS THAT
GENERATE OUR SOCIAL MEDIA FEEDS
AND OUR GOOGLE SEARCH RESULTS,
STORIES CAN DISCRIMINATE.
THROUGHOUT WESTERN MEDICINE, THE
STORE HE OOO OF HYSTERIA WHICH
LIVES ON HAS PRESUMED THAT WOMEN
ARE UNRELIABLE NARRATORS OF
THEIR OWN BODIES.
I DON'T NEED TO TELL MOST FOLKS
IN THIS ROOM THAT THIS IS A
STORY THAT HAS HAUNTED M.E. AS
WELL AS CONDITIONS SUCH AS
ASTHMA, ENDOMETRIOSIS, AND MS.
THIS IS THE STORY INVOKED WHEN
MEDICAL EXPERTS, WHEN THE
NATION'S LEADING HEALTH
AUTHORITY DECIDES TO ASK, IS
ANXIETY A RISK FACTOR FOR LONG
COVID?
RATHER THAN ASKING, WHAT COMMON
FACTORS MIGHT MAKE PARTICULAR
PEOPLE MORE VULNERABLE TO
ANXIETY AND LONG COVID?
WHAT FORMS OF TREATMENT ARE
ALREADY AVAILABLE FOR THE
PHYSIOLOGICAL SYMPTOMS WE FOUND
IN M.E. AND LONG COVID AND WHAT
MIGHT WE INVESTIGATE TO IMPROVE
PATIENT OUTCOMES AND CURRENT
QUALITY OF LIFE?
M.E. HAS BEEN NAMED FOR OVER A
HALF CENTURY.
IF TRADITIONAL METHODS FOR
ADDRESSING ANXIETY AND
DEPRESSION WERE TENABLE
SOLUTIONS WE'D BE OVERRUN WITH
MIRACULOUS RECOVERY STORIES AND
WE'RE NOT.
BUT THIS STORY REMAINS
PERSUASIVE BECAUSE IT FEEDS ON
EXISTING STEREOTYPES ABOUT
WOMEN, ABOUT DISABILITY AND
ABOUT WHOSE PAIN NEEDS TO BE
TAKEN SERIOUSLY.
LET ME TRY A DIFFERENT STORY.
I GET SICK AT 19 YEARS OLD.
I SPEND WEEKS IN BED SAMPLING
ALL THE SOUPS THAT HOUSTON HAS
TO OFFER, BECAUSE IT TAKES TOO
LONG FOR ME TO GET BETTER, I
TODDER TO MY JOB, I DIGITIZE VHS
TAPES, I DO THIS OVER AND OVER
AGAIN IN THE COMING YEARS,
CHOOSE WORK OVER THE CRY OF MY
BODY.
AFTER THE GIRLFRIEND AND I BREAK
UP, AFTER MY FRIENDS STOP ASKING
ME TO COME OUT, AFTER I STOP
TALKING TO MY PARENTS BECAUSE
THEY SUSPECT I AM FAKING MY
PAIN, BECAUSE THEY ARE RELIEVED
WHEN THE GIRLFRIEND AND I BREAK
UP, BECAUSE THEY AND I HAVE BEEN
LOOKING FOR AN EXCUSE THROUGHOUT
MY LIFE ANYWAY.
I GO TO WORK BECAUSE I NEED THE
MONEY.
BECAUSE I HAVE BEEN TAUGHT THAT
MY VALUE LIES IN MY ABILITY TO
OUT WORK, THAT I CAN BREAK
MYSELF FOR WHAT OTHERS WILL NOT.
I WONDER IF THIS IS WHAT
RESIGNED ME TO A LIFE OF ILLNESS
AND HOW MUCH OF IT IS MY FAULT.
HOW AS A NOT YET OUT TRANS
PERSON OF COLOR I BECAME SO
PRACTICED IN HEATING MY BODY
WISHING AWAY I PRESUMED IT
SHOULD HURT THIS BAD.
BUT JUST AS I ABSORBED THE
STORIES THAT EXPECT MY PAIN, SO
TOO HAVE MY PHYSICIANS, SO TOO
HAVE ENTIRE SCIENTIFIC
DISCIPLINES THAT ALMOST NEVER
THINK TO ASK ABOUT THE GENERAL
HEALTH NEEDS OF TRANS PEOPLE OR
ABOUT THE HEALTH INEQUITIES
EXPERIENCED BY ASIAN AMERICANS,
SO TOO HAVE THE INSTITUTIONS
THAT HAVE BEEN CONTENT TO LET
PEOPLE WITH M.E. AND LONG COVID
DISAPPEAR FROM PUBLIC LIFE.
IN 2020, I FINALLY LEARNED WHAT
I HAVE AS ME/CFS.
I LEARNED THAT IN THE
INTERVENING YEARS THAT I SPENT
TRYING TO PROVE MY VALUE IN A
WORLD WHERE TRANS AND DISABLE
AND BLACK AND BROWN LIVES ARE
PRESUMED DISPOSABLE, IN THE
YEARS WHEN EVERY DOCTOR I SAW
INSISTED THAT I WAS FINE, THAT I
COULD PUSH THROUGH, I MIGHT HAVE
IRREVERSIBLY WORSENED MY DISE
DISEASE.
I WATCH FROM THE BED WHERE I
SPEND HOURS OF EACH DAY FIGHTING
TO SIT UP A VIRAL PANDEMIC STORM
ACROSS THE COUNTRY.
WHILE THE U.S. PRESIDENT BLAMES
PEOPLE WHO LOOK LIKE ME FOR THE
OUTPOURING OF SUFFERING.
BY THE TIME THERE'S DATA ON LONG
COVID, IT CONFIRMS WHAT I
ALREADY KNEW.
WHAT M.E. PATIENT ACTIVISTS HAVE
ALREADY BEEN SCREAMING FROM
THEIR SICK BEDS, THAT MANY
PEOPLE WITH COVID-19 WILL FIND
THAT SOME SYMPTOMS, SOMETIMES
MANY SYMPTOMS, SOMETIMES
DEVASTATING NEW LIFE LIMITATIONS
HAVE COME TO STAY.
BY THE TIME POST EXERTIONAL
MALAISE IS A TERM MY PHYSICIANS
RECOGNIZE, IT IS A CERTAINTY MY
BODY HAS HELD FOR YEARS.
IT IS A PITFALL I HAVE RUN HEAD
LONG INTO OVER AND OVER AGAIN,
UNDER THE REASSURANCE THAT TALK
THERAPY AND EXERCISE WOULD CARRY
ME TO FREEDOM.
BY THE TIME YOU ARE LISTENING TO
ME SPEAK, I HAVE BEEN SICK FOR
ALL OF MY ADULTHOOD.
I TURN 35 THIS YEAR.
I'M RECOGNIZING THAT I'M GOING
TO AGE INTO THIS DISEASE.
THAT I MAY NEVER AGAIN FEEL ANY
BETTER THAN I DO RIGHT NOW,
STANDING IN FRONT OF YOU WITH MY
DIZZY THOUGHTS AND ACHING BODY.
BUT THIS IS NOT JUST MY STORY.
IT'S A STORY OF MEDICAL NEGLECT,
WELL DOCUMENTED IN UNREST AND
THE FORGOTTEN PLAGUE.
IT'S A STORY ABOUT MEDICAL
RACISM BETTER DESCRIBED BY BLACK
WOMEN ACTIVISTS INCLUDING
WILHELMINA JENKINS, ASIAN
DEDANIEL, SAMIR SMITH SWEENEY.
IT'S A STORY OF HOSTILITY THAT
ERODES TRANS AND QUEER LIVES
COMBATED THROUGH CAREERS.
IN THIS WAY, M.E. AND LONG COVID
ARE NOT EXCEPTIONAL.
THEY BELONG TO A LITANY OF
MEDICAL COMPLISSITIES THAT
INCLUDE NOT ONLY HYSTERIA BUT
ALSO SCHIZOPHRENIA, A DIAGNOSIS
THAT WAS USED TO
INSTITUTIONALIZE BLACK CIVIL
RIGHTS ACTVISTS.
CHINESE MIGRANTS WERE EXILED
THROUGH ACCUSATIONS OF SMALLPOX,
SYPHILIS AND PLAGUE, A STRATEGY
REPEATED WITH COVID-19.
AND TRANS AND QUEER COMMUNITIES,
PARTICULARLY COMMUNITIES OF
COLOR, WERE DEVASTATED BY
GOVERNMENTAL AND SOCIAL
RESPONSES TO HIV/AIDS.
THIS IS A STORY WE'VE BEEN
SCREAMING FOR CENTURIES ACROSS
GENERATIONS.
IN RECENT YEARS, M.E. RESEARCH
HAS SEEN SIGNIFICANT PROGRESS.
HOWEVER, THIS PROGRESS IS LITTLE
COMFORT FOR PEOPLE WHO HAVE
LIVED WITH M.E. FOR SO LONG.
WHAT'S CONSIDERED PROGRESS IS
OFTEN WHAT WE'VE ALREADY KNOWN.
FOR EXAMPLE, WHEN WHITE
RESEARCHERS DISCOVER THAT PEOPLE
OF COLOR RECEIVE POORER
TREATMENT FOR COMPLEX CHRONIC
DISEASES.
WHAT'S CONSIDERED PROGRESS IS
SOMETIMES OBSERVATIONAL STUDIES
THAT LITERALLY QUANTIFY THE
KNOWLEDGE OF OUR BODIES.
WHAT'S CONSIDERED PROGRESS IS
SOMEONE ELSE'S CAREER
ADVANCEMENT FOR NAMING OUR
SUFFERING.
IT IS THE SAME INSTITUTIONS THAT
ONCE NEGLECTED OUR DISEASES
TAKING CREDIT FOR IDENTIFYING
OUR PAIN.
I'M ASKING YOU TO UNDERSTAND OUR
STORIES AS MORE THAN DISCRETE
ANECDOTES, BUT AS POINTS IN A
MUCH LARGER CONSTELLATION OF
KNOWLEDGE.
ONE THAT HONORS BOTH PEER
REVIEWED STUDIES AND THE
EXPERIENTIAL WISDOM OF LIVING A
DISEASE.
I'M SPEAKING TO YOU AS BOTH A
PATIENT AND A RESEARCHER, AS
SOMEONE WHO HAS SPENT MY CAREER
THINKING ABOUT WHICH COMMUNITIES
ARE MOST IMPACTED BY MY WORK AND
HOW I HOLD MYSELF ACCOUNTABLE TO
THEM.
IF TO HAVE PAIN IS TO HAVE
CERTAINTY, THEN TO HEAR ABOUT
PAIN IS TO BE ENTRUSTED WITH
SOMEONE ELSE'S TRUTH.
WHAT WILL YOU DO WITH THAT
TRUST?
THANK YOU.
[APPLAUSE]
>> THANK YOU.
THAT WAS IMPORTANT AND MOVING.
AND REALLY SETS THE STAGE FOR
OUR SESSION.
I'M GOING TO INTRODUCE DR. MARK
DAVIS FROM STANFORD, WHO'S GOING
TO TALK ABOUT OXIDATIVE STRESS
AND A SHARED CHARACTERISTIC
BETWEEN ME/CFS AND LONG COVID.
MARK?
>> OKAY.
HOPE ALL THIS IS WORKING.
SO I DON'T THINK I NEED TO TELL
THIS AUDIENCE BUT NUMBERS JUST
CAME OUT ESTIMATED 3 MILLION
PEOPLE IN THE U.S. ALONE
SUFFERING FROM ME/CFS.
MANY MILLIONS MORE SUFFERING
FROM LONG COVID.
AND THERE'S JUST MANY MYSTERIES.
THE LACK OF A REAL DIAGNOSTIC,
THE LACK OF ANY MECHANISTIC
POTENTIAL CLUES AS TO WHAT'S
ACTUALLY GOING ON.
BUT THIS IS ALSO A GREAT STORY
ABOUT A YOUNG STUDENT OF MINE
WHO STARTED IN MY LAB AS AN
UNDERGRADUATE, STARTING IN
COMPUTATION, BUT ALONG THE WAY,
HE READ THIS BOOK, "THE PUZZLE
SOLVER," BY TRACIE WHITE WITH
RON DAVIS, AND REALLY WAS MOVED
BY THE STORY AND THE SUFFERING
THAT WE JUST HEARD ABOUT
ACTUALLY.
AND IT'S TALENTED YOUNG
SCIENTISTS LIKE VISHNU WHO TAKE
ON THE CHALLENGE.
AND MANY PEOPLE TAKE ON THE
CHALLENGE AND ONLY A FRACTION
SUCCEED.
BUT I THINK HE'S SUCCEEDED IN A
REALLY IMPORTANT WAY THAT GIVES
US AN OPENING INTO THE DISEASE
THAT WE NEVER HAD BEFORE, AND
THE PROSPECT OF AN ACTUAL
DIAGNOSTIC THAT WE'D NEVER HAD
BEFORE.
THIS DOESN'T OCCUR IN A VACUUM.
IT'S REALLY IMPORTANT THAT
PEOPLE GATHER THAT PATIENTS
DONATE BLOOD SAMPLES AND THAT
INVESTIGATORS COLLECT THOSE AND
STORE THOSE.
THERE ARE VERY GOOD WAYS TO
STORE BLOOD SAMPLES NOW.
YOU CAN STORE SAMPLES FOR
10-PLUS YEARS.
AND THIS IS A CRITICAL VARIED
ENTRY, BECAUSE IF YOU HAVE TO
START FROM SCRATCH, IT CAN TAKE
YEARS TO ACCUMULATE THE SAMPLES.
BUT IF THE SAMPLES FOR A DISEASE
LIKE ME/CFS ARE ALREADY THERE IN
THE BANK, YOU CAN TEST THINGS
MUCH MORE EASILY, MUCH MORE
QUICKLY, AND THAT'S BEEN A KEY
TO ALL SORTS OF DISEASE ANALYSIS
IN HUMANS.
SO BANKS ESTABLISHED YEARS AGO
BY RON DAVIS AND MORE RECENTLY
BY HECTOR BONILLA, WHO IS THE
HEAD OF THE ME/CFS/LONG COVID
CLINIC AT STANFORD AND MYSELF
HAVE BEEN BANKING SAMPLES FOR
YEARS IN SOME CASES.
AND THAT REALLY ENABLES IDEAS
LIKE VISHNU'S TO BE TESTED
QUICKLY.
SO I WANT TO JUST GIVE A PLUG
FOR THAT.
THERE'S ALSO, OF COURSE, HUGE
INTEREST IN LONG COVID, AND
THESE ARE OFTEN CO-DIAGNOSED
BECAUSE THEY HAVE SUCH SIMILAR
CHARACTERISTICS, ESPECIALLY
FATIGUE AND GETTING WORSE AFTER
EXERCISE AND ALL SORTS OF OTHER
UNPLEASANT THINGS.
IT'S NOT JUST ABOUT ME/CFS OR
LONG COVID THAT HAS THESE
SYMPTOMS.
THERE'S LYME DISEASE, FOR
EXAMPLE, VERY SIMILAR, AND ALSO
THERE'S A KNOWN INFECTIOUS
AGENT, AND THERE'S THIS REALLY
EXCELLENT REVIEW BY AKIKO
YOVASAKI POINTING OUT THAT MANY
INFECTIOUS DISEASES HAVE
SYNDROMES INCLUDING FATIGUE LONG
AFTER THE BUG IS GONE.
AND IN OUR OWN WORK, WE TOUCHED
ON THIS SOME YEARS AGO, WE SAW
THAT PATIENTS THAT HAD HEPATITIS
C THAT WERE CURED PROFOUNDLY
WITH A NEW DRUG THAT BECAME
AVAILABLE A FEW YEARS AGO, STILL
A YEAR AFTER THE VIRUS WAS GONE,
THEY HAD DAMAGE TO THEIR IMMUNE
SYSTEM IN PARTICULAR WAYS.
AND EVEN MORE RECENTLY, LOOKING
AT SARS-COV-2 VACCINATION AND
INFECTION, WE FOUND THAT PEOPLE
THAT GOT THE PFIZER VACCINE BUT
HAD HAD COVID PREVIOUSLY HAD A
MUCH REDUCED CD8 T-CELL RESPONSE
COMPARED TO PEOPLE THAT WERE
NAIVE TO THE DISEASE.
SO THERE'S MORE AND MORE
EVIDENCE THAT THERE'S SOMETHING
THAT HAPPENS DURING A SEVERE
DISEASE THAT EVEN WHEN THE
PATHOGEN IS GONE, THERE'S LONG
TERM DAMAGE TO THE IMMUNE SYSTEM
THAT CAN MANIFEST ITSELF IN
FATIGUE AN AND IN OTHER WAYS.
IT'S STILL SUCH AN EMERGING
AREA, IT HASN'T BEEN STU STUDIT
ALL MUCH, AND WE HAVE A LOT
BETTER TOOLS NOW THAN WE DID A
FEW YEARS AGO.
SO I THINK THERE'S GOING TO BE
SOME RAPID PROGRESS.
BUT VISH NA STARTE VISHNU STARTA
KIND OF A NAIVE BUT PENETRATING
IDEA FOCUSING ON FATIGUE.
, THAT
IF FATIGUE IS THE MAIN ESTIMATE,
DOESN'T THAT SUGGEST AN
ENERGETIC DEFECT, SOMETHING
GOING WRONG WITH THE METABOLISM,
SPECIFICALLY MITOCHONDRIAL
METABOLISM, WHICH IS THE SOURCE
OF ENERGY AT THE POWERHOUSE OF
THE CELL.
AS YOU MAY REMEMBER, ALMOST ALL
CELLS HAVE MIGHT MITOCHONDRIA.
IF THEY USE A LOT OF ENERGY LIKE
MUSCLE CELLS THEY CAN USE
HUNDREDS OF MITOCHONDRIA, AND
THIS PROVIDES THE ATP THAT
REALLY RUNS A LOT OF THE
MACHINERY AND ACTIVITY OF THE
CELL.
SO HE SPENT A YEAR ACTUALLY IN
HIS ROTATIONS AS AS A STARTING
IMMUNOLOGY STUDENT TWO YEARS AGO
AT STANFORD, AND HE ROTATED
HIMSELF THROUGH EVERY LAB HE
COULD FIND THAT STUDIED ENERGY
OR STUDIED MITOCHONDRIA.
SO REALLY LEARNED ALL THE WAYS
YOU CAN ANALYZE MITOCHONDRIA.
THEN WHAT SYSTEM, IT SEEMS LIKE
A NEUROLOGICAL DISEASE, SO YOU
CALL YOUR NEUROLOGIST IN, AND
TALKING TO HECTOR, NO, HE'S
TRIED TO CALL THE NEUROLOGISTS
BUT THEY DON'T ANSWER.
THEY'RE BUSY TRYING TO
UNDERSTAND HOW THE BRAIN WORKS.
AND SO ACTUALLY SINCE WE'RE
IMMUNOLOGISTS, IT WAS NATURAL TO
LOOK AT THE IMMUNE SYSTEM.
AND THE IMMUNE SYSTEM USES AS
MUCH ENERGY AS THE BRAIN.
IT USES AN ESTIMATED 20 TO 30%.
AND IF YOU'RE INFECTED, IT USES
A LOT MORE, BECAUSE YOU'RE
TRYING TO FIGHT OFF THE
INFECTION, YOUR CELLS ARE
DIVIDING LIKE CRAZY IMMUNE CELLS
TO TRY TO FIGHT OFF THE PATHO
PATHOGEN.
SO THAT'S HOW WE GOT TO THE
IMMUNE SYSTEM.
THE OTHER HUGE ADVANTAGE OF THE
IMMUNE SYSTEM IS IT'S
ACCESSIBLE, IT'S RIGHT THERE IN
YOUR BLOOD SAMPLE.
SO YOUR BLOOD SAMPLE IS FULL OF
RED CELLS WHICH PROVIDE OXYGEN
BUT ALSO WHITE CELLS, WHICH ARE
A MYRIAD, DOZENS AND DOZENS OF
DIFFERENT IMMUNE CELLS THAT DO
IMPORTANT THINGS LIKE MAKE
ANTIBODIES OR KILL INFECTED
CELLS.
AND WE SAW A HINT OF THIS SOME
YEARS AGO IN WORK WITH JOSE
MONTOYA, WHERE THERE SEEMED TO
BE A CERTAIN INFLAMMATORY
CYTOKINES IN THE BLOOD OF
CHRONIC FATIGUE PATIENTS.
SO THAT WAS KIND OF A STARTING
POINT, BUT NOT A -- THE REAL
DEAL WAS LOOKING AT REACTIVE
OXYGEN SPECIES, WHICH ARE
PRIMARILY IN THE MITOCHONDRIA,
AND REACTIVE OXYGEN SPECIES ARE
BASICALLY OXYGEN RADICALS.
IF YOU KNOW SOME CHEMISTRY,
RADICALS ARE DANGEROUS ENTITIES
THAT THEY CAN FORM THINGS LIKE
HYDROGEN PEROXIDE, PARTICULARLY
ARE JUST HUGELY REACTIVE.
THEY'RE UNSTABLE, AND THEY'RE
LACKING FOR SOMETHING TO BIND
TO, AND THAT MAY NOT BE
SOMETHING YOU WANT THEM TO BIND
TO.
BUT THEY ARE AN IMPORTANT
COMPONENT OF T-CELL ACTIVATION.
SO YOU NEED TO ELEVATE ROS
LEVELS IN THE MITOCHONDRIA AS
PART OF -- AND I'LL SHOW YOU A
MORE DETAILED ROUNDUP IN A
MINUTE.
IT'S A KEY PART OF THE
ACTIVATION STEP IN ACTIVATING
T-CELLS TO RESPOND TO INFECTION.
BUT TOO MUCH ROS IS DAMAGING.
IT'S GOING TO DEGRADE YOUR
MITOCHONDRIA AND DAJ ITS ABILITY
TO MAKE ENERGY.
SO THAT'S THE LEAD-IN TO THIS
ACTUAL DATA, WHERE WITH ME/CFS
PATIENTS, THAT WE LOOKED AT
COMPARED -- ORIGINALLY LOOKED AT
COMPARED TO HEALTHY CONTROLS ARE
BLUE, ME/CFS ARE RED.
IN CD19B CELLS, CD4 ARE T-CELLS,
CD8 ARE ANOTHER FORM OF T-CELL.
SO YOU CAN SEE THERE'S IN
GENERAL HIGH LEVELS OF ROS
LEVELS, REACTIVE OXYGEN SPECIES
LEVELS, BUT IT'S MORE COMPLEX
THAN THAT BECAUSE IF YOU NOTICE
THE SPOTS HERE, THERE'S SORT OF
TWO CATEGORIES.
THERE'S A HIGH COLLECTION AND A
LOW COLLECTION.
IT TURNS OUT THIS IS -- SORRY.
THIS IS A DIFFERENCE BETWEEN
MALES AND FEMALES.
SO IT TURNS OUT THAT FEMALES
WITH ME/CFS HAVE THE HIGH ROS
LEVELS, BUT THE MALES DO NOT.
IF WE LOOK -- IT SHOULD HAVE
BEEN THE OTHER WAY AROUND.
IF WE LOOK AT LONG COVID
TOGETHER WITH ME/CFS, WE ALSO
SEE ELEVATION OF ROS LEVELS, AND
THESE ALSO RESOLVE INTO MALE AND
FEMALE DIFFERENCES.
SO IT SEEMS LIKE THE DISEASE IS
MANIFESTING ITSELF VERY
DIFFERENTLY IN WOMEN VERSUS MEN.
AND SO THAT'S A WAY I'M ABLE
TO -- OKAY.
SO HERE IS WOMEN HERE ON THIS
SIDE.
AND IF YOU LOOK AT, SAY,
CD8 T-CELLS, HEALTHY CONTROLS
ARE HERE, VERY LOW.
AND ME/CFS, WOMEN ARE WAY UP
HERE.
SIMILARLY, LONG COVID ARE ALSO
UP HERE.
AND THEN IF YOU LOOK AT MALES,
IT'S REALLY NOT DISTINGUISHABLE
FROM NORMAL.
NOW, THAT DOESN'T SAY THAT THERE
ISN'T A STRESS PROBLEM IN MALES.
THERE IS.
IT'S JUST COMING UP DIFFERENTLY.
AND SO PART.
ROS PATHWAY, HOW DO YOU
DOWNREGULATE ROS?
ROS LEVELS ARE OBVIOUSLY
DANGEROUS, AND YOU NEED TO
REGULATE THEM.
AND ONE WAY YOU REGULATE THEM IS
WITH REDUCED GLUTATHIONE.
AND SO -- YEAH, SO JUST LOOKING
AT GLUTATHIONE, REDUCE
GLUTATHIONE LEVELS, THEN WE CAN
SEE ACTUALLY BOTH MALES AND
FEMALES HAVE ELEVATED,
ESPECIALLY ME/CFS HAS ELEVATED
GLUTATHIONE, LONG COVID TO A
LESSER EXTENT BUT STILL
SIGNIFICANTLY ABOVE BACKGROUND.
AND THIS IS -- WE DON'T HAVE
ENOUGH DATA WITH THE MALES JUST
YET, BUT THE TREND IS CLEAR THAT
WITH THESE DIFFERENT
LYMPHOCYTES, WE ARE SEEING
ELEVATED GLUTATHIONE LEVELS IN
BOTH FEMALES AND MALES.
SO THAT SAYS THAT THESE ARE
RELATED.
THEY'RE NOT DIFFERENT DISEASES.
IT'S JUST THAT PROBABLY THERE
WERE HIGH ROS LEVELS EARLIER IN
MALES BUT THEN SOMEHOW MALES ARE
ABLE TO REDUCE THOSE LEVELS, BUT
THEY STILL HAVE SIGNS OF A
PROBLEM IN THEIR -- IN THIS
PATHWAY AND IN THE
MITOCHONDRIAL -- IN THE ENERGY
GENERATION.
SO THIS IS JUST A TECHNICAL
EXPLANATION OF WHERE ROS COMES
IN IN TERMS OF THE T-CELL
ACTIVATION PATHWAY, SOMEWHERE IN
HERE.
AND WE CAN EVEN SEE NOW, IF WE
STIMULATE T-CELLS FROM ME/CFS
PATIENTS, VERSUS HEALTHY
CONTROLS, WE CAN SEE THAT
THERE'S A RELATIONSHIP BETWEEN
THE ROS LEVELS AND T-CELL
ACTIVATION, NAMELY LACKING AT
T-CELL DIVISION, T-CELL
PROLIFERATION.
SO WHAT DOES THAT MEAN?
THAT MEANS THAT YOUR T-CELLS AND
B CELLS ARE PRONE TO DIVIDE MUCH
MORE READILY THAN HEALTHY
CONTROLS, THAT HEALTHY CONTROLS
HAVE A CERTAIN BALANCE, BUT THAT
WITH ELEVATED ROS LEVELS OR
OTHER ASPECTS OF THIS
PHENOMENON, YOUR T-CELLS ARE
GOING TO PROLIFERATE MORE THAN
THEY SHOULD, WHICH MEANS THEY'RE
GOING TO USE MORE ENERGY THAN
THEY SHOULD, BUT THEN ALSO
YOU'RE DAMAGING THE
MITOCHONDRIA, SO YOU'RE GOING TO
BE LESS EFFICIENT AS PRODUCING
ENERGY.
SO YOU'RE REALLY HEADED TO AN
ENERGY DEFICIT.
AND THIS IS CONSISTENT WITH A
PAPER THAT WAS PUBLISHED A
LITTLE WHILE AGO LOOKING AT
INFLUENCE OF VACCINATION.
AND THEY SAW THAT THERE WAS
INCREASED CELLULAR PROLIFERATION
IN CFS PATIENTS VERSUS HEALTHY
CONTROLS.
AND THEN THE REALLY EXCITING
THING IS, CAN WE TREAT THIS?
ANOTHER ADVANTAGE OF WORKING
WITH IMMUNE CELLS IS WE'VE HAD
50, 60 YEARS OF WAYS TO
MANIPULATE IMMUNE CELLS AND TO
GET THEM TO PROLIFERATE, GET
THEM TO RESPOND, GET THEM TO DO
ALL KINDS OF TRICKS.
WHICH MEANS THAT THIS
HYPERPROLIFERATION PHENOMENON,
WE CAN TREAT THAT IN CULTURE.
AND SO VISHNU HAS.
THIS IS A BIT COMPLICATED, BUT
THE BOTTOM LINE IS THAT IF YOU
STIMULATE T-CELLS FROM A ME/CFS
PATIENT WITH NONSPECIFIC WAYS OF
STIMULATING THE T-CELL
PROLIFERATION, YOU GET A HUGE
BUNCH OF SIMULA STIMULATED T-CES
SHOWN HERE, BUT IF YOU LOWER THE
ROS LEVELS WITH N ACETYLCYSTEINE
OR METFORMIN OR LIP ROWXSTATIN,
YOU CAN GET A MUCH MORE NORMAL
DISTRIBUTION.
NOW, THIS DOESN'T SAY YOU'RE
GOING TO CURE ME/CFS WITH ANY OF
THESE DRUGS.
BUT IT PROVIDES A WAY, A TEST
TABLEHYPOTHESIS THAT MAYBE THISA
WAY TO HELP AND ALSO, MORE
GENERALLY, THIS IS A WAY TO
DISCOVER BETTER DRUGS.
THE MORE SOPHISTICATED WE CAN DO
THESE ASSAYS, THE MORE OPEN FOR
DRUG DISCOVERY.
DRUG DISCOVERY, YOU CAN DO IN
LAB DISH.
IT'S WAY FASTER AND MORE
EFFICIENT THAN DRUG DISCOVERY IN
LIVE PEOPLE.
YOU DON'T WANT TO GET TO LIVE
PEOPLE UNTIL YOU'RE PRETTY SURE
THAT YOU'RE DOING SOMETHING
USEFUL.
I THINK THIS IS -- WE'RE GETTING
BOTH A USEFUL DIAGNOSTIC ASSAY,
WHICH IS -- WHICH THERE'S BEEN A
HUGE NEED FOR AND A WAY FORWARD
IN TERMS OF DRUG TESTING AND
DRUG DISCOVERY.
I THINK IT'S VERY EXCITING.
THIS ALSO CORRELATES WITH A
RECENT PAPER THAT TREATED LONG
COVID PATIENTS WITH METFORMIN
AND FOUND THAT ALMOST HALF, 42%,
RESPONDED TO THIS TREATMENT.
SO IT'S SORT OF VERY HOPEFUL
THAT -- AND THIS IS AN
FDA-APPROVED DRUG.
IT'S ACTUALLY ALMOST A MIRACLE
DRUG.
I THINK IT PREVENTS AGING AND
MAKES YOU BREAKFAST IN BED.
I'M NOT SURE WHAT ELSE.
[LAUGHTER]
SO TO SUMMARIZE, WE SEE GREATLY
ELEVATED ROS LEVELS IN ME/CFS
WOMEN, ALSO IN LONG COVID WOMEN.
BUT NOT IN MEN.
AND I WOULD EXPECT WE'RE GOING
TO SEE THIS IN OTHER POST
INFECTION SYNDROMES.
THE MALE SEQUELAE IS MORE
COMPLEX, BUT WE CAN SEE CLEAR
EVIDENCE, I'M NOT SHOWING ALL
THE EVIDENCE, THAT OXIDATIVE
STRESS HAS BEEN THERE.
IT'S NOT THERE NOW.
IT SEEMS LIKE MALES CAN RESOLVE
THE HIGH ROS LEVELS MORE
EFFICIENTLY THAN FEMALES.
BUT THERE'S STILL SIGNS OF
MITOCHONDRIAL DAMAGE, AND ENERGY
DEFICIT.
I MENTIONED, AT LEAST FROM THE
FEMALE PATIENTS, THE T-CELLS
HYPERPROLIFERATE.
I'M NOT SURE IF THAT'S GOING TO
HAPPEN, WE DON'T HAVE ENOUGH
MALE PATIENTS THAT WE'VE STUDIED
YET, BUT WE WILL.
AND THAT WE CAN SUPPRESS THIS
WITH DRUGS LIKE METFORMIN AND
THERE'S SOME EVIDENCE THAT
METFORMIN MIGHT BE USEFUL TO AN
INTACT HUMAN BEING AS WELL.
SO AS I MENTIONED THIS IS A WAY
FORWARD TO OPTIMIZE DRUG
TREATMENTS AND DRUG DISCOVERY.
AND THEN IN THE WILD SPECULATION
DEPARTMENT, WHAT DOES THIS MEAN,
AND HOW CAN WE UNDERSTAND THIS
AT A DEEPER LEVEL?
AND WHY IS IT THAT THIS DEFECT
IN YOUR IMMUNE SYSTEM WOULD
CAUSE YOU FATIGUE?
AND NEUROLOGICAL SYMPTOMS?
AND SO THE WILD SPECULATION HERE
IS THAT IF YOUR IMMUNE SYSTEM IS
USING UP TOO MUCH ENERGY, IT
COULD ACT AS AN ENERGY SINK,
MEANING IT CAN DRAIN ENERGY THAT
YOU WOULD NORMALLY USE FOR
NEUROLOGICAL FUNCTION.
AND THIS MAKES SOME SENSE IN
TERMS OF WHAT HAPPENS WHEN YOU
HAVE A SEVERE INFECTION, ACTIVE
INFECTION, YOU FEEL LIKE CRAP.
YOU'RE NOT FEELING GOOD.
AND SOME OF THE THINGS THAT
WE'RE SEEING IN ME/CFS AND OTHER
THINGS IS JUST THAT WHAT ENERGY
YOU HAVE IS BEING DEVOTED TO
YOUR IMMUNE SYSTEM BECAUSE YOU
MIGHT DIE FROM THE INFECTION.
THAT'S THE SORT OF EMERGENCY
RESPONSE.
SO I DON'T THINK -- I MEAN, THE
QUESTION HAS COME UP AND IT'S A
GOOD QUESTION, ARE WE GOING TO
SEE -- IF WE COULD GET BRAIN
TISSUE FROM ME/CFS PATIENTS,
WOULD WE SEE HIGH ROS LEVELS OR
MITOCHONDRIAL DYSFUNCTION.
MY GUESS IS, NO, THAT IT ALL
CONNECTED, AND IF YOU'RE
DEVOTING ENERGY, AN INORDINATE
AMOUNT OF ENERGY TO YOUR IMMUNE
SYSTEM TO DO WHAT YOU THINK
YOU'RE FIGHTING OFF AN INFECTION
EVEN THOUGH THE PATHOGEN MIGHT
NOT BE THERE ANYMORE, THAT COULD
BE WHAT'S HAPPENING.
BUT WE'RE JUST THINKING ABOUT
THIS AND IT DOESN'T MEAN WE
REALLY KNOW ANYTHING.
AND THEN THE OTHER QUESTION IS,
WHY IS IT THAT SOME PEOPLE ARE
GETTING THIS SYNDROME AFTER AN
INFECTION OF LONG COVID OR
WHATEVER IS HAPPENING IN ME/CFS
OR SOME OF THESE OTHER THINGS?
WHY IS IT HAPPENING TO YOU IS
WHAT YOU PROBABLY WANT TO KNOW.
AND THERE, I THINK IT MIGHT HAVE
TO DO WITH PEOPLE'S IMMUNE
SYSTEMS HAVE VARIABLE RESPONSES
TO INFECTION.
AND THE IMMUNE SYSTEM USES UP AN
ENORMOUS NUMBER OF GENES,
THOUSANDS OF GENES, AND THESE
ARE ALL TARGETS FOR MUTATION,
AND THOSE MUTATIONS MAY NOT BE
CLINICALLY EVIDENT, EXCEPT WHEN
YOU GET SOME OF THESE DISEASES.
AND THEN IF YOUR IMMUNE SYSTEM
IS NOT VERY EFFICIENT AT GETTING
RID OF A VIRUS OR OTHER
PATHOGEN, YOU MIGHT HAVE A
PROLONGED PERIOD OF T-CELL
ACTIVATION, B CELL ACTIVATION
AND ELEVATED ROS LEVELS, AND
THEN IT BECOMES A QUESTION OF,
OKAY, ARE YOU DAMAGING YOUR
ENERGY METABOLISM IN TRYING TO
FIGHT THIS OFF.
AND ACTUALLY JUST FRIDAY, WE
HEARD A TALK WHERE THERE'S
EVIDENCE THAT SOME INDIVIDUALS
WITH LONG COVID STILL HAVE A
VERY ACTIVE T-CELL RESPONSE
AGAINST THE SARS-COV-2 VIRUS.
SO THAT'S CONSISTENT WITH THE
HYPOTHESIS THAT THESE SYNDROMES
ARE COMING ABOUT BECAUSE YOUR
IMMUNE SYSTEM IS NOT WORKING AS
WELL AS IT COULD TO CLEAR THE
VIRUS OR PATHOGEN, AND THAT PUTS
A LOT MORE STRESS AND THEN THAT
COULD LEAD TO DAMAGE TO
MITOCHONDRIA THROUGH ELEVATED
ROS LEVELS AND MAYBE OTHER
THINGS AS WELL.
SO THESE ARE SPECULATIONS AND
OUR WORKING HYPOTHESIS.
SO IT'S THINKING ABOUT HOW DO WE
GO FORWARD IN UNDERSTANDING
THIS, AND THESE ARE JUST
POSSIBILITIES WE'RE THINKING
ABOUT.
SO WITHOUT FURTHER ADO, I WANT
TO ACKNOWLEDGE ESPECIALLY
VISHNU, WHO'S JUST BEEN
INCREDIBLE IN FIGURING OUT WHAT
WERE TO DO IN THIS.
WE'VE BEEN WORKING ON CHRONIC
FATIGUE FOR SIX OR SEVEN YEARS,
AND WITHOUT REALLY ANY SUCCESS.
AND IT'S ONLY THESE IDEAS OF
VISHNU'S AND CARRYING THEM
THROUGHTHROUGH WITH THE KIND OFE
MINDEDNESS AND PASSION THAT IS
JUST FANTASTIC.
OF COURSE EASE HAD SOME HELP
FROM PEOPLE IN OUR GROUP, RON
DAVIS, HECTOR BONILLA HAS BEEN A
FANTASTIC CLINICAL COLLABORATOR,
RON DAVIS REALLY HELPED US GET
STARTED ON THIS AND HELPED FUND
SOME OF THE WORK.
WE'VE ALSO HAD INPUT FROM MIKE
SNYDER, VISHNU'S DAD SADASIVAN
SHANKAR, AND GENEROUS FUNDING
FROM BOTH THE KHOSLA FAMILY
FOUNDATION, HHMI INSTITUTE AND
NIAID.
SO I'LL STOP THERE.
THANK YOU.
[APPLAUSE]
>> THERE'S A SUBSTANTIAL ONLINE
PRESENCE SO I'M GOING TO TRY AND
GO THROUGH A FEW QUESTIONS.
[SPEAKER O OFF MIC]
[INAUDIBLE]
>> WHAT ARE PDEM?
>> POST EXERTIONAL MALAISE.
>> IN TERMS OF SURVEYS OF
FATIGUE, THERE WAS NOT A
CORRELATION.
WE LOOKED AT THAT.
BUT I THINK FATIGUE IS A TRICKY
THING IN TERMS OF IF YOU HAVE A
SUDDEN ONSET OF FATIGUE, I THINK
YOU'LL NOTICE IT, BUT IF IT'S A
SLOW, CRAWLING THING, YOU WOULD
HAVE A HARD TIME NOTICING IT.
SO WE DEFINITELY LOOKED AT THAT,
BUT WE DIDN'T SEE A CLEAR
CORRELATION.
>> ONE MORE QUESTION.
>> SURE.
>> YOU TALKED ABOUT POTENTIALLY
[INAUDIBLE] I'M WONDERING IF YOU
HAVE ANY COMMENTS ON WHETHER THE
PRODUCTION CHANGE [INAUDIBLE]
>> COULD YOU GET CLOSER TO THE
MICROPHONE?
>> YOU TALKED ABOUT AN ENERGY
SINK WITHIN THE IMMUNE SYSTEM AS
POTENTIALLY ONE WAY AROUND SOME
OF THESE -- ENERGY -- I WAS
WONDERING IF YOU HAD ANY
COMMENTS OR IF YOU LOOKED AT --
LOOKING AT GLYCOLYSIS VERSUS
PERHAPS [INAUDIBLE] PRODUCTION
INSTEAD OF SINK?
>> I THINK WE LOOKED A LITTLE AT
THAT BUT DIDN'T SEE ANYTHING
OBVIOUS, BUT OF COURSE THAT'S A
BIG DEAL IN CANCER AND HOW YOU
USE THE ENERGY.
WE HAVE LOOKED AT ATP PRODUCTION
AND THERE DEFINITELY IS A
REDUCED ATP PRODUCTION IN MOST
OF THE PATIENTS.
BUT IT HASN'T GOTTEN TO THE
SUGAR QUESTION YET, AND I DON'T
THINK SUGAR IS GOING TO BE THE
ANSWER.
THERE WAS A QUESTION OVER HERE?
>> I JUST WANTED TO SAY THAT
PEOPLE ONLINE CAN'T HEAR THE
QUESTIONS, SO IF YOU COULD
REPEAT THEM.
>> WHAT WAS IT?
SORRY?
>> PEOPLE ONLINE CAN'T HEAR THE
QUESTIONS.
>> O I HAVE TO REPEAT THE
QUESTION.
OKAY.
SURE.
YEAH, THERE WAS JUST A QUESTION
ABOUT HAVE WE LOOKED AT
GLYCOLYSIS AND BASICALLY SUGAR
AS THE MAIN FUEL FOR THE
MITOCHONDRIA TO MAKE ATP, AND
NOTHING OBVIOUS CAME OUT OF
THAT.
WE HAVEN'T LOOKED AT IT
EXTENSIVELY, BUT NOTHING OBVIOUS
WAS THERE.
>> HI, MARK.
VERY BRIEFLY, IS THIS EFFECT
SPECIFIC TO B AND T-CELLS OR
HAVE YOU LOOKED AT OTHER IMMUNE
CELLS?
>> YEAH, SO THE QUESTION IS,
HAVE WE JUST LOOKED AT T-CELLS
OR HAVE WE LOOKED AT OTHER
CELLS.
AND THE ANSWER IS WE LOOKED AT B
CELLS AND T-CELLS.
AND WE'RE SEEING THE SAME
THINGS.
WE HAVEN'T LOOKED AT SOME OF THE
OTHER WHITE BLOOD CELLS LIKE
MACROPHAGES AND SO FORTH.
BUT WE'LL DO THAT EVENTUALLY.
>> THANKS VERY MUCH.
I'D LIKE TO INTRODUCE OUR NEXT
SPEAKER, DR. DERYA UNUTMAZ FROM
JACKSON LABS.
ONE OF THE ME/CFS CENTERS FOR
COLLABORATED RESEARCH FUNDED BY
NIH.
DEDERYA?
>> OKAY.
FIRST OF ALL, THANKS VERY MUCH
FOR REMIND RE -- FOR INVITING MO
THIS REALLY WONDERFUL MEETING.
I'D LIKE TO THANK JOE AND VICKY
AND ALL NIH.
SO WHAT I'M GOING TO TRY TO DO
IS, I'M THE P.I. OF THE JACKSON
LABORATORY CHRONIC FATIGUE
SYNDROME CENTER SUPPORTED BY
NIH, AND WE'VE BEEN DOING A LOT
OF WORK IN THE LAST FIVE YEARS
AND I'M GOING TO TRY TO CONDENSE
ALL OF THAT AND MAKE SOME SENSE
OUT OF IT.
I HOPE I CAN SUCCEED.
I'M AN IMMUNOLOGIST, SO MY FOCUS
HAS BEEN IN IMMUNOLOGY BUT AS I
WILL SHOW YOU, A LOT OF THE DATA
IS NON-IMMUNOLOGICAL, BECAUSE WE
WANTED TO UNDERSTAND TWO KEY
QUESTIONS AS IT RELATES TO
IMMUNE SYSTEM AND ME/CFS.
SO WE KNOW THERE'S OVERWHELMING
EVIDENCE THAT MULTIPLE PARTS OF
THE IMMUNE SYSTEM ARE PERTURBED
IN ME/CFS, BUT WE DON'T YET
UNDERSTAND HOW AND WHY THE
IMMUNE SYSTEM IS PERTURBED
DURING THE DISEASE, AND
IMPORTANTLY, WE ASK WHETHER THIS
KNOWLEDGE CAN HELP US UNDERSTAND
ME/CFS PATHOGENESIS AND
HOPEFULLY LEAD TO SOME
ACTIONABLE TARGETS FOR THE
TREATMENT.
SO JUST A VERY BRIEF BACKGROUND
ON THE IMMUNE SYSTEM, IMMUNE
RESPONSE.
IN THE MOST SIMPLISTIC WAY, WHEN
YOU'RE EXPOSED TO AN INFECTION,
YOUR T-CELLS OR YOUR B CELLS ARE
ACTIVATED BY AN ANTIGEN
PRESENTED BY THESE CELLS CALLED
ANTIGEN PRESENTING CELLS THAT
ARE DERIVED FROM VIRUSES OR
BACTERIA, THE CELLS GET
ACTIVATED, THEY EXPAND, THEY
CREATE AN ARMY, THEY
DIFFERENTIATE, THEY PRODUCE
ANTIBODIES THAT BLOCK
NEUTRALIZING VIRUSES OR THEY
BECOME A VARIETY OF EFFECTOR
T-CELLS THAT SWORD OF COMMENDS
TO OTHER IMMUNE PARTS TO CLEAR
OFF THE INFECTION.
ONCE THE INFECTION IS GONE, MOST
OF THESE CELLS ARE ALSO GONE.
A FEW OF THEM REMAIN ALIVE AND
THEY BECOME WHAT WE CALL MEMORY
CELLS.
THAT'S ACTUALLY THE BASIS OF HOW
WE HAVE IMMUNITY AFTER
VACCINATION OR INFECTIONS.
BUT SOMETIMES THIS DOESN'T
ALWAYS WORK THIS WAY.
EITHER THE IMMUNE SYSTEM SORT OF
RESPONSE TO SELF-ANTIGENS OR
THREATS THAT ARE NOT REALLY
THREATS, OR AFTER THE INFECTION,
THE SYSTEM DOES NOT RETURN TO
ITS STEADY STATE.
AND WE THINK SOME OF NIECE OF TE
THINGS ARE HAPPENING IN ME/CFS.
OBVIOUSLY THIS IS VERY COMPLEX.
IF YOU THINK OF THE IMMUNE
SYSTEM AS AN ARMY, YOU HAVE
MANY, MANY DIFFERENT DIVISIONS.
I'VE BEEN STUDYING T CELLS FOR
THE PAST 30 YEARS.
WE'VE IDENTIFIED SOME OF THESE
TARGETS, BUT THERE ARE MANY
DIFFERENT SUBPOPULATIONS.
THERE'S A DIFFERENT LABOR OF
DIVISION WITHIN THE IMMUNE
SYSTEM.
THERE ARE CELLS SUCH AS TH17
CELLS THAT RESPOND TO BACTERIA,
FUNGI, THERE ARE OTHERS THAT
RESPOND TO PARASITES.
WE HAVE THESE T-REGS, REGULATORY
CELLS THAT ACTUALLY ARE SORT OF
LIKE BUREAUCRATS THAT TRY TO
CONTROL THE IMMUNE RESPONSES.
THEY CAN BE GOOD OR BAD.
THEY'RE GOOD TO RESOLVING
RESPONSES BUT THEY COULD BE BAD
IF THERE'S TOO MUCH BUREAUCRACY,
AS YOU KNOW, YOU DON'T GET WORK
DONE, SO THERE ARE CELLS THAT
HEP B CELLS MAKE ANTIBODIES AND
SO ON AND SO FORTH.
CELLS THAT KILL VIRAL INFECTED
CELLS, WHICH WE CALL CYTOTOXIC
CELLS, AND I'M GOING TO MENTION
ABOUT THESE POPULATIONS OF CELLS
THAT ARE SO-CALLED NON-CLASSICAL
T CELLS.
AND THEN YOU HAVE DIFFERENT
FLAVORS OF THESE SUBSETS.
WHAT THESE FLAVORS MEANS IS THAT
FUNCTIONALLY, THESE CELLS CAN
CHANGE.
THEY ARE DYNAMIC AND FLEXIBLE.
FOR EXAMPLE, CELLS THAT PRODUCE
IL-17 AT SOME POINT CAN ALSO
PRODUCE IL22.
WE EITHER CALL THEM TH22 OR T
TH22TH17.22.
THEY CAN HAVE DIFFERENT
CHEMOKINE RECEPTORS ON THEIR
SURFACE THAT USUALLY ASSOCIATES
WITH THEIR EFFECTOR FUNCTION AND
THIS IS VERY IMPORTANT BECAUSE
KEEP KINE RECEPTORS ARE LIKE ZIP
CODES, THE CELLS HAVE TO KNOW
WHERE TO GO.
BECAUSE IF YOUR CELLS ARE GOING
TO LUNG INSTEAD OF LIVER, YOU'RE
GOING TO HAVE PROBLEMS.
BECAUSE THE INFECTION IS IN THE
WRONG PLACE.
AS I SAID, THIS CAN BE BOTH
SOMEWHAT IMPRINTED DURING
DIFFERENTIATION BUT ALSO
FLEXIBLE, SO THE CELLS ON ONE
EFFECTOR POPULATION CAN BE
RECRUITED TO ANOTHER SUBSET.
OF COURSE THE REASON I'M
PRESENTING THIS IS BECAUSE THIS
COMPLEXITY REQUIRES A VERY CLOSE
COMMANDING REGULATION BECAUSE IF
ANY OF THESE THINGS GO WRONG,
THEN YOU'RE GOING TO HAVE MAJOR
PROBLEMS.
THEN YOU HAVE WHAT WE CALL
NON-CLASSICAL T CELLS BECAUSE
THEY DON'T RECOGNIZE PEPTIDES.
THEY RECOGNIZE, FOR EXAMPLE,
THESE CELLS RECOGNIZE SMALL
MOLECULES, METABOLITES FROM
VITAMIN BQ PATHWAY, FOR EXAMPLE.
THERE ARE OTHERS THAT ARE CALLED
NK T CELLS THAT RECOGNIZE
GLYCOLIPIDS.
THERE ARE CELLS WHAT WE CALL
GAMMA-DELTA CELLS THAT CAN
ACTUALLY RESPOND TO MOLECULES
INDUCED BY STRESS.
THESE THINGS ARE ACTUALLY
MOLECULES EXPRESSED BY OUR CELLS
BUT THEY ARE INDUCED BY STRESS
AND THEY COULD BE SENSED BY
THESE GAMMA-DELTA CELLS.
SO THE IMMUNE SYSTEM IS TRYING
TO SENSE ANY SORT OF STRESS, ANY
SORT OF DANGER AND THREAT THAT'S
NOT NECESSARILY HAVE TO BE A
VIRAL OR BACTERIAL OR
PATHOGEN-ASSOCIATED MOLECULE.
IT COULD JUST BE COMING FROM THE
CELLS.
THEY CAN RECOGNIZE
PHOSPHOANTIGENS THAT ARE DERIVED
FROM BACTERIA OR VIRUSES.
SO THERE'S A LOT OF, AS I SAID,
LABOR OF DIVISION, LOTS OF
DIFFERENT POPULATIONS.
SO HOW DO WE STUDY THIS IN THE
CONTEXT OF A DISEASE LIKE
ME/CFS, WHICH IS ALREADY A VERY
COMPLEX DISEASE, AND ABOUT SIX
YEARS AGO, WHEN WE INITIATED
THIS PROJECT, WE PROPOSED SORT
OF A MULTI-OMICS TOPOLOGICAL
ANALYSIS.
WHAT I MEAN BY TOPOLOGICAL?
SO IF YOU WANT TO UNDERSTAND THE
IMMUNE SYSTEM, OBVIOUSLY YOU
HAVE TO ANALYZE DOZENS OR
HUNDREDS OF DIFFERENT
POPULATIONS OF IMMUNE CELLS, BUT
THAT DOESN'T GET YOU TO THE
ANSWER WHY ARE THOSE POPULATIONS
CHANGING, WHAT'S CAUSING THAT.
SO WE HYPOTHESIZE THAT THIS MUST
BE -- HAVE TO DO SOMEHOW WITH
THE METABOLISM, BECAUSE
METABOLITES ACT ON THE IMMUNE
SYSTEM, AND AS YOU HEARD IN THE
PREVIOUS TALK, THEY REALLY
AFFECT THE ENERGETICS, NERVE
FUNCTION, EVERYTHING, AND ONE OF
THE MAIN SOURCES OF THE
METABOLITES ARE THE BACTERIA
THAT LIVE IN THE GUT, NAMELY THE
MICROBIOTA OR WE CALL IT THE
MICROBIOME.
SO THERE MUST HAVE SOME KIND OF
LINK BETWEEN THESE DIFFERENT
SPACES, AND OF COURSE YOU HAVE
TO LINK THAT TO THE CLINICAL
SYMPTOM.
IF ANYTHING WE OBSERVE DISTURBED
HAS ANYTHING TO DO WITH ME/CFS
SYMPTOMS, THAT'S ANOTHER POORN
IMPORTANT QUESTION BECAUSE THEY
COULD BE JUST BYSTANDER EFFECTS.
YOU HAVE THESE DIFFERENT STATES
THAT YOU CAN IMAGINE, AND WE
WANTED TO ANALYZE THEM WITHIN
EACH SPACE AND THEN TOAP
LOGICALLY WE WANT TO CREATE
THESE LINKS SO THAT WE CAN SEE
THE WHOLE PICTURE.
AND SORT OF A HOLISTIC APPROACH
TO UNDERSTAND WHAT'S GOING ON.
AND IMPORTANTLY, WHEN WE DESIGN
THESE STUDIES, THANKS TO CINDY
BAITMAN, SHE HAD PROPOSED THAT
WE SHOULD DIVIDE THE PATIENTS
INTO SHORT TERM AND LONG TERM
PATIENTS.
AS YOU WILL SEE, THAT TURNED OUT
TO BE A REALLY, REALLY GREAT
IDEA AND VERY IMPORTANT.
SHORT TERM, PEOPLE WHO HAD THE
DISEASE LESS THAN FOUR YEARS,
LONG TERM, PEOPLE WHO HAVE THE
TEASE MORE THAN 10 YEARS.
BECAUSE CINDY HYPOTHESIZED THAT
THERE MUST BE SOME DIFFERENCES
IN THEIR BIOLOGY, AND SHE WAS
ALSO OBSERVING DIFFERENCES IN
THEIR SYMPTOMATOLOGY, FOR
EXAMPLE.
AND LASTLY BUT NOT LEASTLY, WE
ALSO HAD A TEMPORAL SUBJECTS,
TEMPORAL MEANING THAT WE
COLLECTED THESE SUBJECTS, NAMELY
FECAL SAMPLES, PLASMA AND IMMUNE
CELLS, AT THREE DIFFERENT TIME
POINTS.
YEAR ONE, YEAR TWO AND YEAR
THREE.
BECAUSE WE WANTED TO SEE HOW
THINGS CHANGE, OR ARE THEY
CONSISTENT OVER TIME.
SO OF COURSE THIS IS LOTS OF
LOTS OF DATA, AND I'M GOING TO
TRY TO SHOW YOU SOME OF IT IN A
CONDENSED FORM.
SO AS I SAID, THE WHOLE
FRAMEWORK HERE IS THAT WE WANTED
TO LINK THE MICROBIOME, WHICH
PRODUCES PROBABLY ABOUT 20, 30%
OF THE METABOLITES IN YOUR
BLOOD, IT AFFECTS ALL YOUR
PHYSIOLOGY, AND WHETHER THESE
METABOLITES CAN IMPACT THE
IMMUNOLOGY AND, IN TURN, THIS
COULD IMPACT THE PHENOTYPE, THE
SYMPTOMS OR THE PHYSIOLOGY OR
PATHOLOGY.
SO THIS IS JUST A SAMPLE OF THE
TYPES OF TATA DATA WE USE.
WHEN WE SAMPLED THE IMMUNE CELLS
WE SAW LOTS OF DIFFERENT
DISRUPTIONS.
I'M GOING TO SHOW YOU TWO
EXAMPLES OF THIS, BUT THERE WERE
MANY ESPECIALLY EFFECTOR CELLS,
EFFECTOR T CELLS.
WHEN I SAY EFFECTOR, CELLS THAT
PRODUCE A DIFFERENT SET OF
CYTOKINES, FOR EXAMPLE.
SO NAIVE CELLS, THEY'RE
UNEDUCATED, RIGHT, SO THEY DON'T
KNOW WHAT TO BECOME.
WHEN THE CELLS BECOME EFFECTOR
AND MEMORY, THEY ACQUIRE CERTAIN
FUNCTIONS.
THOSE FUNCTIONS CAN BE VERY
USEFUL OR THEY CAN BE VERY
DANGEROUS IF IT'S NOT CONTROLLED
PROPERLY, AND IN FACT WE SAW
THOSE CHANGES HAPPENING.
BUT IMPORTANTLY, WE ALSO SAW
DIFFERENCES BETWEEN THESE TWO
PATIENT GROUPS.
THE LONG TERM AND THE SHORT TERM
PATIENTS HAD SIGNIFICANT
DIFFERENCES IN THEIR IMMUNE
PROFILING, WHICH WERE ALSO
DIFFERENT FROM HEALTHY CONTROLS,
BUT EVEN WITHIN THOSE TWO GRO
GROUPS, WHEN WE AGE-MATCH AND
SEX-MATCH, THERE WERE
SIGNIFICANT DIFFERENCES.
SO THIS WAS VERY IMPORTANT DATA.
I JUST WANT TO SHOW YOU TWO
EXAMPLES OF THIS BECAUSE THEY
ARE RELEVANT FOR THE REST OF THE
STORY THAT I'M GOING TO TELL
YOU.
ONE OF THEM IS THAT WE'VE FOUND
DESTRUCTION IN THIS POPULATION
CALLED TH17 CELLS.
THE NAME COMES FROM THE FACT
THAT THEY PRODUCE IL-17, WHICH
IS A VERY IMPORTANT CYTOKINE,
HAS LOTS OF LOTS OF FUNCTION,
AND WE FOUND THAT IN PARTICULAR,
PATIENTS WITH MORE THAN 10 YEARS
OF DISEASE HAD FUNCTIONAL
DEFECTS IN THESE TH17 CELLS, IN
OTHER WORDS, THEY PRODUCED LESS
IL-17 OR LESS INTERFERON GAMMA
AND LESS IL-17 TOGETHER, AND WE
THOUGHT THAT THIS WAS VERY
EXCITING BECAUSE WE WERE
ACTUALLY WORKING ON THESE
POPULATIONS FOR MANY YEARS, AND
WE KNEW THAT TH17 CELLS WERE
LINKED TO TWO IMPORTANT
PHENOMENA.
ONE IS THAT THEY WERE LINKED TO
AUTOIMMUNITY.
A LOT OF AUTOIMMUNE DISEASES ARE
ASSOCIATED WITH TH17 CELLS, SO
THEY CAN BE BAD MOSTLY.
THE SECOND IS THAT THEY WERE
ALSO LINKED TO THE MICROBIOME.
THE BACTERIA THAT LIVE IN YOUR
GUT MOSTLY BUT ALSO IN YOUR
SKIN.
SO THERE WAS A VERY INTIMATE
RELATIONSHIP BETWEEN THE
MICROBIOTA WHICH PRODUCED
METABOLITES THAT ACTUALLY SHAPED
TH17 CELLS, WHICH, IN TURN,
COULD BE RESPONSIBLE FOR
AUTOIMMUNE DISEASES OR SOME
CHRONIC DISEASES.
OBVIOUSLY THEY HAVE ALSO SOME
VERY IMPORTANT FUNCTIONS IN
DEFENDING US AGAINST FUNGAL OR
BACTERIAL DISEASES.
THE SECOND POPULATION THAT WE
THOUGHT WAS VERY INTERESTING
THAT WE FOUND DIFFERENT IS CAL
CALLED -- I SHOWED YOU THESE
CELLS ARE SO-CALLED
NON-CLASSICAL CELLS.
THEY RECOGNIZE BACTERIAL
METABOLITES, SO BACTERIAL
METABOLITES DERIVED FROM THIS
PATHWAY WHICH TURNS OUT TO BE
PRODUCED BY THE BACTERIA, THE
VITAMIN B2 IN YOUR GUT, AND THE
METABOLITES FROM THE PATHWAY CAN
ALSO ASSOCIATE WITH THIS
MOLECULE CALLED MR1, WHICH THEN
ACTIVATES THESE T CELLS JUST
LIKE OTHER T CELLS.
THAT'S WHY WE CALLED THEM
ESPECIALLY -- THEY ALSO HAVE
THEM IN T-CELL RECEPTOR.
THESE CAN ALSO BE POTENT
PRODUCERS OF INFLAMMATORY
CYTOKINES.
SUCH AS INTERFERON GAMMA, SOME
OF THEM EXPRESSED IL-17 AND SOME
EXPRESS GZA, A MEDIATOR WHICH
CAN ACTUALLY KILL BACTERIA
INFECTED CELLS AND SO ON.
SO WHAT WE FOUND IS THAT THE
OPPOSITE OF WHAT I JUST SHOWED
YOU, IN THE SHORT TERM PATIENT,
FUNCTIONALLY THESE CELLS WERE
ALSO DISRUPTED.
SO THE GZA CAPACITY WAS
PERTURBED, EITHER DECREASED OR
INCREASED IN THE PATIENTS THAT
HAD THE DISEASE LESS THAN FOUR
YEARS, BUT NOT MORE THAN 10
YEARS.
SO AGAIN, THESE CELLS ARE ALSO
LINKED TO THE MICROBIOME.
WE THINK THEY'RE SORT OF THE
GUARDIANS OF THE ECOSYSTEM.
WE'VE DONE SOME STUDIES ON THAT,
THEY CAN DISCRIMINATE BETWEEN
DIFFERENT BACTERIA SPECIES,
BASED ON THE METABOLITES THEY
PRODUCE, AND SO ON AND SO FORTH,
SO WE THINK THAT THEY PLAY A
VERY IMPORTANT ROLE IN SENSING
THIS DIVERSITY OR HETEROGENEITY
OF THE MICROBIOME AND THEY SEEM
TO BE REALLY AFFECTED ESPECIALLY
IN THE SHORT TERM PATIENTS.
JUST KEEP THAT IN MIND.
SO THAT IS A SEGUE TO THE NEXT
SPACE, WHICH IS THE MICROBIOME.
AS I SAID, THERE'S TRILLIONS OF
BACTERIA THAT LIVE IN YOUR GUT,
AND THESE ARE REALLY, REALLY
IMPORTANT IN OUR BIOLOGY AND
PHYSIOLOGY, BUT IF THEY ARE
PERTURBED OR WHAT WE CALL
DYSBIOSIS HAPPENS, THEIR
PROPORTIONS CHANGE, THEIR
DIVERSITY GETS SMALLER, THERE'S
THOUSANDS OF DIFFERENT STRAINS,
THEN YOU GET ALL KINDS OF
PROBLEMS, CHRONIC DISEASES,
ACCELERATES AGING, IT EVEN
IMPACTS THE DRUGS WE TAKE DURING
CANCER LIKE IMMUNOTHERAPY DRUGS,
AND THIS COULD HAPPEN BY A
VARIETY OF REASONS.
YOUR DIET, USE OF TOO MUCH
ANTIBIOTIC, PATHOGEN INVASION,
SO ON AND SO FORTH, SO THEY PLAY
A REALLY MAJOR ROLE, AND THEY
ARE TIGHTLY LINKED TO THIS
IMMUNE PATHWAYS OR IMMUNE
ACTIVATION BECAUSE OBVIOUSLY THE
IMMUNE SYSTEM ALSO HAS TO KEEP
THEM IN THE LUMEN OF THE
INTESTINE, BUT AT THE SAME TIME,
THOSE BACTERIA PRODUCE A LOT OF
PRODUCTS THAT HELP THE IMMUNE
SYSTEM TO RESPOND TO THE
PATHOGENIC BACK TIER Y BACTERIA.
ONE PROBLEM IS THAT JUST LIKE
THE IMMUNE SYSTEM, THE
MICROBIOME IS ALSO PERSONALIZED.
SO EVERYONE IN THIS ROOM HAS
SOMEWHAT DIFFERENT MICROBIOTA
BECAUSE YOU HAVE DIFFERENT
STRAINS.
HOWEVER, THE BIGGER SORT OF WHAT
WE CALL PHYLA, THE BIGGER GROUPS
CAN BE QUITE SIMILAR, LIKE THE
RATIORAISH CARATIO CAN BE SIMILU
MIGHT HAVE DIFFERENT SUBSTRAINS
UNDERNEATH THAT.
SO TO GET AROUND THAT PROBLEM,
JULIO AT JACKSON LAB DESIGNED
THIS PROJECT WHERE WE, AGAIN,
TOOK FECAL SAMPLES THIS TIME
FROM EARLY, LATE ME/CFS
PATIENTS, AS WELL AS HEALTHY
CONTROLS, AND THEN WE SEQUENCED
ALL THESE BACTERIA IN THEIR
FECAL SAMPLES, WHICH KIND OF
REFLECTS WHAT'S IN THEIR GUT AND
PERFORMED A REALLY MASSIVE
ANALYSIS ON THAT.
THIS DATA WAS PUBLISHED
RECENTLY, WHICH I THINK IS
REALLY A FANTASTIC PAPER.
IT WAS BACK TO BACK WITH LIEN WN
LIPKIN'S GROUP WHICH CLEARLY
SHOWS THERE IS A MAJOR PROBLEM
IN THE MICROBIOME.
HOWEVER, GOING BACK TO OUR
PATIENT COHORTS, NOW WE REALIZED
THE WISDOM OF CINDY BAITMAN THAT
WE FOUND THAT THE MICROBIAL
DYSBIOSIS WAS HAPPENING MOSTLY
IN THE SHORT TERM ME/CFS
PATIENTS.
THIS WAS RATHER SURPRISING TO US
BECAUSE THE LONG TERM PATIENTS
CAN HAVE MORE SIGNIFICANT
SYMPTOMS AS WELL, AND THE GUT
MICROBIOME ON LONG TERM PATIENTS
WERE MORE SIMILAR TO CONTROLS
BUT THEY WERE NOT LIKE THE
HEALTHY CONTROLS BECAUSE THEY
ALSO HAD LOW ABUNDANCE OF
SPECIES AND DIFFERENCES IN THEIR
HETEROGENEITY.
HOWEVER, THEY WERE SORT OF NOT
AS BAD AS THE SHORT TERM ME/CFS
PATIENT MICROBIOME.
SO WHAT MIGHT BE GOING ON HERE?
AND SO I'M JUST GOING TO READ
THESE BECAUSE I THINK THESE ARE
VERY INTERESTING CONCLUSIONS
FROM THIS STUDY.
SO THE ABNORMALITIES IN SHORT
TERM COHORT COULD RESULT IN
POTENTIAL INCREASES IN ABERRANT
TRANSLOCATION OF MICROBIAL
METABOLITES THAT COULD AFFECT
HOST IMMUNE AND METABOLIC
PROCESSES.
IF THE IMMUNE ECOSYSTEM IS
PERTURBED, THAT COULD AFFECT
IMMUNE AND METABOLIC.
BUT WITHIN EXAMPLE IS THESE
SHORT CHAIN FATTY ACIDS SUCH AS
BUTYRATE AND TRYPTOPHAN
PRODUCERS.
IN SOME WAYS THE LONG TERM
PATIENT, THE DAMAGE HAS BEEN
DONE, SO THE PROGRESSION MAY
BEGIN WITH A LOSS OF BENEFICIAL
MICROBES, PARTICULARLY THESE
SHORT CHAIN FAT FATTY ACID PRODS
RESULTING IN MORE PERVASIVE GI
PHENOTYPES LATER REFLECTED IN
PLASMA METABOLITE LEVELS, THIS
IN TURN MAY LEAD TO MORE
ESTABLISHED METABOLIC AND
PHENOTYPIC CHANGES IN LONG TERM
ME/CFS PATIENTS.
THE DAMAGE HAS BEEN DONE, THE
DAMAGE HAS BEEN DONE THROUGH THE
METABOLISM, METABOLIC SYSTEM AND
THE I MEUP SYSTEM.
IMMUNE SYSTEM.
SO IS THAT THE CASE?
THAT COMES TO THE NEXT SPACE.
AND THE NEXT SPACE IS THE
METABOLISM.
THIS IS ACTUALLY A VERY BIG
SPACE.
THERE ARE THOUSANDS OF
METABOLITES THAT MOST OF THEM
ARE NOT EVEN IDENTIFIED YET.
I JUST MENTIONED SHORT CHAIN
FATTY ACIDS, THERE ARE ALL KINDS
OF METABOLITES THAT COME FROM
THE DIET THAT, COME FROM THE
BACTERIA, BUT ALSO PRODUCED BY
YOUR CELLS THAT ARE HAVING
DIFFERENT TYPES OF EFFECTS, FROM
BILE ACIDS TO LIPIDS, SUGARS AND
SO ON AND SO FORTH.
SO TO GET AROUND THAT PROBLEM IN
THIS FINAL SPACE, WE TOOK SORT
OF A SIMILAR APPROACH WHERE WE
TOOK THE PLASMA OF THE PATIENT
SAMPLES, THE SAME PATIENTS THAT
WE HAVE DONE THE IMMUNE
PROFILING WHERE WE HAD HUNDREDS
OF IMMUNE PROFILE DATA, WHERE WE
HAD THOUSANDS OF MICROBIAL
SPECIES IDENTIFIED, AND WE TRIED
TO IDENTIFY AS MANY METABOLITES
AS WE CAN.
WE DID THAT THROUGH A COMPANY
TALLED METABOLOME, WE THIS HAD
THOUSANDS OF METABOLITES THEY
COULD IDENTIFY.
THE REAL NUMBER IS PROBABLY MUCH
HIGHER THAN THAT, BUT THOSE WE
CAN SAY IN A REPRODUCIBLE
FASHION WE CAN IDENTIFY THEM AND
WE'VE PERFORMED THESE
METABOLOMICS ON ALL OF THESE
PATIENTS, SHORT TERM AND LONG
TERM.
AND AGAIN, WE FOUND LOTS OF
DIFFERENCES BETWEEN PATIENTS.
AND HEALTHY CONTROLS.
I'M JUST SHOWING YOU A VERY
SMALL EXAMPLE HERE.
I'LL SHOW YOU MORE DATA ON IT.
BUT AGAIN IMPORTANTLY, WE FOUND
DIFFERENCES BETWEEN THE SHORT
TERM AND THE LONG TERM PATIENTS.
SHORT TERM IN BLUE AND LONG TERM
IN RED.
YOU CAN SORT OF APPRECIATE THAT
THERE IS A BIGGER DIFFERENCE
BETWEEN THE LONG TERM PATIENTS
AND HEALTHY CONTROLS THAN THE
SHORT TERM AND THE HEALTHY
CONTROLS.
ALTHOUGH THERE WERE DIFFERENCES
IN BOTH GROUPS COMPARED TO THE
HEALTHY CONTROL.
OF COURSE THERE'S LIKE A
THOUSAND OF THESE, RIGHT?
SEVERAL HUNDRED OF THEM CAN BE
DIFFERENT FROM PATIENT TO
PATIENT, SO IT'S VERY DIFFICULT
TO LOOK AT THESE GRAPHS AND SAY
WHAT'S GOING ON.
YOU REALLY NEED TO SEE THE WHOLE
PICTURE, AND SORT OF THIS HEAT
MAP HELPS A BIT.
AGAIN, EACH OF THESE ARE
DIFFERENT METABOLITES.
YOU HAVE PATIENTS LESS THAN
4 YEARS, MORE THAN 10 YEARS, AND
HEALTHY CONTROLS.
YOU COULD SORT OF GET A FEEL
THAT IF YOU LOOK AT, FOR
EXAMPLE, XENOBIOTICS, THE
BACTERIA COMING FROM THE OUTSIDE
ARE MORE DIFFERENT IN THE LESS
THAN 4 YEAR GROUP THAN COMPARED
TO THE MORE THAN 10 YEAR GROUP,
BECAUSE THE MORE THAN 10 YEAR
GROUP SOMEWHAT LOOKS SIMILAR TO
THE HEALTHY CONTROL.
BUT THESE LOOK VERY DIFFERENT.
SO RED BECOMES BLUE, BLUE
BECOMES RED HERE.
IN THAT SORT OF DISEASE SCORE.
WHEREAS THE LIPIDS, IT'S THE
OTHER WAY AROUND, THAT YOU SEE
THAT THERE'S A BUNCH OF LIPIDS
THAT ARE SORT OF MORE DIFFERENT
IN MORE THAN 10 YEARS AND LESS
THAN 4 YEARS.
IN FACT, IN JULIO' O'S PAPER WE
HAD A HINT OF THAT.
WHEN YOU LOOK AT SEVERAL LIPIDS,
THERE WERE MORE DIFFERENTIAL
COUNTS OF LIPIDS IN THE LONG
TERM PATIENTS THAN THE SHORT
TERM PATIENTS, WHICH KIND OF
SUPPORTED THE HYPOTHESIS WE HAD
MADE IN THAT PAPER, THAT
SOMETHING IS GOING DIFFERENTLY.
BOTH PATIENT GROUPS ARE
DISRUPTED FOR THESE METABOLITES,
BUT THERE ARE MAJOR DIFFERENCES
BETWEEN THE SHORT TERM AND THE
LONG TERM PATIENTS.
SO THE NEXT QUESTION WAS, HOW DO
WE NOW START TO LINK THIS
TOGETHER?
SO YOU HAVE DIFFERENCES IN THE
IMMUNE SYSTEM, IN THE
METABOLISM.
HOW DO WE BRING THOSE TWO SPACES
TOGETHER?
SO WE STARTED TO DO THAT AND
THEY'VE DONE REALLY PHENOMENAL
WORK ON THIS.
WE'RE JUST PREPARING A PAPER TO
SUBMIT, THAT HE WAS ABLE TO LINK
A VARIETY OF IMMUNE SUBSETS TO
DIFFERENT METABOLITES THAT ARE
FOUND IN THE BLOOD.
OBVIOUSLY THIS IS A VERY
COMPUTATIONALLY RICH AND INTENSE
ANALYSIS, AND HE WAS ABLE TO
COME UP WITH MANY DIFFERENT
SUBPOPULATIONS, EACH OF WHICH
LINK TO DIFFERENT METABOLITES IN
THE SAME PATIENTS' BLOOD.
WHAT WAS INTERESTING IS THAT IN
HEALTHY CONTROLS, THERE WAS MUCH
FEWER ASSOCIATION, SO THERE
SEEMS TO BE MUCH GREATER
ASSOCIATION BETWEEN METABOLIC
PER TURBANS AND IMMUNE CELL
FREQUENCIES OR FUNCTIONALITY IN
THE PATIENT POPULATION.
SO THAT WAS VERY SATISFYING.
WE THINK THIS IS PROBABLY ONE OF
THE FIRST SUCH DATASETS EVER TO
BE GRADED AT LEAST AT THIS SCALE
BECAUSE IT ALSO GIVES YOU WAYS
TO HYPOTHESIZE OR IDENTIFY SOME
NEW PATHWAYS, HOW ONE METABOLITE
MIGHT LINK TO A PARTICULAR
POPULATION AND WHAT THAT MIGHT
MEAN AS ACTIONABLE TARGETS,
WHICH I WILL COME AT THE VERY
END.
OKAY.
SO THIS IS ALL GREAT BUT NOW WE
WANTED TO LINK EVERYTHING.
SO WE WANT ALL THESE DIFFERENT
SPACES, THE SYMPTOMS,
METABOLISM, MICROBIOME, IMMUNE
SPACES, ALL TOPICOLOGICALLY
LINKED TOGETHER.
SO OBVIOUSLY A HUMAN MIND CANNOT
POSSIBLY DO THAT SO WE TURNED TO
A.I.
WE ARE FORTUNATE IN THE RECENT
YEARS, THERE'S BEEN TREMENDOUS
ADVANCE ESPECIALLY IN THE DEEP
LEARNING, SO AGAIN, JULIO AT
JAX, SHE APPLIED THIS A.I.
ANALYSIS.
AGAIN, A PAPER THAT'S IN
PREPARATION.
WHERE IN A VERY SIMILAR PUSH TO
DEEP LEARNING WITH NEURAL
NETWORKS, WE UPLOADED THESE
DIFFERENT IMMUNE DATASETS, SOME
OF WHICH WAS ALREADY IN THE
DATABASES, BUT MOST OF IT IS OUR
DATA BECAUSE WE USE THE PREVIOUS
DATA TO SORT OF VALIDATE WHAT
WE'RE FINDING OR TRAIN THE SETS
AS THEY WOULD CALL IN THE A.I.
FIELD AND SEE WHAT WOULD COME
UP.
SO I'M REALLY VERY EXCITED ABOUT
THIS BECAUSE THIS REALLY SORT OF
WAS OUR DREAM WHEN WE STARTED
THIS PROJECT SIX YEARS AGO, THAT
WE WILL BE ABLE TO SOMEHOW BRING
TOGETHER THIS MASSIVE DATASETS
TOGETHER AND LINK THEM AT
DIFFERENT SPACES, BUT WE DIDN'T
KNOW HOW WE'D BE ABLE TO DO IT,
YOU KNOW, LOOKING FORWARD TO
FIVE YEARS OR SIX YEARS IN
ADVANCE.
BUT THE A.I.-DRIVEN APPROACH
REALLY ENABLES THIS BECAUSE IT
ALLOWS YOU, VERY ROBUST
ASSOCIATIONS, DEEP INTEGRATIONS,
AND ALLOWS YOU TO MAKE
HYPOTHESES, WHICH I THINK IS
VERY, VERY IMPORTANT, AND ALSO
OBVIOUSLY PREDICT DISEASE
BIOMARKERS, CLINICAL PHENOTYPES,
BECAUSE THE MORE RICH TH THE DAA
IS FROM DIFFERENT SPACES, THE
BETTER YOUR BIOMARKERS ARE GOING
TO BE, AND REALLY, MAYBE THE
MOST IMPORTANT IS THIS LAST
POINT, ADDRESS THE HETEROGENEITY
OF THIS SUCH COMPLEX DISEASE.
OBVIOUSLY NOT EVERY ME/CFS
PATIENTS HAVE THE SAME PROBLEM.
THEY HAVE DIFFERENT PROBLEMS.
IT MIGHT BE DUE TO THE AGE.
I JUST SHOWED YOU LESS THAN FOUR
YEARS, MORE THAN 10 YEARS
ALREADY HAVE HUGE DIFFERENCES
BETWEEN THEM, EVEN WITHIN THOSE
GROUPS, THERE ARE OBVIOUSLY
MANY, MANY DIFFERENCES.
SO THIS MIGHT BE THE MOST
EXCITING SLIDE.
SO WE WERE ABLE TO DO THIS DEEP
ME/CFS AND REALLY LINK THE
MICROBIOME, THE METABALOME AND
THE IMMUNE CELLS ACROSS THESE
SPACES.
I WON'T GO INTO DETAILS, THE
PAPER IS IN PREPARATION, BUT WE
COULD DO THAT, WE CAN CREATE
THESE SIGNATURES OF TOPOLOGICAL
ANALYSIS FOSH ME/ FOR ME/CFS VES
HEALTHY DONORS.
NOT EVEN THAT, WE CAN ACTUALLY
GO EVEN DEEPER, WE CAN LOOK AT
THE MALE PATIENTS, THE ELDERLY,
THOSE WHO HAD INFECTION, THOSE
WHO HAD LONG COVID OR PART OF
LONG DISEASE OR SHORT DISEASE,
WE ALSO HAVE LONG COVID AS WELL,
FEMALE, SO ON AND SO FORTH.
AND THEN YOU CAN EVEN GO
EVENTUALLY AT THIS SINGLE-PERSON
INDIVIDUAL LEVEL, WHICH WOULD BE
SORT OF THE HOLY GRAIL OF
PERSONALIZED PRECISION MEDICINE,
I GUESS.
SO FINALLY, I JUST WANT TO SHOW
YOU ONE VERY IMPORTANT SLIDE,
WHERE USING THIS DEEP ME/CFS
ANALYSIS, WE WERE ABLE TO
IDENTIFY OR CONFIRM -- REMEMBER
I MENTIONED TO YOU ABOUT THIS
BUTYRATE AND TRYPTOPHAN BEING
DISRUPTED IN THE MICROBIOME
PATHWAY, BUT THIS TIME WE
ACTUALLY BROUGHT ALL THE DATA
TOGETHER, AND WE WERE ABLE TO
LINK DIFFERENT SUBPOPULATIONS OF
IMMUNE CELLS, DIFFERENT
METABOLITES, MICROBIOME, SHORT,
LONG TERM, AND ACTUALLY CONFIRM
THAT THE BUTYRATE AND TRYPTOPHAN
WERE RELEVANT TARGETS.
IT WAS NOT JUST A BYSTANDER
EFFECT OR RANDOM EFFECT, THAT
THERE WAS A MECHANISTIC LINK
BETWEEN THESE POPULATIONS.
AND IN FACT, WE KNEW THAT
BUTYRATE AND TRYPTOPHAN AFFECTS
THE IMMUNE SYSTEM TREMENDOUSLY,
THESE TH17 CELLS THAT I SHOWED
YOU, BUT FOR THE FIRST TIME, WE
WERE ABLE TO SEE THAT BY
BRINGING ALL THIS DATA TOGETHER,
OBVIOUSLY THIS IS KIND OF A GOLD
MINE WHERE WE COULD HOPEFULLY
IDENTIFY OTHER ACTIONABLE
TARGETS THAT COULD BE IMPORTANT
FOR THERAPEUTICS.
SO I'M GOING TO STOP THERE AND
REALLY CITE ALL THE PEOPLE WHO
DID THE WORK.
MY TEAM AT JAX, WE WERE
RESPONSIBLE FOR THE IMMUNE
SYSTEM.
WE COULDN'T DO ANY OF THIS
WITHOUT THE CLINICAL TEAM.
CINDY BAITMAN AND SUZANNE
VERNON, WHO PROVIDED ALL OF THE
SAMPLES AND THE QUALITY OF THE
SAMPLES WAS SO IMPORTANT BECAUSE
THEY HAD TO BE REALLY WELL
DIAGNOSED AND I THINK THAT MADE
THE QUALITY OF THE DATA
TREMENDOUSLY BETTER.
WE REALLY ARE GRATEFUL TO THEM.
JULIA OH, WHO'S A STAR IN THE
MICROBIOME FIELD, DID ALL THE
MICROBIOME WORK AND A.I. WORK.
SHUZHAO LI DID ALL THE
METABOLOMICS.
XUDO -- IDENTIFICATION OF THE
MICROBIOME FROM THE PATIENTS.
OF COURSE I WANT TO ACKNOWLEDGE
ALL OUR FUNDING SOURCE, NIH,
NINDS AND NIAID.
THANK YOU.
[APPLAUSE]
>> HELLO. I HAD A COMMENT TO
MAKE.
>> I CAN BARELY HEAR YOU.
>> WITH ADEQUATE EFFORT, ONE
CAN -- DAMAGING VIRUSES FROM
CHRONIC FATIGUE SYNDROME
PATIENTS.
WE'VE DONE THAT, AND THE BEST
CHARACTERIZED VIRUS HAS THE
INTERESTING ASPECT THAT --
>> I STILL CAN'T HEAR YOU.
CAN YOU GET CLOSER TO THE
MICROPHONE?
SORRY.
>> I'LL SPEAK AS LOUD AS I CAN.
SO WHAT WE'VE GOT IS DNA
SEQUENCED DATA OF A VIRUS
REPEATEDLY CULTURED FROM A
CHRONIC FATIGUE SYNDROME PATI
PATIENT.
WE'VE CLONED THAT, AND OF 249
CLONES, WHAT'S FASCINATING, 34
OF THE CLONES HAVE BACTERIAL
SEQUENCES.
THE BACTERIAL SEQUENCES ARE NOT
REPRESENTED IN ORDINARY
BACTERIAS, EXCEPT FOR MYCOPLASMA
FER MEN TINS THAT HAD BEEN
LINKED AS A POSSIBLE CO-FACTOR.
BUT THE OTHER ONES ARE ALSO
BASICALLY ALPHA PROTEOBACTERIA
WITH NUCLEOTIDE PLASMID, THERE'S
STILL NO DIRECT MATCHING ON GEN
BANK, BUT WHAT THIS IMPLIES
IMPORTANTLY, THE ATYPICAL
VIRUSES THAT INFECT CHRONIC
FATIGUE SYNDROME PATIENTS, WHICH
I REFER TO AS STEALTH ADAPTED
VIRUSES, BECAUSE IN THE
SEQUENCING, THEY'VE LOST OR
MUTATED THE GENES, COATI CODINGR
THE RELATIVELY FEW TARGETS, THE
IMMUNE SYSTEM IS TAKEN AWAY FROM
THE EQUATION, AT LEAST THE
CELLULAR IMMUNE SYSTEM.
WHERE THE VIRUS REGAINS ITS
INFECTIVITY IS PICKING UP
ADDITIONAL SEQUENCES.
THEY CAN PICK THEM UP FROM THE
CELLULAR GENOME OR THEY CAN PICK
THEM UP FROM OTHER MICROBES.
THE FACT THAT THEY CAN PICK THEM
UP FROM BACTERIAL SPECIES
IMPLIES THAT THESE VIRUSES CAN
ACTUALLY INFECT THE BACTERIA.
AND WE KNOW THAT IF VIRUSES
BECOME SIMPLE ENOUGH, THEY
BECOME LIKE PLASMIDS AND THEY
CAN INFECT BACTERIA.
SO THE ALTERED MICROBIOME YOU'RE
IDENTIFYING IN THESE PATIENTS
COULD BE A RESULT OF VIRUS
INFECTION INTO THE BACTERIA.
WHAT THIS IS HUGELY IMPORTANT
FOR, EVEN THOUGH THE BACTERIA
WERE IDENTIFIED, PROTEOBACTERIA
AND OTHER UNUSUAL BACTERIA, WHEN
YOU HAVE ILLNESSES LIKE CHRONIC
LYME DISEASE, IT'S PERFECTLY
CONSISTENT WB THE FACT THAT THEY
HAVE THESE STEALTH-ADAPTED
VIRUSES BUT IN A CELL THAT HAS
BARILLIA INVOLVED IN THE SAME
CELL, THE VIRUS CAN ACQUIRE SOME
BARILLIA VIRUS.
PEOPLE ARE IDENTIFYING
STREPTOCOCCAL TYPE GENES --
>> DO YOU HAVE A QUESTION
BECAUSE I THINK --
>> NO, THE QUESTION WAS
BASICALLY, I GUESS -- THE
COMMENT, PLEASE CONSIDER THE
FACT THAT THE ALTERED MICROBIOME
IS A SECONDARY EFFECT OF STEALTH
ADAPTED VIRUS INFECTION, AND
PLEASE CONSIDER THAT IN TERMS OF
NOT YOUR OWN WORK BUT THE OTHER
PEOPLE'S WORK IN TERMS OF THE
TRANSMISSION OF THESE ATYPICAL
VIRUSES BECAUSE IF THEY ARE
INFECTING BACTERIA, THAT POSES A
TOTALLY NEW UNDERSTANDING OF HOW
THE DISEASE COULD BE TRANSMI
TRANSMITTED.
THANK YOU FOR YOUR TALK.
>> I APPRECIATE THAT.
I MEAN, THERE'S OBVIOUSLY A
WHOLE UNIVERSE OF PHAGES THAT
INFECT THESE BACTERIA AND WE
DON'T KNOW MUCH ABOUT THEM, BUT
I'M NOT THE VIRUS EXPERT AND
MAYBE THE NEXT SPEAKER CAN
RESPOND TO THAT.
THANK YOU.
>> SO I THINK IF WERE YOU A COME
POSER, I WOULD CALL THAT AN
OPUS.
WHAT GREAT WORK, FAN TAS FICK
WORK.
CONGRATULATIONS.
I'M GOING TO HAVE TO BE NARROW
BECAUSE THERE WAS SO MUCH TO
ADDRESS THERE AND I HAVE NO MANY
QUESTIONS, BUT THERE'S BEEN SOME
WORK IN SONIA MARSHAL'S GROUP,
OUR GROUP REALLY, REALLY EARLY
THAT SUGGESTED THAT TO USE THE
MARKER -- USE THE INTRACELLULAR
GZA CONTENT, NOT ALL THE
BEAUTIFUL WORK SINCE THEN THAT
HAD SINGLE CELL GENOMICS, BUT
RATHER USING THE ACTUAL CONTENT
OF FLOW CYTOMETRY TO PREDICT THE
FUNCTION OF THE CYTOTOXIC T-CELL
AS WELL AS THE NK CELL, SOME
WORK SAYS THEY'RE BOTH BROKEN
AND IT'S NOT JUST NK CELLS, VERY
IMPORTANT I THINK OBSERVATION TO
UNDERSTAND SOME OF THE VIRAL
THINGS CONSIDERING AS WELL AS
OTHERS.
SO I'M WONDERING IN YOUR WORK,
THE WAY YOU APPROACHED IT, WILL
YOU BE ABLE TO TELL US WHETHER
OR NOT THERE WAS A QUANTITATIVE
DIFFERENCE IN PREFERENCING
GRANZYMES, AND WHAT YOU THINK IS
GOING ON THERE.
WE WERE THINKING IT WAS
EXHAUSTION, USING IT UP, NOT
NECESSARILY THAT YOU WEREN'T
MAKING IT.
BUT THAT'S HYPOTHESIS.
>> DEFINITELY.
IN FACT, GRANZYME A ESPECIALLY
BUT ALSO B WERE SOME OF THE
MAJOR DIFFERENCES THAT WE FOUND,
BOTH IN MAI T CELLS THAT I
SHOWED BUT ALSO IN CYTOTOXIC T
CELLS.
SO IF YOU LOOK AT GRANZYME A
EXPRESSING CD8s, YOU DON'T SEE
A DIFFERENCE IN THE TOTAL
CYTOTOXIC T CELLS, BUT
FUNCTIONALLY THOSE WERE
DIFFERENT.
SO YOUR POINT IS WELL TAKEN.
THERE'S SOMETHING GOING ON WITH
THE GRANZYME.
THOSE ARE INVOLVED IN BACTERIAL
DEFENSE AS WELL AND THEY HAVE
OTHER FUNCTIONS IN THE
CYTOTOXICITY AS WELL SO IT'S A
VERY INTERESTING LINK.
THERE'S PROBABLY BURIED DATA
HERE, WE MIGHT BE ABLE TO MAKE
SOME LINKS TO THE METABOLISM AS
WELL.
>> I THINK I'M GOING TO HAVE TO
STOP THERE.
>> THANK YOU.
APOLOGIZE IN ADVANCE THAT WE
CAN'T ADDRESS ALL THE QUESTIONS,
BUT WE ARE HEADED TO A BREAK.
WE ARE GOING TO CATCH UP A
LITTLE BIT, WE'RE GOING TO GIVE
15 MINUTES FOR OUR BREAK, SO
PLEASE COME BACK AT 11:05.
AND I WANT TO MAKE SURE THAT YOU
KNOW THAT IN POSTERS FROM THE
YOUNG INVESTIGATOR IN ME/CFS,
THE SPARK MEETING CAN BE VIEWED
AT THE BREAKS AND CERTAINLY AT
THE LUNCH, WHICH IS WHERE LUNCH
WILL ALSO BE, WHICH IS PROVIDED
BY THE OPEN MEDICINE FOUNDATION
FOR NETWORKING PURPOSES.
IF YOU GO OUT THESE DOORS, TURN
RIGHT AT THE COFFEE SHOP, THAT'S
WHERE THE TERRACE IS.
I SHOULD NOTE THAT'S ALSO WHERE
THE QUIET ROOMS ARE.
THERE ARE TWO QUIET ROOMS THERE
IF ANYBODY NEEDS A QUIET SPACE.
THANK YOU.
I'LL SEE YOU AT 11:05.
GOOD MORNING AGAIN.
WE'RE GOING TO GET STARTED WITH
OUR NEXT SESSION.
WHICH IS CALLED THE VIROLOGY OF
ME/CFS AND LONG COVID.
ONE OF THOSE WE THINK WE KNOW
THE VIRUS, THE OTHER, WE'RE
STILL LACKING.
LOOKING.
YOU'RE GOING TO HEAR ABOUT SOME
OF THAT IN THIS SESSION.
AND ACTUALLY IN OTHER TALKS
DURING THIS.
AS SIMILAR TO THE LAST SESSION,
WE'RE GOING TO START WITH A
LIVED EXPERIENCE PERSPECTIVE AND
WE'RE REALLY FORTUNATE TO HAVE
WITH US TODAY ASHANTI DANIEL,
WHO'S GOING TO TELL US HER
PERSPECTIVE, TO HELP FRAME OUR
SCIENTIFIC SESSION.
ASHANTI?
>> ALL RIGHTY.
GOOD MORNING.
AS JOE STATED, I'M ASHANTI
DANIEL, A DISABLED REGISTERED
NURSE AND PERSON WITH POST VIRAL
MYALGIC ENCEPHALOMYELITIS, AKA
ME/CFS, OR JUST M.E., WHICH I
PREFER.
PLUS, POTS, AUTOIMMUNE AUTONOMIC
NEUROPATHY AND MAST CELL
ACTIVATION SYNDROME.
I'M ALSO A SINGLE MOTHER OF TWO,
A FORMER FITNESS ENTHUSIAST AND
IN CASE YOU HADN'T NOTICED, A
BLACK WOMAN.
YOU MAY BE WONDERING WHY I
POINTED OUT MY RACE.
STAY TUNED AND YOU'LL FIND OUT.
BUT FIRST, LET ME START BY
TAKING YOU BACK TO AUGUST 2016.
I WAS LIVING MY BEST LIFE,
WORKING IN MY DREAM CAREER AS A
NEONATAL AND CONGENITAL CARDIAC
ICU NURSE.
I WAS AN ACTIVE SINGLE PARENT
AND WORKING OUT VIGOROUSLY FIVE
TO SIX DAYS A WEEK.
I WAS LITERALLY "THE" PICTURE OF
HEALTH.
WHEN COXSACKIE B VIRUS BLIND
SIGHTED ME, TAKING MY LIFE AND
CAREER AS I KNEW IT.
NOW IS THE MOMENT YOU ALL HAVE
BEEN WAITING FOR.
STRUCTURAL RACISM AND ITS IMPACT
ON PATIENTS WITH COMPLEX CHRONIC
DISEASES SUCH AS M.E. AND LONG
COVID.
FOR CLARITY, STRUCTURAL RACISM
IS SIMPLY THE HISTORICAL AND
CONTEMPORARY PRACTICES AND NORMS
THAT CREATE AND MAINTAIN WHITE
SUPREMACY.
NOW, IMAGINE NAIVELY THINKING
BECAUSE YOU'RE A NURSE, WITH
INSIDE KNOWLEDGE ON HOW TO
NAVIGATE THE HEALTHCARE SYSTEM,
THAT YOU WILL BE IMMUNE TO THE
STRUCTURAL RACISM WITHIN IT.
THAT JOKE WAS DEFINITELY ON ME.
BEING A NURSE DID NOT SAVE ME
FROM PHYSICIANS WHO DIDN'T TAKE
ME SERIOUSLY, NOR DID IT SAVE ME
FROM HEALTHCARE PROFESSIONALS
WHO DIDN'T APPRECIATE ME
EXERCISING AUTONOMY OVER MY
BLACK BODY.
HOW DARE I HAVE THE AUDACITY TO
DO THAT, RIGHT?
THOSE MOMENTS QUICKLY REMINDED
ME THAT DUE TO IMPLICIT BIAS,
WHICH IS SUBCONSCIOUS PREJUDICE
AND STRUCTURAL RACISM IN
HEALTHCARE, I AMFAR LESS LIKELY
TO BE BELIEVED AND PROPERLY
CARED FOR THAN WHITE MEN AND
EVEN WHITE WOMEN, REGARDLESS OF
MY PROFESSION.
AFTER MULTIPLE HOSPITALIZATIONS,
IT STILL TOOK THREE MONTHS OF ME
RELENTLESSLY ADVOCATING FOR
MYSELF TO FINALLY CONVINCE MY
PULMONOLOGIST THAT MY PROFOUND
MUSCLE WEAKNESS, VOICE
HOARSENESS, COGNITIVE
DYSFUNCTION, WHAT I NOW KNOW WAS
POST EXERTIONAL MALAISE, AND
BONE CRUSHING FATIGUE WAS MORE
THAN JUST A, QUOTE, SEVERE
ASTHMA EXACERBATION, AND THAT I
NEEDED TO BE REFERRED TO OTHER
SPECIALISTS TO FIGURE OUT WHAT
WAS MAKING ME SO SICK.
UNFORTUNATELY, THAT EXAMPLE OF
STRUCTURAL RIS RACISM I DIERNEDS
MINUSCULE COMPARED TO EGREGIOUS
EXAMPLE I'M GOING TO SHARE NOW.
THREE YEARS INTO MY ILLNESS
AFTER A TWO-WEEK STAY IN THE
HOSPITAL, A NURSE WAS DETERMINED
TO STRIP ME OF MY AUTONOMY.
I HAVE A PORT A CATH IN MY CHEST
AND DID AT THE TIME OF THIS
ADMISSION.
SINCE I WAS STILL INCREDIBLY
WEAK, I DECIDED TO BE DISCHARGED
FROM THE HOSPITAL WITH MY PORT
STILL ACCESS.
WELL, THIS NURSE, A CHARGE NURSE
NO LESS, WAS ABSOLUTELY NOT
HAVING THAT.
SO MUCH SO THAT SHE LITERALLY
THREATENED TO CALL PEOPLE TO
HOLD ME DOWN TO DEACCESS MY PORT
AGAINST MY WILL, AND IT DIDN'T
STOP THERE.
HELL BENT ON EXERCISING CONTROL
OVER MY BLACK BODY AND
UNFORTUNATELY COMMON EXPERIENCE
FOR BLACK PEOPLE IN AMERICA, THE
NURSE WENT SO FAR AS TO STAND IN
FRONT OF MY WHEELCHAIR AND PLACE
HER FOOT ON TO PREVENT ME AND MY
MOTHER, ANOTHER BLACK WOMAN,
FROM EXITING THE ELEVATOR TO
LEAF THE HOSPITAL.
SHE DID ALL OF THIS KNOWING I
HAD MY DISCHARGE PAPERS IN HAND
TO SAY THAT WAS A HORRIFYING AND
TRAUMATIC ORDEAL THAT RESULTED
IN NEGATIVE SEQUELAE FOR MY
HEALTH WOULD BE A GROSS
UNDERSTATEMENT.
THE POST EXERTIONAL MALAISE I
ENDURED AFTER THAT DEBACLE
ALMOST RESULTED IN A HOSPITAL
READMISSION.
THIS IS JUST ONE EXAMPLE OF
MANY, DEMONSTRATING WHAT CAN
HAPPEN WHEN BIASES GO UNCHECKED,
AND HOW IT IMPACTS PEOPLE OF
COLOR, PARTICULARLY BLACK WOMEN,
WHILE ACCESSING HEALTHCARE.
WITH THAT BEING SAID, LET ME
LEAVE YOU WITH THIS: STRUCTURAL
RACISM IS A PUBLIC HEALTH
CRISIS, AND EACH AND EVERY ONE
OF YOU HERE HAS THE POWER TO DO
SOMETHING ABOUT IT.
FOR HEALTHCARE PROFESSIONALS IN
ATTENDANCE, THOSE OF US WITH
COMPLEX CHRONIC ILLNESSES DES
DESPERATELY NEED YOU TO CHECK
YOUR IMPLICIT BIASES AT THE
DOOR.
BELIEVE PATIENTS WHEN THEY
DESCRIBE WHAT IS HAPPENING TO
THEIR BODIES.
NO MATTER HOW OUTLANDISH IT
SOUNDS.
AND DON'T BE SO QUICK TO BLAME
THEIR SYMPTOMS ON ANXIETY,
WEIGHT, THEIR SKIN COLOR,
GENDER, OR ANYTHING OTHER THAN
SOMETHING PHYSIOLOGICAL.
EVEN IF YOU DON'T HAVE THE
ANSWERS TO WHAT IS AILING THEM,
SIMPLY BELIEVING YOUR PATIENTS
AND BEING COGNIZANT OF WHAT YOU
CHART IN THEIR NOTES GOES SUCH A
LONG WAY.
ADDITIONALLY, I URGE AND
ENCOURAGE YOU TO CONSIDER
BECOMING INFECTION ASSOCIATED
CHRONIC CONDITION SPECIALISTS.
AS IT IS, THERE ARE TOO FEW
SPECIALISTS IN THE COUNTRY WHICH
LIMITS ACCESS TO CARE DUE TO
FINANCIAL CONSTRAINTS, LOGISTICS
IN TERMS OF TRAVELING TO A
SPECIALIST, AND VERY LENGTHY, UP
TO A YEAR IF NOT MORE, WAITS TO
GET NEW PATIENT APPOINTMENTS
WITH THE CURRENT SPECIALISTS.
CHRONIC ILLNESS WARRIORS NEED
APPROPRIATE MEDICAL
INTERVENTIONS AND TREATMENTS, SO
WE CAN GET BACK TO OUR
PRE-ILLNESS LIVES.
WE WERE NURSES, DOCTORS,
TEACHERS, LAWYERS, SCIENTISTS,
PARENTS, PARTNERS AND ALMOST
ANYTHING ELSE YOU CAN THINK OF
BEFORE THESE DISEASES BULLDOZED
OUR LIVES.
PLEASE HELP MAKE OUR DREAM OF A
FUTURE WITHOUT COMPLEX CHRONIC
DISEASES A REALITY.
OUR LOVED ONES NEED US, SOCIETY
NEEDS US.
[APPLAUSE]
THANK YOU, GUYS.
>> THANK YOU SO MUCH, ASHANTI.
THAT WAS REALLY ELOQUENT AND
MOVING.
AND A REALLY IMPORTANT REMINDER
OF SOME THINGS THAT ARE NOT
ALWAYS SO OBVIOUS, BUT ARE SUPER
IMPORTANT.
OBVIOUS TO EVERYONE IN THE
RESEARCH ENTERPRISE.
I WANT TO INTRODUCE OUR NEXT
SPEAKER, DR. IAN LIPKIN, FROM
COLUMBIA, WHO'S GOING TO GIVE US
INSIGHTS AND FORESIGHTS INTO THE
MICROBIOLOGY, IMMUNOLOGY OF
ME/CFS.
IAN?
>> THANK YOU, JOE.
THAT WAS REALLY QUITE MOVING.
I'M GOING TO HOPE THAT THIS
WORKS.
SO WE WERE WORKING EARLIER.
WHILE WE'RE GETTING SET UP, I
REALLY SPEND MOST OF MY CAREER
DOING WHAT WE CALL PATHOGEN
DISCOVERY.
THOUGH I REALLY BEGAN WITH NINDS
AND THEN WITH NIAID FOR MANY
YEARS.
>> CAN'T HEAR YOU, IAN.
>> I SPINT SPENT MOST OF MY LIG
ON PATHOGEN DISCOVERY, CHIEFLY
AROUND OUGHTBREAKS GLOBAL IN
SCOPE BUT NOTHING HAS BEEN QUITE
AS CHALLENGING AS ME/CFS, AND IF
WE CAN GET THIS TO RUN, I'LL
HAVE A CHANCE TO SHOW YOU WHAT
OUR THINKING IS.
THE HISTORY OF INFECTION WITH
ME/CFS GOES BACK A VERY, VERY
LONG TIME.
SEVERAL DECADES, AND THERE HAVE
BEEN A NUMBER OF OUTBREAKS THAT
HAVE BEEN DESCRIBED.
THE ONE WHICH I THINK IS
PROBABLY THE MOST USEFUL FOR US,
I'LL TALK ABOUT IN JUST A
MOMENT, BUT CAN YOU HEAR ME NOW?
GREAT.
SO THERE ARE ESTIMATES OF THE
NUMBER OF PATIENTS WHO HAVE
REPORTS OF INFECTION PRECEDING
CHARACTERIZING -- PRIOR TO
ME/CFS.
MY OWN MOVEMENT INTO THIS FIELD
REALLY BEGAN WITH WORK WITH THE
CDC, WHEN THERE WAS TALK ABOUT
BORNA DISEASE VIRUS BEING
IMPLICATED AS THE CAUSE OF
ME/CFS, AND THERE WERE TWO VERY
PROMINENT PAPERS THAT CAME OUT
THAT SUGGESTED THAT THIS WAS THE
CASE, AND WE WERE ASKED TO LOOK
INTO THIS.
AT THIS TIME, THERE WERE MANY
PEOPLE WHO WERE TALKING ABOUT
THIS BEING A PRIMARILY
PSYCHOLOGICAL ILLNESS WE DIDN'T
FIND ANY EVIDENCE FOR BORNA
VIRUSES BUT WHAT WE DID FIND WAS
THAT THE MAJORITY OF PATIENTS WE
STUDIED IN THE SWEDISH COHORT
HAD ANTIBODIES THAT REACTED WITH
A WIDE RANGE OF DIFFERENT
EPITOPES.
SO THERE WAS CLEARLY SOME SORT
OF IMMUNE SYSTEM DYSREGULATION.
NOW, MAUREEN HANSON AND JOHN CHI
AND OTHERS HAVE TALKED ABOUT
ENTEROVIRUSES IN ME/CFS.
WE HAVE FOUND NO EVIDENCE TO
SUPPORT THAT AS YET.
BUT THAT DOESN'T MEAN IT'S NOT
THE CASE.
THIS IS SOMETHING THAT I THINK
NEEDS TO BE STUDIED
APPROPRIATELY.
USING A VARIETY OF DIFFERENT
TYPES OF TECHNIQUES.
AND I WILL TELL YOU SOMETHING
ABOUT THIS.
WE ORIGINALLY BECAME INVOLVED IN
LOOKING AT ENTEROVIRUSES AND
CHRONIC DISEASES BECAUSE THERE
WERE REPORTS LINKING
ENTEROVIRUSES TO ALS.
WHICH AS YOU ALL KNOW IS LOU
GEHRIG DISEASE, MOTOR NEURON
DISEASE.
WE FOUND NO EVIDENCE FOR THAT
WHATSOEVER.
AND WE'VE DONE SIMILAR KINDS OF
WORK WITH MMR VACCINE AND
AUTISM, BORNA VIRUSES AND
NEUROPSYCHIATRIC DISEASES, AND
THEN MORE RECENTLY, XMRV AND
PMLV IN ME/CFS, WHERE WHAT WAS
REQUIRED TO REFUTE THIS
HYPOTHESIS WAS TO GET THE
ORIGINAL INVESTIGATORS TO LOOK
VERY CLEARLY AT NEW SAMPLES
USING RIGOROUS TECHNIQUES THAT
THEY ALONE WOULD DETERMINE, AND
USING THAT APPROACH, THEY WERE
UNABLE TO REPLICATE THEIR OWN
WORK.
NOW DO I THINK INFECTIONS ARE
IMPLICATED IN ME/CFS AS THE
TRIGGER OR EXACERBATING FACTOR?
THE ANSWER THERE IS PROBABLY
YES.
IF YOU JUST LOOK AT THE
PROTEOMIC EVIDENCE, WE SEE
EXAMPLES WHERE PEOPLE HAVE
CERTAIN KINDS OF CLONAL RYE
RESPONSES TO B CELLS SUGGESTING
THERE'S SOME SORT OF A TARGET.
THERE'S NO PROOF THAT'S CLEAR,
BUT AS DAR YA CAYA CAME UP WITHD
DESCRIBED IN HIS LAST TALK, WE
DO HAVE CLEAR EVIDENCE OF
DYSBIOSIS IN THE GI MICROBIOME.
AND SOME OF THE WORK THAT'S COME
OUT AS A RESULT OF THIS HAS BEEN
TO SUGGEST THAT THERE MAY BE
SOME SORT OF LEAKINESS IN THE
GUT WHICH RESULTS IN TRANSFER OF
PRODUCTS FROM THE INSIDE OF THE
INTESTINE INTO THE SYSTEMIC
CIRCULATION WHICH CAN THEN HAVE
EXTRAORDINARY IMPACT, NOT ONLY
ON THE IMMUNE SYSTEM, BUT ON
MITOCHONDRIA.
AS I'LL GO INTO IN JUST A
MOMENT.
SO WE AND OTHERS HAVE FOUND
ELEVATED LEVELS OF LPS/LBP
BINDING RECEPTOR, S CD14 AND SO
FORTH.
WHAT THIS IS LEADING TO IS SOME
ROLE FOR THE INNATE IMMUNE
SYSTEM IN THE PATHOGENESIS OF
THESE DISORDERS.
NOW WE HAVE PURSUED
CROSS-SECTIONAL MICROBIAL
STUDIES IN PATIENTS WITH ME/CFS.
WHAT I MEAN BY CROSS-SECTIONAL
IS THAT WE COLLECT SAMPLES FROM
PEOPLE AT VARIOUS STAGES OF
DISEASE AND LOOK FOR WHETHER OR
NOT WE CAN FIND VIRUSES, BACK
BACTERIA OR FUNGI.
TO DATE, THIS HAS BEEN
DISAPPOINTING, BUT THIS DOES NOT
EXCLUDE A ROLE FOR MICROBIAL
PATHOGENS IN THE PATHOGENESIS OF
ME/CFS.
BECAUSE WE MAY HAVE HIT-AND-RUN
VIRAL EXPOSURES, AND WE MAY ALSO
HAVE CRYPTIC OR INACCESSIBLE
SITES.
IF WE'RE SUPPORTED DURING THE
NEXT CYCLE OF THE CENTERS
APPLICATIONS, WE HAVE TWO
PROJECTS WHICH WILL SPECIFIC
FOCUS ON THIS.
ONE OF THESE, WE REFER TO AS THE
GOOD DAY/BAD DAY PROJECT THAT'S
LED BY TONY, WHO'S HERE NOW.
THE IDEA IS THAT AS PATIENTS
DEVELOP CHANGES IN THEIR
CLINICAL COURSE, WE WILL ACCESS
MATERIALS AND ASK QUESTIONS
RIGOROUSLY.
THE THIRD PROJECT FOCUSED ON
PATHOGEN DISCOVERY USING SAMPLES
THAT WE OBTAIN FROM THE SERUM
REPOSITORY AT THE DEPARTMENT OF
DEFENSE.
MORE ON THAT SHORTLY.
SO THIS IS THE CONSTRUCTION OF
THE SECOND CYCLE OF THE CENTER
FOR ME/CFS, WHICH IS A NATIONAL
PROGRAM, AND NOW ALSO INCLUDES
AN INDIVIDUAL IN SCOTLAND WHO
WILL DO GENETICS ABOUT WHICH I
WON'T SPEAK.
SO PROJECT ONE WILL LOOK AT 60
ME/CFS SUBJECTS AND 60 HEALTHY
MATCH CONTROLS, AND FOR NURSE
DANIELS, WE ARE SPECIFICALLY
TRYING TO FOCUS ON COLLECTING
SAMPLES FROM PATIENTS WHO ARE
NOT WHITE AND ARE NOT WEALTHY
AND SO ON.
AND THIS WILL REQUIRE SOME
ADDITIONAL SUPPORT FROM NIH.
BUT WE'RE GOING TO LOOK AT EVERY
ACCESSIBLE SAMPLE WE CAN
POSSIBLY COLLECT.
WE'LL LOOK ON BAD DAYS, WE'LL
LOOK THREE WEEKS LATER TO SEE IF
THERE'S SOME SORT OF AN INTERVAL
CHANGE, EITHER WITH PROTEOMICS,
METABOLOMICS, TRANSCRIPTOMICS OR
SEROLOGY, WHICH WILL GIVE US
CLUES AS TO WHAT MIGHT HAVE
CHANGED THE CONSEQUENCE.
WE WILL BE USING A PHONE APP,
WHICH ASKS VERY SPECIFIC
QUESTIONS THAT PATIENTS CAN
ANSWER FROM THE COMFORT OF THEIR
OWN HOMES.
THAT THEN LEADS TO A TRIGGER FOR
A COORDINATOR WHO GOES THEN AND
COLLECTS THE APPROPRIATE
SAMPLES.
I DON'T HAVE TIME TO TALK ABOUT
GIGENOTYPIC ANALYSIS BUT WE'RE
VERY EXCITED ABOUT THIS BECAUSE
IT'S A COLLABORATION THAT WOULD
DECODE ME WITHIN THE U.K. GROUP.
I TALKED A LITTLE BIT ABOUT THE
DEPARTMENT OF DEFENSE PROGRAM.
THERE ARE TENS OF MILLIONS OF
SAMPLES THAT HAVE BEEN COLLECTED
PRIMARILY FOR HIV SEROLOGY TO
LOOK AT ZERO CONVERSION.
SEROCONVERSION.
THIS ALLOWS US TO SEE WHETHER
THERE ARE CHANGES IN ANTIBODY
TITE RMENT S DIRECTED AGAINST
SPECIFIC ANTIGENS REPRESENTED BY
DIFFERENT BACTERIA, WHICH WILL
THEN ALLOW US TO GO BACK AND SAY
THERE IS OR IS NOT SOME SORT OF
A LINK.
NOW WE'RE USING ICD10
CATEGORIES, AND ICD-9
CATEGORIES, AND UNFORTUNATELY,
WE'RE NOT GOING TO BE ABLE TO
USE ME/CFS DIRECTLY.
WE'RE GOING TO HAVE TO RELY ON
CHRONIC FATIGUE UNSPECIFIED BUT
WE THINK THIS WILL BE USEFUL
NONETHELESS.
I'M GOING TO TALK A LITTLE ABOUT
THE METHODS THAT WE USE.
THESE WERE REALLY DEVELOPED
PRIMARILY FOR LOOKING AT
OUTBREAKS, BUT THEY'RE NOW BEING
USED IN ME/CFS.
CAPTURE SEQUENCING, WHICH IS
EXTRAORDINARILY POWERFUL, AND IS
NOW BEING USED CLINICALLY AS
WELL AS FOR RESEARCH, ALLOWS YOU
TO GET A THREE ORDER OF
MAGNITUDE ENRICHMENT, WHICH
SIMPLIFIES BIOINFORMATICS, GIVES
YOU THE SENSITIVITY THAT YOU
NEED TO LOOK FOR AGENTS THAT
MIGHT BE PRESENT.
THERE'S A BACTERIAL CORRELATE
WHICH HAS SIMILAR KINDS OF
PERFORMANCE CHARACTERISTICS.
WE ALSO USE VERY GRANULAR
APPROACHES FOR SEROLOGY, AND
THIS AS YOU'LL SEE IS EXTREMELY
IMPORTANT.
WE BEGAN BY USING MICRO ARRAYS
WITH OVERLAPPING PEPTIDES, AND
UNFORTUNATELY, WE CAN NO LONGER
ACCESS THOSE ARRAYS.
SO WE'VE NOW TURNED TO SORT OF A
GRANULAR PHASE DISPLAY APPROACH
WHICH I'LL DESCRIBE FOR YOU IN A
MOMENT.
I'M GOING TO GIVE YOU ONE
EXAMPLE OF HOW WE USE SEROLOGY
TO IMPLICATE A SPECIFIC VIRUS IN
ACUTE FLACCID MY LIGHTS.
MYELITIS.AS YOU CAN SEE, THERE S
DISEASE THAT TENDS TO GO UP
EVERY YEAR UNTIL THE ONSET OF
THE PANDEMIC, WHEN PEOPLE BECAME
ISOLATED AND USING MASKING AND
SO FORTH TO REDUCE TRANSMISSION.
WE WERE ABLE TO FIND A REGION
THAT CORRELATED WITH ENTEROVIRUS
D68, SAME TAIN JUSTLY EVALUATING
ALL THE VIRUSES KNOWN TO
SCIENCE, AND WE HAVE A SIMILAR
SORT OF APPROACH WHICH CAN BE
USED FOR OTHER VIRUSES AS WELL.
BECAUSE WE CAN NO LONGER ACCESS
THESE ARRAYS, WE NOW USE PHAGE
DISPLAY BUT IT'S NOT THE PHAGE
DISPLAY THAT MANY OF YOU WILL BE
FAMILIAR WITH.
IT IS MUCH MORE GRANULAR.
IT APPLIES VERY SHORT PEPTIDE
SEQUENCES THAT ALLOWS US TO
DISCRIMINATE BETWEEN DIFFERENT
SEROTYPES.
THUS FAR WE'VE BEEN ABLE TO
COMPARE THE RESULTS WE OBTAINED
WITH MICRO ARRAYS VERSUS PHAGE
DISPLAY AND THERE'S VERY GOOD
OVERLAP WHEN WE'RE LOOKING AT
HERPES VIRUS AND WHEN WE'RE
REVIEWING PATIENTS WITH COVID-19
AND LOOKING AT CORONAVIRUS.
I'M GOING TO MOVE NOW TO THE
SPECULATIVE PORTION OF MY TALK,
WHERE I'M GOING TO DESCRIBE FOR
YOU WHY I THINK THE INNATE
IMMUNE SYSTEM IS GOING TO BE
IMPORTANT.
I REFERENCED EARLY ON THE PAPER
THAT WAS DESCRIBED BY DERYA
UNUTMAZ, WORK LED BY JULIA O AND
BY BRENT WILLIAMS AT OUR CENTER,
WHERE WE FOUND THAT THERE WERE
DIFFERENCES IN POPULATIONS OF
BACTERIA IN FECES OF INDIVIDUALS
WITH ME/CFS VERSUS MATCHED
CONTROLS.
AND THE IMPORTANT POINT THAT
DERYA HIGHLIGHTED EARLIER WAFS
THAT THERE WAS A REDUCTION IN A
FATTY ACID KNOWN ATTRIBUTE RATE
WHICH HAS IMPORTANT IMMUNE
REGULATORY PROPERTIES.
THERE'S ANOTHER FEATURE WHICH I
THINK IS ALSO IMPORTANT AND THAT
IS THAT THIS PARTICULAR MOLECULE
IS EXTREMELY IMPORTANT IN
MAINTAINING TIGHT JUNCTIONS IN
THE COLON SO THAT MOLECULES
DON'T TRANSIT IT EASILY FROM THE
UNSIDE OF THE GUT INTO THE
SYSTEMIC CIRCULATION WHERE THEY
MIGHT TRIGGER IMMUNE RESPONSES.
AND THESE ARE THE KEY PAPERS
THAT I THINK GIVE US INSIGHT
INTO THIS LEAKY GUT HYPOTHESIS.
THE INCREASED LEVELS OF LPS, THE
BINDING PROTEIN ST14, TWO
DIFFERENT GROUPS O HAVE REPORTED
VERY, VERY SIMILAR SORTS OF
FINDINGS.
NOW THE OTHER ASPECT, THE OTHER
SIDE OF THE COIN, IF YOU WILL,
IS THE HEIGHTENED SENSITIVITY
THAT WE SEE TO SOME OF THESE
AGENTS.
SO HERE IS AN EXAMPLE WHERE
WE'VE TAKEN SAMPLES DIRECTLY OUT
OF A PATIENT'S ARM, HAVE PLACED
THEM IN INCUBATION CHAMBERS
WHERE THEY'RE EXPOSED TO
SPECIFIC CYTOKINES, AND THEN WE
MEASURE IN THE SUPERNATENT WHAT
HAS ALLUDED INTO THAT OVER A
PERIOD OF 48 HOURS.
WHEN WE LOOK AT PRO-INFLAMMATORY
CYTOKINES, THE MOST ROBUST
RESPONSES AS YOU CAN SEE ON THE
FAR LEFT ARE IN WOMEN.
PRIMARILY WOMEN OVER THE AGE OF
45, AND THIS IS LINKED TO
CHANGES IN ESTROGEN.
BUT IN MALES, OLDER MALES AS
WELL, YOU SEE THERE'S AN
INCREASED RESPONSE TO THIS
SUPERANTIGEN TRIGGER OF
IMMUNITY.
SO AGAIN, IF YOU HAVE POROSITY
OF THE CLON COLON IK EPITHELIUMH
ALLOWS EXPOSURE AND YOU HAVE AN
IMMUNE SYSTEM THAT'S PRIMED IN
THIS WAY, YOU CAN GET THE SORT
OF SICKNESS BEHAVIOR THAT MANY
OF US ARE TALKING ABOUT.
SO I DESCRIBE VERY BRIEFLY,
BECAUSE I'M NOT AN IMMUNOLOGIST,
WHAT I UNDERSTAND ABOUT THE
INNATE IMMUNE SYSTEM AND WHY I
THINK THIS IS LIKELY TO BE
IMPORTANT.
THERE ARE A WHOLE SERIES OF
RECEPTORS IN HUMANS AND OTHER
MAMMALS THAT ARE CALLED TOLL
LIKE RECEPTORS.
ACTUALLY HIGHLY CONSERVED, YOU
CAN EVEN FIND THEM IN
INVERTEBRATES.
THEY RESPOND TO A WIDE VARIETY
OF DIFFERENT TYPES OF PATHOGENS.
THE ACTIVATION OF THESE
RECEPTORS LEADS TO THE
PRODUCTION TO THE RECRUITMENT OF
INTERMEDIATE MOLECULES, WHICH
TRAVEL INTO THE NUCLEUS ITSELF
AN INCREASE TRANSCRIPTION
ULTIMATELY RESULTING IN THE
EXPRESSION OF VARIOUS CYTOKINES.
NOW THIS IS A VERY SIMPLE SORT
OF DIAGRAM OF WHAT THIS LOOKS
LIKE, BUT YOU CAN SEE THE
OUTSIDE OF THE CELL AT THE TOP
AND YOU CAN SEE HERE THE
INTERNAL ORGANELLES.
I'D LIKE TO DRAW YOUR ATTENTION
TO THE FACT THAT THE TOLL-FREE
RECEPTOR, WHICH IS THE ONE WE
TYPICALLY SEE WITH VIRAL
INFECTIONS, AND THE TOLL
4 RECEPTOR WHICH IS THE ONE
THAT'S ACTIVATED WITH BACTERIAL
INFECTIONS, BOTH ACT THROUGH A
CONVERGENT PATHWAY, WHICH IS
THIS FACTOR NF KB.
AND ONE HYPOTHESIS THAT WE WOULD
LIKE TO ENTERTAIN IS THAT VIRAL
INFECTION INCREASES THE
SENSITIVITY TO THESE BACTERIAL
PRODUCTS WHICH MAY TRAFFIC FROM
THE INSIDE OF THE INTESTINE.
SO THE QUESTION THEN IS, CAN ABV
OR OTHER VIRAL INFECTIONS,
COXSACKIE WAS SOMETHING WE HEARD
ABOUT JUST A MOMENT AGO, ACT TO
RESET THE SET POINT FOR
PRO-INFLAMMATORY RESPONSES IN
INNATE IMMUNITY.
AND THAT, OF COURSE, WILL LEAD
TO A CORRELATE QUESTION.
CAN WE MODULATE THE ACTIVITY,
AND WOULD SUCH MODULATION IMPACT
THE CLINICAL COURSE OF ME/CFS?
THE OTHER THING I THINK WE
SHOULD CONSIDER WHEN WE'RE
THINKING ABOUT VIRAL INFECTIONS
OF THE CELL IS THE IMPACT ON THE
MITOCHONDRIA.
THIS GETS TO WHAT MARK DAVIS WAS
TALKING ABOUT EARLIER.
SO THERE IS EVIDENCE FROM A
NUMBER OF DIFFERENT GROUPS NOW
THAT INTERACTIONS BETWEEN VIRAL
PROTEINS AND ITS WIDE RANGE OF
TUMOR VIRUSES AND THE
MITOCHONDRIA WHICH FACILITATE
IMMUNE SURVEILLANCE ESCAPE, IF
YOU WILL, HAVE AN IMPACT ON
MITOCHONDRIAL FUNCTION.
AND THIS IS NOT OUR WORK BUT I
FOUND IT VERY, VERY EXCITING.
SO WITH EPSTEIN-BARR VIE RU YOU
CAN OVEREXPRESS THIS PROTEIN
LMP2, OR YOU CAN LOOK AT A
NATURAL INFECTION AND YOU CAN
SEE AS A RESULT OF THAT FISSION
WHICH OCCURS INSIDE THE
MITOCHONDRIA WHICH MIGHT HAVE AN
IMPACT ON THE ABILITY OF THOSE
MITOCHONDRIA TO FUNCTION.
NOW AS WE GO LOOKING FOR
TRIGGERS OF INFECTION, IT'S
IMPORTANT TO RECOGNIZE THAT NOT
ALL THE ASSAYS THAT WE USE ARE
GOING TO BE EQUAL IN TERMS OF
THEIR POTENCY AND
CHARACTERISTICS.
SO IF YOU USE THE COMMERCIAL EBV
ASSAYS FOR EXAMPLE AGAINST THOSE
TARGETS SEEN BELOW, YOU DON'T
SEE ANY DIFFERENCE BETWEEN
IMMUNOACTIVITY PROFILES CASES
VERSUS CONTROLS.
WE CREATED THIS PEPTIDE ARRAY
THAT I ALLUDED TO EARLIER, WHICH
ALLOWS US TO LOOK IN A MUCH MORE
GRANULAR FASHION AT
IMMUNOREACTIVITY.
THIS ALLOWED UTI US TO DESCRIBE
DIFFERENT PEPTIDE PATTERNS IN
ME/CFS CASES VERSUS CONTROLS.
NOW, WE HAVE FOCUSED PRIMARILY
ON WHAT WE'VE SEEN THUS FAR,
WHICH HAS BEEN WITH A WIDE RANGE
OF DIFFERENT HERPES VIRUSES,
CHIEFLY HSV-1, EBV, HHV-6.
WE HAVE NOT SEEN ANY DIFFERENCES
WITH RESPECT TO TICK-BORNE
DISEASE AGENTS OR TO ANTIVIRUS.
NOW DOES THIS MEAN THAT THEY
CAN'T BE IMPLICATED?
I'M NOT CERTAIN BUT IT'S NOT
LEADING US IN THAT WAY.
NOW, IF WE USE INSTEAD THINGS
THAT SEPARATE WITHIN EBV AND
OTHER HERPES VIRUSES THOSE
PROTEINS WHICH ARE ASSOCIATED
WITH REACTIVATION VERSUS THOSE
THAT ARE CONSTITUTIVELY
EXPRESSED, WE DO BEGIN TO SEE
DIFFERENCES.
SO IF YOU LOOK AT THE LEFT,
EBNA-1, EBNA-2, THERE'S NO
DIFFERENCE REALLY BETWEEN THE
CASES AND CONTROLS.
HOWEVER, WHEN YOU LOOK AT THESE
OTHER PROTEINS LIKE THE DNA
POLYMERASE OR BZLF1, YOU BEGIN
TO SEE DIFFERENCES.
NOW THEY'RE NOT SIGNIFICANT YET.
BUT THE NUMBERS REMAIN SMALL,
AND WE HAVEN'T USED A TRULY
QUANTITATIVE ASSAY LIKE AN ELI
ELIZABUT I THINK THERE'S LIKELYE
SOME FRUIT HERE.
IF YOU LOOK AT THIS MOLECULE IN
TERMS OF EPSTEIN-BARR VIRUS, IF
YOU LOOK AT THE TOP PANEL FOUR
OVER, YOU CAN SEE A VERY, VERY
DIFFERENT PATTERN THAN YOU SEE
IN THE NORMAL CONTROLS.
THIS SUGGESTS TO US THAT THERE
MAY BE SOME EVIDENCE OF
REACTIVATION OF SOME SORT WITH
EPSTEIN-BARR VIRUS IN
ASSOCIATION WITH DISEASE.
NOW, MIND YOU WE HAVE NOT LOOKED
AT ALL AT WHETHER OR NOT THESE
FINDINGS CAN BE LINKEDIN LINKEE
FATION TO AN INCREASE OF
SEVERITY OF DISEASE OR SOME SORT
OF IMPROVEMENT.
AND THIS GOOD DAY/BAD DAY
PROJECT, WHICH IS NUMBER ONE IN
OUR NEXT CENTER PROPOSAL, WILL
ALLOW US TO DO THIS.
NOW, AS I WAS THINKING MORE AND
MORE ABOUT INNATE IMMUNITY, I
CAME ACROSS WORK TALKING ABOUT
IL37, AND IT'S REALLY
INTRIGUING.
THIS IS A MEMBER OF THE IL-1
SUPERFAMILY.
IT IS BROADLY DISTRIBUTED BY
ORGANS AND BY CELLS AND HAS THE
ABILITY TO INTERFERE WITH INNATE
IMMUNITY.
AND WHAT HE AND HIS COLLEAGUES
HAVE DONE IS TO EXAMINE THIS LPS
MODEL.
THIS IS A COMPOUND THAT'S
RELEASED BY GRAM-NEGATIVE
BACTERIA, AND YOU CAN SEE IN
PANEL A THAT IF YOU TAKE ANIMALS
THAT ARE EXPOSED TO LPS AND YOU
PRE-TREAT THEM WITH IL-37, THEY
DON'T HAVE A ROBUST RESPONSE IN
TERMS OF EXPRESSION OF IL-6 AND
YOU CAN ACTUALLY SHOW THAT
THERE'S A DRAMATIC IMPROVEMENT
IN THEIR MOBILITY.
SO THEIR RUNNING TIME REDUCTION
IS LARGELY ABROGATED AS A RESULT
OF THE EXPOSURE TO IL-37.
IT SEEMS TO PROTECT THE MICE.
WE ALSO SEE THAT IN HEALTHY
MICE, WHICH IS IN FIGURE 2,
THERE IS ALSO AN IMPROVEMENT IN
THE ENDURANCE OF THESE ANIMALS.
SO THIS IS REALLY EXCITING
BECAUSE IT'S CORRELATED WITH AN
INCREASE IN OXYGEN CONSUMPTION.
SO I'VE NEVER ACTUALLY SEEN
ANYTHING BEFORE THIS WHERE
THERE'S BEEN ONE MOLECULE THAT'S
BEEN ABLE TO SOMEHOW TRANSFORM
THIS RESPONSE TO INNATE IMMUNE
STIMULI AND PREVENT THE SICKNESS
BEHAVIOR.
AND I'LL COME BACK TO THAT AT
THE VERY END.
NOW, I DON'T ACTUALLY PRACTICE
CLINICAL MEDICINE ANYMORE, BUT I
WORK VERY CLOSELY WITH A NUMBER
OF CLINICIANS.
AND I WANT TO JUST REFERENCE TWO
OF THEM IN PARTICULAR.
ONE WAS VANESSA LI, WHO WAS THE
CO-FOUNDER OF THE MICROBE
DISCOVERY PROJECT WHICH LAUNCHED
MUCH OF OUR WORK.
SADLY, WE LOST HER TO SUICIDE IN
2015.
THERE'S ANOTHER YOUNG WOMAN,
THIS IS HER PSEUDONYM,
CHRISTINA.
I'VE BEEN FOLLOWING HER FOR AT
LEAST FOUR YEARS, AND I'VE
WORKED WITH YAN PETERSON IN
GETTING HER TREATMENT.
SHE INITIATED AMPLIGEN TREATMENT
IN 2022, AND OVER A PERIOD OF
MONTHS, SHE'S BEEN ABLE TO GET
TO THE POINT WHERE SHE'S LEFT A
DARKROOM.
FIRST SHE SAT UP, NOW SHE CAN GO
OUTSIDE AND SHE'S ABLE TO
TOLERATE FAR MORE IN THE WAY OF
NOISE AND STIMULI.
THIS HAS BEEN AN ABSOLUTELY
EXTRAORDINARY ROWRY SPONS.
-- RESPONSE.AGAIN WE NEED TO TE
INNATE IMMUNE SYSTEM AND THE
WAYS IN WHICH YOU MIGHT INTERACT
WITH SOME OF THESE DIFFERENT
DRUGS.
NOW, THOSE OF YOU WHO KNOW ME
WELL KNOW THAT OVER THE PAST
YEAR, I'VE HAD A LOT OF HEALTH
DIFFICULTIES.
AND WHAT THIS HAS ACTUALLY DONE
FOR ME IS TO GIVE ME A MUCH
DEEPER APPRECIATION OF THE
URGENCY OF GETTING TO SOLUTIONS
FOR ME/CFS.
MY PROBLEMS STARTED STRUCTURAL
BUT THEY'VE BECOME METABOLIC AS
WELL.
CONGESTIVE HEART FAILURE, A
VARIETY OF OTHER SORTS OF
PROBLEMS.
I TAKE A WIDE RANGE OF DRUGS AT
THIS POINT.
KEY IN MANAGING MY MEDICAL
THERAPY HAS BEEN THE
AVAILABILITY OF A BIOMARKER.
IN THIS CASE, B TYPE NATRIATIC
PEPTIDE.
SO IT STARTED EXTREMELY HIGH, IT
DROPPED WITH DRUG THERAPY, IT
WENT UP AFTER A COUPLE OF
OPERATIONS AND NOW IT'S COMING
BACK TOWARDS NORMAL.
SO I HAVE A DEEPER APPRECIATION
FOR THE IMPACT OF AUTO MO MIBG
DYSFUNCTION AND FATIGUE ON DAILY
LIFE, AS WELL AS AN APPRECIATION
FOR THE IMPORTANCE OF
BIOMARKERS.
SO I'M GOING TO SUMMARIZE MY
TALK VERY, VERY RAPIDLY BY
SIMPLY TELLING YOU THAT I DO
THINK THERE'S LIKELY TO BE AN
IMPORTANT ROLE FOR INFECTION IN
TRIGGERING AND EXACERBATING
DISEASE WITH ME/CFS.
WE JUST HAVEN'T CLARIFIED WHAT
IT IS, AND IT'S UNLIKELY THAT
IT'S GOING TO BE A SINGLE AGENT.
AND I THINK SARS-COV-2 EXPOSURE
AND LONG COVID GIVES BETTER
CREDENCE TO THIS SORT OF
HYPOTHESIS.
WE'VE NOT YET BEEN ABLE TO
IDENTIFY THE AGENT OR AGENTS
THAT ARE RESPONSIBLE FOR THIS.
HOWEVER, WE HAVEN'T LINKED
SAMPLE COLLECTION TO CHANGES IN
CLINICAL STATUS, NOR HAVE WE
USED HIGH RESOLUTION SEROLOGY.
BOTH OF THESE ARE NOW PLAUSIBLE.
WE BELIEVE THAT DYSREGULATION OF
THE GUT MICROBIOME BASED ON SOME
OF THE DA DATA THAT DERY.
A SHOWED US
LATER IS GOING TO BE IMPORTANT
BECAUSE IT MOD LATES
INFLAMMATION AND IT'S ALSO
ASSOCIATED WITH POROSITY OF THE
BACTERIAL CELL WALL TO THE
TRANSFER OF PRODUCTS THAT CAN
IMPACT INNATE IMMUNITY.
AND I WOULD SAY THAT ALTHOUGH WE
DON'T FULLY UNDERSTAND THE
PATHOPHYSIOLOGY OF ME/CFS, IT IS
NOT PREMATURE TO ASK WHETHER OR
NOT THERE'S SOMETHING WE SHOULD
CONSIDER, AS LONG AS IT DOESN'T
HAVE PROFOUND ADVERSE EFFECTS
AND AS LONG AS IT'S UNDERTAKEN
THROUGH SOME SORT OF A
RANDOMIZED CLINICAL TRIAL.
SO THESE WOULD BE PRE AND
PROBIOTICS THAT ADDRESS
DYSBIOSIS AND RESULT IN AN
INCREASE IN LEVELS OF BUTYRATE
IN THE GUT, AS WELL AS DRUGS
THAT MODULATE INNATE IMMUNE
RESPONSES SUCH AS POLYIC, ALSO
KNOWN AS AMPLIGEN OR IL37.
I WILL SAY THAT THE COST RIGHT
NOW FOR POLY I-:C IS ABSURD.
THIS IS A VERY CHEAP MOLECULE TO
MAKE AND THERE'S NO REASON IT
SHOULDN'T BE AVAILABLE AT A FAR
LOWER COST.
AND FROM MY OWN PERSONAL
EXPERIENCE WITH CONGESTIVE HEART
FAILURE, I CAN TELL YOU THAT IF
WE WANT TO PURSUE PRECISION
MEDICINE, WE ARE GOING TO NEED
BIOMARKERS THAT ALLOW YOU TO
FORECAST CHANGES IN CLINICAL
STATUS, BECAUSE THE CHANGES AS
THEY OCCUR TOWARD IMPROVEMENT
ARE GOING TO BE VISUALIZED ON A
TIME SCALE PROBABLY ONE TO TWO
YEARS.
THANK YOU.
[APPLAUSE]
DO I HAVE TIME FOR QUESTIONS?
I CAN TAKE TWO QUESTIONS
APPARENTLY.
I THINK WE HEARD FROM JOHN
MARTIN EARLIER.
IF HE'S STILL HERE.
>> IS THIS ON?
OKAY.
HI.
I WAS CURIOUS IF YOU COULD SPEAK
TO -- I DON'T FOLLOW, YOU KNOW,
THE AMPLIGEN TRIALS PARTICULARLY
IN DETAIL, BUT ONE OF THE THINGS
I HAD TROUBLE RECONCILING IS HOW
THAT COULD IMPROVE SYMPTOMS IN
PEOPLE WITH CFS, ESPECIALLY IF
ONE OF THE THOUGHTS IS THERE'S
OVERACTIVE INNATE IMMUNITY, TLRT
IT'S CLEARING SOME RESIDUAL
VIRUS AND DO YOU HAVE ANY
INTEREST IN EXAMINING THOSE
RESPONDERS PRE AND POST TO SEE
WHAT EXACTLY IT'S DOING?
>> SO THERE ARE ACTUALLY TWO
QUESTIONS THERE.
ONE OF THEM HAS TO DO WITH HOW
DO YOU RECONCILE IN ONE INSTANCE
WHERE YOU'RE TRYING TO RAMP UP
THE IMMUNE SYSTEM AND THE OTHER,
YOU'RE TRYING TO DAMPEN IT, AND
HOW YOU CAN RECONCILE THOSE TWO.
I DON'T THINK ME/CFS IS A SINGLE
DISEASE.
I THINK THERE ARE PROBABLY
MULTIPLE PHENOTYPES AND MAY ALSO
BE DIFFERENCES.
OVER THE COURSE AS YOU SAW
EARLIER, THERE ARE DIFFERENCES
IN THE FIRST THREE TO FOUR YEARS
OF DISEASE VERSUS LATER.
SO ONE THING THAT MIGHT BE
USEFUL EARLY IN THE COURSE MAY
NOT BE USEFUL LATER ON.
THE OTHER ISSUE IS, IF YOU THINK
BACK TO THE EARLY DAYS OF
HEPATITIS C, WE USED TO TREAT
PATIENTS WITH INTERFERONS AND
WITH RIBOVIRIN, A DRUG THAT
CAUSES MUTATIONS IN THE HVC
GENOME.
NOW WE HAVE SPECIFIC DRUGS.
SO I CAN ENVISION A SITUATION
WHERE YOU HAVE CRYPTIC INFECTION
WITH SOME HERPES VIRUS OR ANY
VIRUS FOR THAT MATTER, AND AS A
FUNCTION OF BEING EXPOSED TO
AMPLIGEN, YOU MIGHT SOMEHOW
INTERFERE WITH THE ABILITY OF
THAT VIRUS TO REPLICATE.
BUT THAT'S PURELY SPECULATIVE.
IT'S SOMETHING THAT WE HOPE TO
GET INTO WITH THIS GOOD DAY/BAD
DAY PROJECT.
>> THANK YOU.
>> THANKS FOR YOUR QUESTION.
OKAY.
>> THANKS VERY MUCH, DR. LIPKIN.
I'D LIKE TO INTRODUCE DR. AVI
NATH FROM THE NATIONAL INSTITUTE
OF NEUROLOGICAL DISORDERS AND
STROKE WHO ACTUALLY AT THIS
MEETING IN 2019, BRIAN WALLIN
AND AVI TOLD US ABOUT A
LONGITUDINAL ME/CFS STUDY THIS
THEY WERE STARTING, AND THEN THE
PANDEMIC HAPPENED AND THEY
SUBSEQUENTLY SET UP A
LONGITUDINAL STUDY FOR LONG
COVID, AND I'M SURE OTHERS THAT
I DON'T KNOW ABOUT.
SO TODAY, AVI IS GOING TO TALK
TO US ABOUT CLINICAL PHENOTYPES
OF LONG COVID,
PATHOPHYSIOLOGICAL MECHANISMS
AND INTERVENTIONS.
>> THANKS, DR. BREEN.
IAN'S TALK IS ALWAYS A HARD ACT
TO FOLLOW.
HE DOES SUCH A SUPERB JOB AND
REALLY NICE WORK.
SO I'M GOING TO TELL YOU A
LITTLE BIT ABOUT WHERE WE STAND
WITH LONG COVID.
AND YOU'LL SEE THAT THERE ARE
PARALLELS BETWEEN THE TWO
DISEASES.
ONE GOOD THING ABOUT WORKING
WITH THE GOVERNMENT IS YOU NEVER
HAVE ANY DISCLOSURES.
[LAUGHTER]
SOMETIMES I WISH I HAD SOME.
OKAY.
SO FIRST OF ALL, WE ALL THINK WE
KNOW WHAT LONG COVID IS.
THE THING IS, NOBODY REALLY
KNOWS WHAT IT ACTUALLY IS.
THE TERM LONG COVID ITSELF WAS
COINED BY PATIENTS.
AND IT WAS LIKE, WELL, I GOT
COVID AND I'M NOT GETTING ANY
BETTER, I GOT LONG COVID.
IT'S AS SIMPLE AS THAT.
NIH CAME UP WITH ANOTHER
DEFINITION.
POST-ACUTE SEQUELAE OF COVID-19.
THAT'S A MOUTHFUL.
AND THEN THE WHO TRIED TO
SIMPLIFY IT, THEY CALL IT
POST-COVID.
SO IF YOU LOOK AT THE WHO
DEFINITION, IT IS THE
CONTINUATION OF OR DEVELOPMENT
OF NEW SYMPTOMS THREE MONTHS
AFTER INITIAL SARS-COV-2
INFECTION WITH THESE SYMPTOMS
LASTING FOR MORE THAN -- FOR AT
LEAST TWO MONTHS, WITH NO OTHER
EXPLANATION.
THE PROBLEM WITH THIS DEFINITION
IS THAT IT ENCOMPASSES ALMOST
EVERYTHING THAT'S GOING ON WITH
YOU AFTER THREE MONTHS OF
INFECTION.
AND SO WHAT IT DOESN'T ACCOUNT
FOR ARE THESE TWO DIFFERENT
POSSIBILITIES.
FIRST, IF YOU'RE ADMITTED IN THE
HOSPITAL, YOU HAVE ACUTE COVID,
IT IS NO SURPRISE THAT WHEN YOU
COME OUT, YOU'RE NOT GOING TO BE
FULLY BETTER.
IT'S GOING TO TAKE A WHILE.
BUT IT'S THE END ORGAN DAMAGE
THAT OCCURRED AS A SINGLE EVENT
DURING THE HOSPITALIZATION THAT
IS THE CAUSE OF YOUR SYMPTOMS.
SO THAT CATEGORY HAS TO BE
SEPARATED.
THEN YOU HAVE THE SECOND
CATEGORY OF INDIVIDUALS WHO
SAID, YOU KNOW, I NEVER WENT TO
THE HOSPITAL, ACTUALLY I GOT
SICK, I NEVER EVEN SAW A DOCTOR.
I GOT BETTER, I ESCAPED IT.
AND THEN A FEW DAYS OR WEEKS GO
BY AND THEY SAY, YOU KNOW WHAT,
I DON'T KNOW, I GOT THIS CHEST
PAIN, I CAN'T REALLY THINK
PROPERLY, I WENT BACK TO WORK
AND I CAN'T CONCENTRATE.
SOMETHING IS REALLY WRONG WITH
ME.
NOW I'M GETTING TIRED.
SO THOSE ARE TOTALLY DIFFERENT
CATEGORIES OF PATIENTS WHERE THE
PATHOPHYSIOLOGY OF BOTH OF THEM
ARE GOING TO BE DIFFERENT AND I
DON'T HAVE A GOOD TERM FOR THE
SECOND CLASS BUT WE'VE GOT TO
SEPARATE THESE TWO.
OKAY.
PEOPLE HAVE TALKED ABOUT
INCIDENCE OF ME/CFS AND COVID,
AND HERE'S DATA FROM THE CDC
SHOWING THAT IF YOU JUST LOOK AT
ADULTS ACROSS UNITED STATES
RIGHT NOW, ABOUT 6% OF ALL
ADULTS HAVE LONG COVID.
AND IF YOU WERE TO LOOK AT THOSE
INDIVIDUALS WHO HAD COVID AND
NOW HAVE LONG COVID IN THE
UNITED STATES, YOU'RE LOOKING AT
ABOUT 11% OR SO.
SO THAT'S A HUGE POPULATION.
THAT'S SUFFERING FROM THIS
DISEASE.
AND IT AFFECTS INDIVIDUALS IN
THE AGE GROUP WHERE THEY'RE MOST
PRODUCTIVE.
IF WE LACK AT LOOK AT THE SYMPS
PEOPLE DEVELOP DURING EARLY
COVID THERE'S A WHOLE LIST OF
SYMPTOMS.
SOME OF THEM GET BETTER, SOME OF
THEM DON'T GET BETTER, SOME OF
THEM GET WORSE.
IF YOU LOOK AT THE NEUROLOGICAL
SYMPTOMS THAT I'VE BOXED AT THE
BOTTOM, THEY ACTUALLY GET WORSE
OR DON'T GET BETTER OVER A
PERIOD OF TIME.
AND IN THIS GRAPH, LET ME SEE IF
THIS POINTER WORKS.
SORRY, MESSED THAT ONE UP.
OKAY.
GOOD.
THIS DOES WORK.
SO YOU SEE THE BOTTOM SYMPTOMS,
THEY SEEM TO GET WORSE OR
PERSIST COMPARED TO WHERE THEY
WERE.
SO THAT TELLS YOU THAT THE
NEUROLOGICAL SYMPTOMS REALLY ARE
THE MAJOR SEQUELAE OF LONG
COVID.
OKAY.
SO IF YOU LOOK AT THESE
INDIVIDUALS, THE SECOND CATEGORY
OF INDIVIDUALS, WHAT YOU CAN DO
IS YOU CAN ACTUALLY DIVIDE THEM
INTO FOUR DIFFERENT BUCKETS.
THEY OVERLAP WITH ONE ANOTHER.
DEPENDING ON WHAT THE
PREDOMINANT SYMPTOM IS.
SO THE FIRST IS SOME INDIVIDUALS
DEVELOP EXERCISE INTOLERANCE,
AND THAT IS IT'S -- ONE
CARDIOLOGIST I REMEMBER FROM
NEW YORK, WHAT SHE TOLD ME WAS
THAT, DOC, AFTER I GOT COVID,
NOW IT'S BEEN A MONTH OR TWO
GONE BY, AND I TAKE ONE FLIGHT
OF STAIRS AND I GET SO EXHAUSTED
THAT I CAN'T EVEN DO
TELEMEDICINE ANY LONGER.
SO IT CAN BE SO DEVASTATING.
SOME DEVELOP DIFFICULTIES WITH
COGNITION, MOOD AND SLEEP
DISORDERS, AND THERE'S ONE
EMPLOYEE HERE AT NIH THAT I SAW,
NO REASON TO BE DEPRESSED OR
ANYTHING, HE SAYS HE GOT COVID,
AND AFTER THAT, HE GOT AFRAID OF
HIMSELF.
SO HE ACTUALLY WENT TO A
SUBURBAN HOSPITAL, GOT ADMITTED
THERE FOR ABOUT A MONTH.
HE CAME OUT, NOW HE'S DOING
FINE.
BUT ACUTE EPISODE OF MAJOR
DEPRESSION CAN BE A
MANIFESTATION.
ANOTHER WOMAN, I'LL GIVE YOU AN
EXAMPLE OF COGNITIVE DISORDER.
SHE WORKS IN CONGRESS AND HER
JOB IS TO TAKE MINUTES.
SHE RECOVERED FROM COVID.
SHE DIDN'T REALIZE THERE WAS
ANYTHING WRONG WITH HER.
SHE ACTUALLY GOES THERE AND
REALIZES SHE CAN'T MULTITASK ANY
LONGER.
SHE COULDN'T TAKE NOTES.
SO THEY CAN BE SUBTLE AND THEY
CAN BE QUITE DRAMATIC.
SOME INDIVIDUALS CAN HAVE
DYSAUTONOMIA.
AN ONCOLOGIST IN VIRGINIA, SHE
CALLED ME AND SAYS YOU KNOW
WHAT, AFTER I GOT COVID NOW, I'M
ACTUALLY LYING DOWN AND TALKING
TO YOU BECAUSE EVEN IF I SIT UP,
I GET DIZZY.
AND SHE COULDN'T GO BACK TO HER
PRACTICE.
THEN THERE ARE A VARIETY OF PAIN
SYNDROMES THAT PEOPLE CAN
DEVELOP AS WELL.
SO WE BROUGHT IN A COHORT OF 17D
FINALLY ENROLLED 12 PATIENTS
THAT WE STUDIED EXTENSIVELY.
WE HAD ALL THESE CRITERIA,
THEY'RE ALL PUBLISHED.
BUT WHAT I WANT TO TELL YOU, WE
ARE LOOKING FOR THOSE
INDIVIDUALS THAT WE CALL
NEUROPATHS, WHICH MEANS THEY
CLEARLY HAVE NEUROLOGICAL
SYMPTOMS AFTER DEVELOPING COVID.
100% OF THEM HAD CHRONIC -- IT
COGNITIVE DIFFICULTIES AND
FATIGUE, AND THEN OTHERS HAD
OTHER VARIETY OF SYMPTOMS THERE.
WHAT ABOUT THE AGE GROUPS?
THIS IS AN INTERESTING STUDY.
THEY COMPARED INDIVIDUALS WHO
HAD ANY KIND OF RESPIRATORY
INFECTION OR IF THEY DEVELOPED
COVID.
COVID IS IN BLUE.
SO YOU CAN SEE AT ALL AGE
GROUPS, IF YOU DEVELOP COVID,
YOUR CHANCES OF DEVELOPING
COGNITIVE DIFFICULTIES ARE MUCH,
MUCH GREATER.
EXCEPT IF YOU'RE 70 YEARS OF
AGE, IT BAD NEWS, IT DOESN'T
MATTER WHAT INFECTION YOU GET,
YOU'RE DONE.
UNFORTUNATELY I'M GETTING CLOSER
TO THAT EVERY DAY.
OKAY.
THIS IS AN INTERESTING PET
STUDY.
HERE WHAT THEY DID IS THEY
LOOKED AT THE BRAIN AND THEY
AVERAGED THE INDIVIDUALS IN THAT
STUDY, SO THIS IS A CONSENSUS
SCAN HERE, AND IF YOU LOOK AT
THE COVID PATIENTS HERE, YOU CAN
SEE THAT THE ENTIRE BRAIN
ACTUALLY IS HYPOMETABOLIC.
AND MORE SO IN THE FRONTAL PARTS
OF THE BRAIN AS WELL AS THE
BASAL GANGLIA.
RELATIVELY THE POSTERIOR PARTS
ARE RELATIVELY SPARED.
THERE'S ANOTHER STUDY THAT
LOOKED AT THIS IN MORE DETAIL
AND WHAT THEY FOUND IS THAT IF
YOU LOOK AT THE HIND PART OF THE
BRAIN, YOU SEE MORE
ABNORMALITIES THERE THAN OTHER
PARTS OF THE BRAIN.
SO WHAT ARE THE UNDERLYING
POSSIBLE PATHOPHYSIOLOGICAL
MECHANISMS? DR. LIPKIN TALKED
ABOUT VIRAL REACTIVATION, SO
THAT'S CERTAINLY A POSSIBILITY
HERE.
COULD BE PERSISTENT VIRAL
INFECTION THAT YOU NEVER GOT RID
OF, OR IT COULD BE IMMUNE
DYSREGULATION OR SOMEHOW THEY
ALL MAY BE INTERLINKEDIN LINKEDE
WAY OR ANOTHER.
SO THIS STUDY JUST PUBLISHED
FROM YALE, AND THEY LOOKED AT
EBV REACTIVATION.
WHAT THEY FOUND WAS THAT, YES,
IN PATIENTS WITH LONG COVID, YOU
CAN FIND EVIDENCE OF
REACTIVATION OF EPSTEIN-BARR
VIRUS.
WHAT ABOUT PERSISTENT INFECTION?
SO WE KNOW AT LEAST WITH COVID,
IT'S ALL IN THE NOSE.
THE VIRUS GETS UP THERE, AND IT
INFECTS -- WE THOUGHT IT WOULD
BE PRETTY SIMPLE, WHAT WILL
HAPPEN IS YOU INFECT THE NASAL
MUCOSA AND THEN IT WILL JUST GO
UP THE CURB FORM PLATE AND
ENTERS THE BRAIN, OBVIOUSLY ALL
KINDS OF STUFF COMING IN FROM
THE NOSE INTO THE BRAIN.
AND YOU HAVE THE OLFACTORY NERVE
THAT GOES UP THERE.
INTERESTINGLY, YOU CAN FIND A
LOT OF VIRUS HERE IN THE NASAL
MUCOSA, AS YOU CAN SEE HERE IN
THIS ELECTRON MICROGRAPH.
ALL THESE BLACK DOTS ARE VIRAL
PARTICLES.
HOWEVER, IF YOU WERE TO LOOK AT
THE OLFACTORY BULB OR THE
OLFACTORY TUBERCLE, THERE'S
HARDLY ANY VIRUS THERE.
SO THE VIRUS DOESN'T GO UP THE
NOSE AND THE REASON FOR THAT IS,
IT DOESN'T INFECT THE OLFACTORY
NERVE.
WHAT IT AFFECTS ARE THE SUPPORT
CELLS, THE SUSTENTACULAR CELLS.
YOU GET THIS INFLAMMATION AND
THAT'S WHAT LEADS TO LOSS OF
SMELL.
WE LOOKED FOR THE VIRUS IN THE
BRAIN, AND BY MULTIPLE DIFFERENT
TECHNIQUES, WE DIDN'T FIND IT.
MOST PEOPLE AGREE WITH US, THERE
ARE SOME FEW REPORTS WHERE
PEOPLE HAVE FOUND RARELY
DETECTED VIRUS AND IF THEY HAVE,
IN VERY SMALL QUANTITIES.
MY COLLEAGUES HERE AT NIH
PUBLISHED THIS FABULOUS PAPER
WHERE THEY -- REALLY NICE WORK
LOOKING FOR SARS-COV-2, AND IF
YOU LOOK AT IT, THEY FOUND VIRUS
IN THE RESPIRATORY TRACT, LESS
THAN 14 DAYS.
YOU CAN FIND 9,000 COPIES, EVEN
BY ONE MONTH IT'S LESS THAN 1.
IF YOU LOOK AT THE BRAIN HERE,
LESS THAN 14 DAYS YOU HAVE 32,
BY ABOUT GREATER THAN A MONTH,
IT'S ALREADY GONE.
SO THIS ALONE CANNOT EXPLAIN
LONG COVID.
IT'S NOT A VIRAL ENCEPHALITIS.
HOWEVER, THERE ARE RARE
INSTANCES IN WHICH THE VIRUS CAN
INFICT FEK THE BRAIN.
THERE ARE TWO CASE REPORTS IN
THE LITERATURE OF CHILDREN WHERE
THEY CLAIM THAT THE VIRUS WENT
TRANSPLACENTALLY AND CAUSES
DEVASTATING NEUROLOGICAL
MANIFESTATION IN THESE CHILDREN,
AND THEY COULD FIND VIRUS AT
AUTOPSY AT LEAST IN THIS ONE
CHILD.
AND DR. EGAN FROM THE NATIONAL
INSTITUTES OF AGING JUST
PUBLISHED THIS PAPER WHERE SHE
DID FIND SOME EVIDENCE OF VIRAL
ANTIGEN IN THE PAPILLA OF THE
TONGUE.
AND THERE ARE THESE REPORTS
CLAIMING THAT THEY CAN FIND SOME
VIRAL ANTIGEN IN PATIENTS IN THE
SERUM TO THE SPIKE PROTEIN HERE,
BUT THIS STILL NEEDS TO BE
REPRODUCED BY OTHER LABS.
BUT WE KNOW THE PRESENCE OF
VIRAL ANTIGEN ALONE DOESN'T
NECESSARILY MEAN THAT'S THE
CAUSE OF DISEASE.
YOU HAVE LOTS OF OTHER DISEASES
WHERE ANTIGEN CAN PERSIST FOR A
LONG PERIOD OF TIME AND MAY OR
MAY NOT DRIVE ANY IMMUNE
DYSFUNCTION OR SYMPTOMS ALONE.
SO WHAT ABOUT IMMUNE
DYSREGULATION?
SO THIS IS A REALLY NICE PAPER
WHERE THEY AGAIN PUBLISHED
EARLIER THIS YEAR, AND WHAT THEY
SHOWED WAS THAT THEY USED THIS
MARKER CALLED TSPO, A LIGAND
THAT BINDS TO ACTIVATED
MICROGLIA IN THE BRAIN.
SO IT'S AN EVIDENCE OF -- CELL
ACTIVATION.
THEY FOUND THOSE INDIVIDUALS WHO
WERE COMPLAINING OF DEPRESSION
OR COGNITIVE DYSFUNCTION HAD
MORE EVIDENCE OF ACTIVATION
OF -- CELLS WITHIN THE BRAIN.
AND THIS IS ANOTHER STUDY FROM
THE NETHERLANDS, WHERE HERE THEY
SHOW WITH THAT SAME LIGAND, YOU
CAN SEE MASSIVE UPTAKE IN THE
BRAIN, WHILE THE NORMAL BRAIN IS
ALL RELATIVELY COLD.
AND WE LOOKED AT IT AT AUTOPSY
AND WE DO FIND THAT IN THESE
PATIENTS, YOU CAN FIND A
MICROGLIAL CELL ACTIVATION BOTH
IN THE GREY AND WHITE MATTER OF
PATIENTS WITH COVID.
BUT THESE ARE INDIVIDUALS WHO
HAD DIED LITERALLY ACUTELY FROM
THE INFECTION.
ALTHOUGH I DO BELIEVE THAT THESE
FINDINGS ARE RELEVANT FOR LONG
COVID AND I'LL TELL YOU WHY.
SO ONE OF THE THINGS YOU CAN DO
AT NIH IS HIGH RESOLUTION MRI
SCANS, AND WE CAN DO IT ON
AUTOPSY TISSUE.
SO WE WERE ABLE TO GET TISSUE
FROM THE MEDICAL EXAMINER'S
OFFICE IN NEW YORK OF
INDIVIDUALS WHO HAD DIED
SUDDENLY AT HOME, SO THESE WERE
NOT INDIVIDUALS WHO HAD MASSIVE
RESPIRATORY INFECTIONS.
MOST OF THEM DIDN'T EVEN REALIZE
THEY HAD ANYTHING WRONG WITH
THEM.
THIS IS EARLY IN THE PANDEMIC,
THEY WERE FOUND DEAD, EITHER IN
THE SUBWAY IN NEW YORK OR AT
HOME.
AND SO THESE INDIVIDUALS, HAD
THEY SURVIVED, THEY PROBABLY
WOULD HAVE DEVELOPED LONG TERM
SYMPTOMS BECAUSE I'LL SHOW YOU
THE PATHOLOGY WHEN YOU LOOK AT
THE BRAIN.
WE DID AN MRI SCAN, WE FOUND
THEIR BLOOD VESSELS WERE
ABNORMAL AND IN THE BLOOD
VESSEL, YOU CAN FIND THREE TYPES
OF PATHOLOGY IN THE SAME BLOOD
VESSEL.
SO YOU'VE GOT THICKENING HERE, A
SMALL CLOT OVER HERE, YOU MAKE A
SECTION FROM THAT BLOOD VESSEL
HERE AND YOU CAN SEE A MICRO
HEMORRHAGE AS WELL.
SO THERE'S VAST MICROVASCULAR
PATHOLOGY IN THESE PATIENTS.
AND WHEN WE LOOK FOR FIBRINOGEN
IN THE BRAIN THIS, IS A SMALL
BLOOD VESSEL HERE AND THE DARK
STAINING IS FIBRINOGEN, THIS IS
A VERY LARGE PROTEIN THAT SHOULD
NEVER ENTER THE BRAIN UNLESS THE
BLOOD VESSELS ARE DAMAGED.
YOU CAN SEE THERE IS LEAKAGE OF
FIBRINOGEN AROUND THE BLOOD
DEVELOPS AND EVEN IN THE
OLFACTORY BULB, YOU CAN SEE THIS
HERE, THIS IS IN THE PONS, AND
YOU CAN SEE THESE HIGH
RESOLUTION MRI IMAGES AT 11
TESLA THAT HAVE NEVER BEEN DONE
BEFORE IN THE HUMAN BRAIN.
SAME THING YOU CAN LOOK AT THE
SUBSTANTIA NIGRA HERE AND YOU
CAN SEE THERE'S LOSS OF SIGNAL
HERE IN THE SUBSTANTIA NIGRA AS
WELL IN THESE INDIVIDUALS, AND
THERE'S LEAKAGE OF FIBRINOGEN,
HERE IT'S RED INSTEAD OF BROWN.
SO WE LOOKED AT THE CELL
INFILTRATION OF THE BRAIN AND
WHAT WE FOUND, YOU FIND A LOT OF
MACROPHAGES BUT THAT'S NO
SURPRISE BECAUSE IF THERE ARE
THINGS LEAKING FROM THE BLOOD
VESSEL, THEN YOU WILL HAVE
MACROPHAGES THAT WILL COME AND
TRY TO CHEW IT UP AND TAKE IT
AWAY.
BUT ONCE THEY GET IN THERE,
THEY'RE YOUR BADDIESTS, THEY BAD
GUESTS, THEY JUST NEVER LEAVE.
WHEN THEY'RE ACTIVATED, THEY
CAUSE ALL KINDS OF DAMAGE AROUND
THEM.
WE FIND OTHER ASTROCYTES WHICH
ARE ACTIVATED, WHAT WE NEVER
FIND ARE T CELLS IN THE BRAIN.
IF THIS WAS A VIRAL
ENCEPHALITIS, YOU WOULD FIND T
CELLS ALL THROUGHOUT THE BRAIN.
YOU CANNOT GET VIRAL
ENCEPHALITIS AND NOT GET T
CELLS.
SO THE ABSENCE OF T CELLS TELLS
ME THAT THIS IS NOT A VIRAL
ENCEPHALITIS.
BUT WHAT YOU DO FIND IS YOU FIND
ACTIVATED PLATELETS SITTING
RIGHT ALONG THE BLOOD VESSEL AND
OCCLUDING SOME OF THESE BLOOD
VESSELS.
AGAIN WHEN WE QUANTIFIED THESE
THINGS, WE FIND MOST OF THE
PATHOLOGY IS PREDOMINANTLY THE
IN LOWER PARTS OF THE BRAIN, BUT
YOU DO FIND IT IN ALMOST ALL
PARTS OF THE BRAIN.
WE LOOKED AT THE BLOOD VESSELS
MORE CLOSELY.
WHAT WE FOUND IS THERE'S
ACTIVATION OF ADHESION MOLECULES
THERE, THERE'S -- WE FOUND MORE
IGM THAN IGG, BUT WE FOUND ALL
THESE ANTIBODIES.
SO WE THINK IT'S AN
ANTIBODY-MEDIATED PROCESS THAT
IS CAUSING DESTRUCTION OF THE
BLOOD VESSELS, MAKING THEM
LEAKY, AND THEN THINGS ARE
LEAKING INTO THE BRAIN.
AND I WANT TO BRING YOU BACK TO
THE COHORT OF PATIENTS THAT WE
BROUGHT HERE AT NIH, AND WHAT WE
FOUND WAS THAT IN ALL OF THEM,
WHEN WE LOOKED AT THE SPINAL
FLUID, THERE WERE ACTIVATED B
CELLS.
AND THE ANTIBODY PRODUCING B
CELLS, THAT AGAIN GOES REALLY
WELL WITH THE PATHOLOGY THAT I
SHOWED YOU THAT WAS AN
ANTIBODY-MEDIATED PROCESS.
AND THIS IS A STUDY FROM
HOPKINS.
THEY LOOKED AT PATIENTS AFTER
COVID AND WHAT THEY FOUND WAS
THAT THERE WAS A LOSS OF
ANTIBODIES DIRECTED AGAINST
H2 WHICH IS A RECEPTOR FOR
SARS-COV-2, THEY FOUND NOT ONLY
WERE THE ANTIBODIES ELEVATED BUT
THERE WAS A LOSS OF SWITCHING
FROM IGM TO IGG.
SO OVER A PERIOD OF THREE WEEKS
OR SO, YOU WOULD THINK THAT
THERE SHOULD BE CLASS SWITCHING
BUT IT NEVER REALLY OCCURRED.
SO HOW DO YOU ALL PUT THIS
TOGETHER I?
ONE WAY TO THINK ABOUT IT IS --
WE FIND ANTIBODIES THERE AND
THEY'RE STICKING TO THE BLOOD
VESSEL.
THE H2 IS EXPRESSED ON THE BLOOD
VESSEL.
IF YOU GET AN ANTIBODY AGAINST
AN ANTIBODY, THAT COULD
POTENTIALLY EXPLAIN THE
OBSERVATIONS THAT YOU SEE HERE.
THERE ARE A LOT OF BLOOD VESSELS
IN THE BRAIN.
THIS JUST SHOWS YOU THAT IF YOU
INVOLVE THE BLOOD VESSEL, ALMOST
ALL ASPECTS OF THE BRAIN.
BECAUSE THE ENTIRE BRAIN IS JUST
FULL OF BLOOD VESSELS.
AND THERE ARE CONSEQUENCES OF
ALL THIS, AND THAT RESULTS IN
NEURONAL DAMAGE.
HERE I'M SHOWING YOU -- IN THE
CEREBELLUM, THAT'S BECAUSE
THERE'S LOSS OF PURKINJE CELLS
SO ALL OF THESE NEURITES ARE
LOST AS WELL.
AGAIN LOOKING AT THE BRAINSTEM
HERE, 11 TESLA MRI SCANNING, YOU
CAN SEE THE MEDULLA OF THE
BRAIN, BEAUTIFULLY WITH ALL THE
NUCLEI THAT YOU CAN MAP.
AND SO I REALLY WANTED TO LOOK
AT THAT AND THE REASON IS THAT I
TOLD YOU THESE PATIENTS HAD DIED
SUDDENLY, WAS NOT ENTIRELY CLEAR
WHY THEY DIED.
ONE WOULD THINK IT WAS A CARDIAC
ARRHYTHMIA BUT THERE WAS NOTHING
REALLY WRONG WITH THEIR HEART,
BUT THERE IS A RESPIRATORY
CENTER, CALLED THE PREBOTZINGER
COMPLEX.
THIS ALLOWED ME TO LOOK AT THAT.
WHEN WE LOOKED AT IT, WHAT WE
FOUND WAS THAT THERE'S NEURON
NEURONAL -- MOST LIKELY THESE
PATIENTS HAD CENTRAL
HYPOVENTILATION, WHICH IS ALSO
TERMED -- CURSE, AND THAT'S HOW
I THINK MOST LIKELY THESE
PATIENTS DIED.
SO THERE ARE TWO STUDIES
RECENTLY PUBLISHED.
THE GUT MICROBIOME AND ISSUES
WITH -- IN PATIENTS WITH ME/CFS.
THIS SUBSCRIBES TO THE SAME
HYPOTHESIS EXCEPT WHAT IT'S
SAYING IS THAT BECAUSE OF ALL
THOSE THINGS, TRYPTOPHAN IS NOT
BEING ABSORBED AND NOT BEING
CONVERTED TO SEROTONIN, AND
THAT'S HOWL SOME OF THESE -- HOE
OF THESE CASCADE OF EVENTS HAVE
BEEN OCCURRING.
NONETHELESS, IT'S INTRIGUING
THAT THERE MAY BE SOMETHING
THERE.
A LOT OF THESE PATIENTS ARE ON
SSRIs AND IT DOESN'T SEEM TO
MAKE A DIFFERENCE, BUT IT
DOESN'T MEAN THAT TRYPTOPHAN MAY
NOT BE INVOLVED IN SOME WAY.
AND THIS IS ANOTHER STUDY THAT
JUST CAME OUT FROM YALE WHERE
THEY LOOKED AT THE EVV ANTIBODY,
BUT ANOTHER IMPORTANT
OBSERVATION THEY MADE WAS THAT
THERE WAS DECREASED LEVELS OF
CORTISOL IN THIS PATIENT
POPULATION.
SO THAT'S ANOTHER THING TO KEEP
A CLOSE WATCH ON.
OKAY.
WHAT ABOUT NEURODEGENERATIVE
DISEASES?
CAN SARS-COV-2 ACCELERATE IN
NEURODEGENERATIVE DISEASE?
IT'S POSSIBLE, BUT HERE IS
EVIDENCE FOR THAT.
AND THAT IS THE -- BIOBANK HAS
PATIENTS THEY'VE BEEN FOLLOWING
FOR A LONG TIME WITH MRI SCANS
BEFORE AND AFTER COVID, AND SO
THEY HAD AN OPPORTUNITY TO
STRATIFY THE POPULATION BY AGE
AND THEY LOOKED AT THE BRAIN
VOLUME AND THEY FOUND THAT HERE
THE BOTTOM LINE IS INDIVIDUALS
WITH COVID, THAT THERE WAS
EVIDENCE OF BRAIN ATROPHY IN
INDIVIDUALS AT LATER AGES OF
LIFE AND THEY ALSO HAD INCREASED
DIFFICULTY WITH COGNITIVE
FUNCTION.
SO THE BOTTOM LINE OF THIS STUDY
IS THAT WHATEVER YOU DO, JUST
DON'T GET OLD.
[LAUGHTER]
IN STUDY LOOKED AT CMF
NEUROFILAMENT LEVELS AND THEY
SHOWED INDIVIDUALS WHO HAD COVID
AND WE HAD HIGHER LEVELS OF
NEUROFILAMENT AND LOWER LEVELS
OF AMYLOID BETA IN THEIR CSF,
AND THAT IS A HALLMARK OF
ALZHEIMER'S DISEASE.
I'M GOING TO SKIP THIS SLIDE
HERE.
AND SOME PATIENTS DEVELOP
AUTONOMIC DYSFUNCTION, POTS,
DYSAUTONOMIA.
THIS IS EVIDENCE FOR THAT
SHOWING INDIVIDUALS STAND UP,
SUDDENLY THEIR HEART RATE GOES
UP AND THE BLOOD PRESSURE FALLS.
THERE ARE MANY DIFFERENT
ITERATIONS OF THIS THAT CAN
OCCUR IN THESE INDIVIDUALS.
AND WE LOOKED AT THAT HERE AS
WELL, WITH DR. GOLDSTEIN, AND
SEVERAL OF OUR PATIENTS HAVE A
SIMILAR KIND OF A SYNDROME HERE.
AND SOME PATIENTS WILL DEVELOP A
SMALL FIBER POLYNEUROPATHY, AND
YOU CAN DIAGNOSE THAT BY -- ON
SKIN BIOPSY.
THIS IS AN INTERESTING STUDY
SHOWING VARIOUS KINDS OF PAIN
SYNDROMES THAT OCCUR IN
INDIVIDUALS.
I'D LIKE TO POINT OUT TO YOU
HEADACHES, SO WE'VE SEEN A LOT
OF INDIVIDUALS WITH VARIOUS
KINDS OF HEADACHES.
SOME OF THEM HAVE UNDERLYING
CAUSES FOR IT.
THEY CAN HAVE THROM BEE SEES OFE
VENOUS SIGHNESSES, SO ONE NEEDS
TO MAKE SURE THERE AREN'T OTHER
CAUSES FOR THE HEADACHE, BUT
THAT'S A MAJOR CAUSE FOR PAIN IN
THIS PATIENT POPULATION.
SO WHAT CAN WE DO ABOUT THESE
PATIENTS?
CERTAINLY THEY SHOULD RECEIVE
SYMPTOMATIC TREATMENT.
A LOT OF THESE THINGS ARE
AMENABLE TO VARIOUS KINDS OF
SYMPTOMATIC TREATMENTS.
I'M NOT GOING TO GO OVER EACH
ONE OF THEM IN DETAIL.
AND THEN PEOPLE HAVE TALKED
ABOUT IMMUNE THERAPIES, IT JUST
DEPENDS ON WHAT WE THINK IS THE
UNDERLYING IMMUNE ABNORMALITY.
ONE CAN USE NONSPECIFIC THINGS,
FOR EXAMPLE, CORTICOSTEROIDS,
PLASMA PHORESIS, WE'RE CURRENTLY
DOING A TRIAL HERE ON IVIG.
ONE CAN ACTIVATE THE INNATE
IMMUNE SYSTEM IN MANY WAYS, AND
ONE WOULD THINK T CELLS WOULD BE
EXHAUSTED BUT YOU CAN REVERSE
THAT AS WELL.
WE NEED TO STRATIFY PATIENT
POPULATIONS AND LOOK AT THEM.
ANOTHER THING YOU CAN DO IS GET
VACCINATED.
YOU CAN PREVENT LONG COVID.
AND SO THIS IS AN INTERESTING
META-ANALYSIS THAT LOOKED AT ONE
DOSE OF THE VACCINE, DIDN'T MAKE
A HUGE DIFFERENCE.
YOU LOOK AT TWO DOSAGES, STARTS
SHIFTING TO THE LEFT, THAT'S
PROTECTING YOU AGAINST LONG
COVID.
LOOK AT THREE DOSAGES, AND IT'S
WAY DOWN TO THE LEFT.
I'VE HAD FIVE, OKAY?
ALL RIGHT.
SO CLINICAL TRIALS THAT WE'RE
DOING HERE, NATURAL HISTORY
STUDY.
WE'RE IN THE PROCESS OF DOING A
VIRAL RESERVOIR STUDY.
AND I TOLD YOU ABOUT IVIG STUDY.
SO I'D LIKE TO CONCLUDE THAT
SAYING DIRECT INVASION OF THE
BRAIN BY SARS-COV-2 IS RARE AND
DOES NOT EXPLAIN THE
NEUROLOGICAL COMPLICATIONS.
-- IMMUNE EXHAUSTION AND
ANTIBODY-MEDIATED PHENOMENON.
CLINICAL TRIALS WITH I KNEW KNOW
THERAPIES COULD BE CONSIDERED IN
PATIENTS WITH LONG COVID.
I'D LIKE TO ACKNOWLEDGE A NUMBER
OF PEOPLE WHO DID THIS WORK.
SO WE GOT THE BRAINS MAINLY FROM
REBECCA IN NEW YORK AND ALSO A
FEW BRAINS FROM MARCOUX HEFTY,
DANIEL PEARL, ELI EYE SER, OUR
NEUROPATHOLOGISTS WHO HELPED
WITH INTERPRETATION OF OUR
STUDIES.
SERENA WROTE A REVIEW PAPER ON
ALL THESE FINDINGS, AND THESE
ARE MY COLLEAGUES WHO DID ALL
THE IMMUNOSTAINING AND ALL THE
PATHOLOGY HERE.
THIS IS THE TH GROUP THAT DID AL
THE MRI WORK OVER HERE AT THE
BOTTOM.
AND THIS WAS OUR CLINICAL TEAM
OVER HERE, AND OUR NURSES, AND
DR. KOROSHETZ, WHO HAS SUPPORTED
OUR STUDIES ALL THE WAY FROM THE
BEGINNING.
SO I'LL STOP HERE AND IF THERE'S
TIME, TAKE QUESTIONS.
[APPLAUSE]
WE[APPLAUSE]
ONE QUESTION.
>> FRANCISCO.
ONE OF THE GRAPHS HINTED AT IT,
BUT DID YOU CONSISTENTLY
SEGREGATE OR ANALYZE YOUR DATA
BY SEX ALSO FOR ALL THE
PARAMETERS THAT YOU MEASURED?
AND DID YOU SEE DIFFERENCES?
>> THERE'S TOO MUCH OF AN ECHO.
CAN YOU REPEAT THE QUESTION?
>> SO IT APPEARS THAT LONG COVID
IS MORE COMMON IN WOMEN AS
COMPARED TO MEN.
NUMBER OF STUDIES HAVE POINTED
THAT OUT.
WHY THAT IS THE CASE, I DON'T
THINK IT'S QUITE EVIDENT TO US
AT THE MOMENT.
>> [INAUDIBLE]
>> EPIDEMIOLOGICALLY YOU SEE
MORE LONG COVID IN WOMEN
COMPARED TO MEN.
THAT'S WHAT I'M SAYING.
THAT'S ALL I KNOW.
>> HI.
I JUST HAD A QUESTION ABOUT THE
CORRELATIONS BETWEEN THE LONG
COVID AND NEURODEGENERATIVE
DISEASES.
DO THE RESULTS SUGGEST THAT IT'S
KIND OF EXACERBATING THE
PRE-EXISTING FORMATION OF THE
NEUROFIB LEAR TANFIBRILLARY TANT
CAUSING THE DIRECT FORMATION OF
NEW ONES LIKE CREATING THIS NEW
SOURCE OF THE NFTs?
>> SO WE DON'T KNOW FOR █SURE,
BUT I THINK IT WOULD BE EASY TO
IMAGINE THAT YOU ARE
PRECIPITATING AN UNDERLYING
DISEASE AND JUST EXACERBATING
IT: THERE ARE IN VITRO STUDIES
SHOWING THAT YOU CAN TAKE THE
SPIKE PROTEIN, TAKE SYNUCLEIN,
AMYLOID OR TAU AND ACTUALLY
CAUSING A GAITIONS.
ONCE THOSE AGGREGATES FORM THEY
PERFORM LIKE A PRION-LIKE
BEHAVIOR AND CAUSE MORE AND MORE
AGGREGATION.
SO ANY KIND OF RESPIRATORY
ILLNESS CAN TRIGGER THESE KINDS
OF THINGS.
IT'S NOT UNCOMMON, EVEN BEFORE
COVID, GRANDMA COMES IN THE
HOSPITAL, ADMITTED TO ICU, SHE
COMES OUT AND SHE'S NOT THE SAME
GRANDMOTHER.
SO I THINK THIS CHRONIC
INFLAMMATION CAN PRECIPITATE
THESE THINGS.
>> THANK YOU.
>> THANK YOU, DR. NATH.
[APPLAUSE]
>> IT'S TIME FOR LUN MP.
LUNCH.
AGAIN I MENTIONED LUNCH IS DOWN
IN THE TERRACE, SO GO OUT THESE
DOORS, GO TO THE RIGHT.
AT THE COFFEE SHOP, THERE WILL
BE SIGNS AND LUNCH HAS BEEN VERY
GRACIOUSLY PROVIDED BY THE OPEN
MEDICINE FOUNDATION TO SORT OF
TRY AND FOSTER SOME NETWORKING
SO YOU DON'T HAVE TO GO -- THERE
ARE CAFETERIAS, OF COURSE, IN
THIS BUILDING, BUT HAVING FOOD
THERE, AND THE POSTERS FROM THE
YOUNG INVESTIGATOR SYMPOSIUM
YESTERDAY.
SO I'D ENCOURAGE YOU TO GO THERE
AND VISIT WITH THE YOUNG
INVESTIGATORS, AND THERE ARE
LUNCHES PROVIDED THERE.
THERE'S ALSO A FEW TABLES FROM
OTHER PRIVATE FOUNDATIONS, AND
ALSO A TABLE FROM RTI, WHICH IS
THE DMCC, THE DATA MANAGEMENT
COORDINATING CENTER FOR THE NIH
ME/CFS NETWORK, WHERE THEY'RE
GOING TO SHOW YOU THEIR MAP
ME/CFS AND OTHER THINGS THAT
THEY'VE BUILT TO INCREASE THE
SHARING IN THE COMMUNITY OF DATA
ACROSS MANY, MANY DIFFERENT
STUDIES.
AND PLEASE COME BACK BY 1:05.
WE'RE GOING TO CUT A LITTLE TIME
SHORT AND TRY AND CATCH UP.
1:05.
THANK YOU.
>> GOOD AFTERNOON.
TODAY WE'RE GOING TO HAVE A TALK
FROM DR. MIKE SNELLER FROM NIAID
THAT ACTUALLY FITS AS THE FINAL
TALK IN THE SESSION THAT ENDED
RIGHT BEFORE LUNCH, AND
DR. SNELLER WAS VERY KIND TO
COME AND GIVE THIS TALK EVEN
THOUGH HE'S ON CLINICAL SERVICE,
SO THANK YOU SO MUCH FOR MAKING
THE TIME.
HIS TITLE IS LONGITUDINAL STUDY
OF COVID-19 SEQUELAE AND
IMMUNITY.
>> THANK YOU, JOE, FOR INVITING
ME TO GIVE THIS TALK.
WHAT I'M GOING DO IS BASICALLY,
AFTER GIVING A FEW BACKGROUND
POINTS, BRIEFLY DESCRIBE THE
STUDY THAT WE'RE DOING LOOKING
AT BOTH CLINICAL FEATURES AND
IMMUNOPATHOGENESIS OF POST COVID
SYNDROME, REVIEW THE DATA WE'VE
GOT SO FAR, MOST OF WHICH WAS
PUBLISHED ABOUT A YEAR AGO IN
THE ANNALS OF INTERNAL MEDICINE
AND THEN LET YOU KNOW WHERE THE
STANDING OF THE PROTOCOL IS NOW
AND WHAT OUR FUTURE DIRECTIONS
ARE AS OF NOW.
FIRST JUST A WORD ABOUT
TERMINOLOGY.
SO OBVIOUSLY THERE'S A NUMBER OF
TERMS THAT HAVE BEEN USED FOR
PERSISTENT SYMPTOMS IN PEOPLE
WHO HAVE BEEN INFECTED WITH
SARS-COV-2.
WHEN WE INITIALLY WROTE THIS
PROTOCOL IN THE SPRING OF 2020,
THE TERM LONG COVID HAD NOT BEEN
COINED YET, SO WE ENDED UP
CALLING IT POST-ACUTE SCWEA LAYE
OF SARS-COV-2 OR PASC.
I MAY LAPSE INTO USING ONE OF
THESE OTHER TERMS DURING THE
TALK, BUT BASICALLY THESE ALL
REFER TO THE SAME ENTITY.
THE SECOND POINT I WANT TO MAKE
IS ABOUT WHETHER YOU TALK ABOUT
POST COVID SEQUELAE, THEY FALL
INTO TWO BROAD GROUPS.
FORTUNATELY ONLY ABOUT 5 TO 10%
OF PEOPLE WHO CONTRACT
SARS-COV-2 INFECTION DEVELOP
VERY SEVERE LIFE-THREATENING
DISEASE THAT REQUIRES INTENSIVE
CARE UNIT ADMISSION, MECHANICAL
VENTILATION, ALL SORTS OF OTHER
THINGS AND IS OFTEN ASSOCIATED
WITH NOT ONLY PULMONARY FAILURE
BUT OTHER MULTISYSTEM ORGAN
FAILURE.
OVER HALF OF THOSE PATIENTS WILL
DEVELOP SOMETHING THAT HAS
PREVIOUSLY BEEN TERMED POST ICU
SYNDROME AND IS IDENTICAL TO
WHAT HAS BEEN DESCRIBED AS POST
ICU SYNDROME THAT INVOLVES
RESIDUAL SEQUELAE FROM ORGAN
SYSTEM DAMAGE DONE DURING ACUTE
ILLNESS, LUNG DAMAGE FIBROSIS
FROM BEING ON A VENTILATOR FOR
MANY WEEKS TO MONTHS, END ORGAN
DAMAGE TO THE KIDNEYS, LIVER,
HEART AND SO FORTH, STROKES, AND
COGNITIVE AND PSYCHIATRIC
CONSEQUENCES THAT PROBABLY
RELATE TO PROLONGED SEDATION AND
PROBABLY ANOXIC BRAIN INJURY.
I'LL TRY TO TALK A LITTLE
LOUDER.
SO THAT SYNDROME, AGAIN, HAS
PREVIOUSLY BEEN RECOGNIZED AND
IT OCCURS IN ALL CRITICAL
ILLNESSES AND OCCURS IN CRITICAL
ILLNESS FROM SARS-COV-2
INFECTION.
FORTUNATELY ONLY ABOUT 10% OF
PEOPLE AT LEAST BACK IN 2020
WOULD GET THAT SEVERE DISEASE.
I SUSPECT THAT'S MUCH LESS NOW
WITH ALL THE VACCINATION AND
IMMUNITY IN THE POPULATION.
THE SECOND SYNDROME, THE VAST
MAJORITY OF PATIENTS DON'T GET
THIS SEVERE CRITICAL DISEASE,
THEY GET MILD/MODERATE DISEASE
THAT DOES NOT REQUIRE
HOSPITALIZATION OR SUM PLEN
TAITION.
SOMEWHERE REPORTED BETWEEN 10
PROBABLY AT THE HIGH END 50% OF
INDIVIDUALS WHO HAVE MILD TO
MODERATE DISEASE WILL HAVE ONE
OR MORE PERSISTENT SYMPTOMS
AFTER RECOVERY FROM THE ACUTE
ILLNESS.
NOW THIS SYNDROME, LONG COVID,
OR WHATEVER YOU WANT TO CALL IT,
BEARS CERTAIN FEATURES TO OTHER
POST INFECTIOUS NON-CRITICAL
POST INFECTIOUS SYNDROMES,
INCLUDING POST INFECTIOUS ME/CFS
AND POST TREATMENT LYME DISEASE.
SO OUR PROTOCOL ENROLLED
PATIENTS IN THIS PRETTY MUCH
EXACT PROPORTION, ABOUT 90% OF
THE PATIENTS CURRENTLY ON OUR
PROTOCOL HAD MILD TO MODERATE
DISEASE THAT DID NOT REQUIRE
HOSPITALIZATION.
AND ONLY ABOUT 10% WERE
CRITICALLY ILL IN AN INTENSIVE
CARE UNIT REQUIRING MECHANICAL
VENTILATION.
SO THE OBJECTIVES OF THIS STUDY
WHEN WE FIRST STARTED OUT IN THE
SPRING OF 2020 WERE TO
CHARACTERIZE THE MEDICAL AND
MENTAL HEALTH SEQUELAE FOLLOWING
RECOVERY OF ADULTS FROM
COVID-19, AND ALSO TO
INVESTIGATE THE PATHOGENESIS OF
ANY IDENTIFIED CLINICAL
SEQUELAE.
SO AT THE TIME THIS PROTOCOL WAS
WRITTEN WE DIDN'T KNOW THAT MUCH
ABOUT LONG COVID, BECAUSE THE
DISEASE HAD ONLY BEEN IN THE
UNITED STATES FOR A FEW MONTHS.
THE ACUTE DISEASE.
SO WE MADE OUR INCLUSION
CRITERIA PRETTY LIBERAL.
THE ONLY THING WE INSISTED ON,
THIS WAS ALL DONE ON ADULTS, WAS
THAT WE WERE DEALING WITH
PATIENTS THAT CLEARLY HAD
COVID-19, SO WE REQUIRED
LABORATORY DOCUMENTATION OF
COVID-19 INFECTION THAT WE HAD
TO HAVE COPIES OF BEFORE WE
WOULD ENROLL THE INDIVIDUAL AND
THOSE CRITERIA ARE LISTED HERE,
BASICALLY A POSITIVE PCR OR
LATER ON ANTIGEN TESTS IN PEOPLE
WHO WERE UNABLE TO GET PCRs
BECAUSE OF LACK OF AVAILABILITY,
THEY COULD BE ELIGIBLE IF THEY
HAD A POSITIVE ANTIBODY TEST
THAT HAD BEEN APPROVED BY THE
FDA FOR EMERGENCY USE
AUTHORIZATION, AND A HISTORY
THAT WAS COMPATIBLE WITH
COVID-19 THAT OCCURRED AFTER
JANUARY 2020.
THE THIRD CRITERIA WAS THAT THEY
HAD TO BE AT LEAST SIX WEEKS
SINCE THE ONSET OF THEIR ACUTE
COVID ILLNESS.
WE DIDN'T REALLY WANT TO START
LOOKING AT PEOPLE UNTIL THEY'D
RECOVERED FROM THEIR ACUTE
ILLNESS.
IT TURNS OUT AS YOU'LL SEE MOST
PATIENTS WERE FAR BEYOND SIX
WEEKS BY THE TIME THEY ENROLLED
IN THE STUDY.
WE ALSO KNEW THERE WAS GOING TO
BE ESSENTIAL, SINCE WE WERE
GOING TO BE DOING A LOT OF
DIAGNOSTIC TESTING ON THESE
INDIVIDUALS, TO HAVE A CONTROL
GROUP WHO HAD NOT HAD COVID-19
AND IT WAS REASONABLY WELL
MATCHED WITH REGARDS TO AGE,
COMORBIDITIES, AND GENDER.
SO WE ENROLLED A CONTROL GROUP.
THE INCLUSION CRITERIA FOR THE
CONTROL GROUP, AGAIN, ONLY
ADULTS, WAS NO PAST KNOWN
DIAGNOSIS OF COVID-19 OR A
COVID-19-LIKE ILLNESS.
AND NO CURRENT SYMPTOMS THAT
WERE SUGGESTIVE OF COVID-19.
THEY ALSO HAD TO HAVE NEGATIVE
SEROLOGY FOR -- INITIALLY FOR
BOTH SPIKE ANTIGEN AND
SARS-COV-2 KNEW CLOA CAPSID
ANTIGEN BUT WITH THE ADVENT OF
VACCINATIONS, WE COULD ONLY LOOK
AT CAPSID ANTIGENS.
-- HAD NO HISTORY OF ANY
COVID-LIKE ILLNESS.
SO THIS WAS TRULY A
MULTIDISCIPLINARY STUDY WHEN WE
SET IT UP AND STILL IS.
FROM NIAID WE HAVE A NUMBER OF
INFECTIOUS DISEASE PHYSICIANS
BESIDES MYSELF, A STATISTICIAN
AND SEVERAL IMMUNOLOGISTS AND
IMMUNOLOGY LABORATORIES INVOLVED
TO HELP US LOOK AT PATHOGENESIS
AS WELL AS VIRAL SEROLOGY LAB,
WE ALSO APPROACHED INVESTIGATORS
FROM NIMH AND MADE SEVERAL OF
THEM CO-INVESTIGATORS.
INCLUDING TWO PSYCHIATRISTS AND
TWO PSYCHOLOGISTS TO HELP WITH
EVALUATING MENTAL HEALTH ASPECTS
OF THIS SYNDROME AND NEURAL
COGNITIVE FUNCTION IN THIS
SYNDROME.
AND WE ALSO HAD NHLBI
INVESTIGATORS THAT ARE
CARDIOLOGISTS AND PULMONOLOGISTS
WHO AGAIN HELPED US WITH THE
INTERPRETATION OF
CARDIOPULMONARY ABNORMALITIES
THAT WE EXPECTED TO SEE IN THESE
INDIVIDUALS.
SO THE STUDY PROCEDURES, SO
EVERYBODY AT THEIR BASELINE
EVALUATION STARTED WITH A
COMPREHENSIVE HISTORY AND
PHYSICAL EXAMINATION.
WE THEN RAN A WHOLE BATTERY OF
ROUTINE LABORATORY STUDIES TO
ASSESS MULTIPLE ORGAN FUNCTION,
KIDNEY, LIVER, EE MA TOPO HE
TICK FUNCTION, COAGULATION
PARAMETERS.
WE ALSO LOOKED AT
AUTOANTIBODIES, BIOMARKERS OF
INFLAMMATION AND TISSUE DAMAGE.
AGAIN REGARDLESS OF SYMPTOMS OF
WHETHER THEY HAD PERSISTENT
SYMPTOMS OR NOT.
ALSO THE PATIENTS FILLED OUT A
BATTERY OF QUESTIONNAIRES TO
ASSESS A VARIETY OF SYMPTOMS AS
WELL AS FUNCTIONAL STATUS.
WE DID SARS-COV-2 SEROLOGY AT
EVERY VISIT LOOKING AT BOTH
ANTIBODIES OF SPIKE PROTEIN AND
ANTICAPSID ANTIGEN AND THOSE WHO
HAD ADEQUATE ACCESS, WE ALSO DID
A PROCEDURE KNOWN AS
LEUKAPHORESIS THAT ALLOWS ONE TO
GET A LARGE AMOUNT OF MONO
NUCLEAR CELLS, LYMPHOCYTES AND
MONOCYTES WITHOUT HAVING TO TAKE
A LOT OF BLOOD VOLUME.
TO BE USE
FORD RESEARCH STUDIES ON THE
PATHOGENESIS OF THIS SYNDROME.
IT ALSO -- THE STUDY PROTOCOLS
INCLUDED A MENTAL HEALTH
EVALUATION, A SUBGROUP OF 200
INDIVIDUALS UNDERWENT FORMAL
PSYCHIATRIC INTERVIEWS BY THE
PSYCHIATRISTS ON THE STUDY.
THERE WERE ALSO A VARIETY OF
MENTAL HEALTH QUESTIONNAIRES
THAT WE ASKED PARTICIPANTS TO
FILL OUT.
AND NEUROCOGNITIVE TESTING
LOOKING SPECIFICALLY AT
PROCESSING SPEED, EPISODIC
MEMORY AND EXECUTIVE FUNCTION.
CARDIOPULMONARY EVALUATIONS
INCLUDED PULMONARY FUNCTION
TESTING, 6 MINUTE WALK TEST, ECG
AND ECHOCARDIOGRAM, WE DID A
CARDIAC MRI ON A SUBGROUP
INITIALLY, WE STOPPED DOING THAT
BECAUSE IT WAS VERY LABOR IN15
SIEVE AND WE WERE NOT FINDING
ANY HINT OF ABNORMALITIES IN OUR
PATIENTS.
FINALLY, WHEN WE WROTE THE
PROTOCOL, WE WEREN'T EXACTLY
SURE WHAT THE FULL SPECTRUM OF
POST COSYD SEQUELAE WOULD BE SO
WE WROTE STEPS THAT WE COULD DO
ANY DIAGNOSTIC TESTING NEEDED
NEEDED TO WORK UP SYMPTOMS OR
ABNORMAL FINDINGS IN EITHER
GROUP.
SO THIS PROTOCOL HAS FOLLOW-UP
VISITS EVERY SIX MONTHS AND
TOTAL DURATION IS THREE YEARS.
MOST OF THE BASELINE STUDIES AND
EVALUATIONS ARE REPEATED AT
EITHER THE SIX MONTH OR THE
12-MONTH FOLLOW-UP VISITS.
WE ALSO, DURING OUR LONGITUDAL
FOLLOW-UP, ARE COLLECTING DATA
ON SARS-COV-2 VACCINATION RATES,
REINFECTION RATES IN THE
COVID-19 GROUP, AND DEVELOPMENT
OF NEW INFECTION IN THE CONTROL
GROUPS WHO WERE INITIALLY
OBVIOUSLY NOT INFECTED OR HADN'T
BEEN INFECTED PRIOR TO
ENROLLMENT.
SO OF AFTER THE FIRST YEAR OF TE
STUDY, WE HAD ENROLLED OVER 300
PATIENTS AS PARTICIPANTS IN THIS
STUDY.
THE FINDINGS WE FELT WERE
IMPORTANT ENOUGH TO WARRANT
PUBLISHING A BASELINE PAPER OF
OUR BASELINE FINDINGS IN PEOPLE
WHO WERE RECRUITED DURING THE
FIRST YEAR OF THE STUDY.
SO THAT WAS JUNE 30TH, 2020
UNTIL JULY 1ST, 2021.
SO THIS IS A FLOW DIAGRAM OF THE
PATIENTS ENROLLED.
AS YOU SEE WE ASSESSED OVER 300
PATIENTS.
A FEW OF THEM DIDN'T MEET
INCLUSION CRITERIA OR DIDN'T
RETURN FOR THEIR FOLLOW-UP
VISITS.
WE ENDED UP ENROLLING 311
INDIVIDUALS.
122 IN THE CONTROL GROUP AND 189
IN THE COVID GROUP.
WE HAD TO EXCLUDE TWO PATIENTS
FROM THE CONTROL GROUP BECAUSE
THEIR ANTIBODY ASSAYS FOR
SARS-COV-2 ANTIBODIES CAME BACK
POSITIVE SO THE FINAL CONTROL
GROUP ANALYSIS GROUP FOR THE
CONTROLS WAS CONSISTENT OF 120
INDIVIDUALS WITH 189 POST COVID
PATIENTS.
SO FOR THE PROTOCOL, WE DEFINED
THE POST PASC OR LONG COVID, IF
YOU WILL, AT ANY SYMPTOM OR
MEDICAL CONDITION THAT BEGAN OR
WORSENED AFTER THE ONSET OF THE
ACUTE COVID-19 ILLNESS AND COULD
NOT BE EXPLAINED BY ANOTHER
DIAGNOSIS AND WAS STILL PRESENT
AT THE TIME OF THE ENROLLMENT OR
BASELINE VISIT.
AND FOR THIS -- TO THIS INITIAL
189 PATIENTS, THE MEANTIME
BETWEEN THE ONSET OF THEIR ACUTE
COVID SYMPTOMS AND WHEN THEY HAD
THEIR FIRST PROTOCOL VISIT WAS
162 DAYS.
SO FOR COMPARISON PURPOSES AND
TO MAKE IT FAIR WITH THE
CONTROLS, FOR SYMPTOMS WE ONLY
COUNTED SYMPTOMS FROM THE
CONTROLS THAT HAD AN ONSET OR
WORSENING WITHIN 162 DAYS OF
THEIR ENROLLMENT INTO THE
PROTOCOL.
SO THIS SLIDE WAS TAKEN
PARTIALLY FROM THE MANUSCRIPT
AND IT SHOWS SORT OF THE
BASELINE CHARACTERISTICS OF BOTH
GROUPS OF PARTICIPANTS.
SO THE CONTROLS ARE LISTED TO
THE LEFT, THE OVERALL COHORT OF
COVID-19 INDIVIDUALS IS SHOWN IN
THE NEXT COLUMN, AND THEN THE
LAST TWO COLUMNS ARE BROKEN DOWN
BY THOSE WITH AND WITHOUT
POST-ACUTE COVID SEQUELAE.
SO AS YOU CAN SEE, SLIGHTLY OVER
HALF OF THE COVID GROUP HAD ONE
OR MORE POST COVID SYMPTOMS.
LOOKING AT THE VARIOUS
CHARACTERISTICS, THIS WAS A
PRETTY WELL MATCHED COHORT.
YOU CAN SEE THE MEDIAN AGE AT
ENROLLMENT WAS VERY CLOSE IN THE
GROUPS.
51 IN THE CONTROL GROUPS AND 50
IN THE OVERALL COVID GROUP AND
DIDN'T REALLY DIFFER MUCH
BETWEEN THOSE WITH AND WITHOUT
PERSISTENT COVID -- POST COVID
SYMPTOMS.
COMPARING THE OVERALL COHORTS,
THEY WERE WELL MATCHED FOR
GENDER, BUT AS YOU CAN SEE, THE
PARTICIPANTS WHO HAD ONE OR MORE
PASCs TENDED TO BE -- HAD A
HIGHER RATE OF FEMALES IN THAT
GROUP.
IT IS PREDOMINANTLY CAUCASIAN
INDIVIDUALS, ALTHOUGH WE DID TRY
AS HARD AS WE COULD TO ENROLL
OTHER ETHNIC GROUPS AND RACIAL
GROUPS.
FINALLY IF WE LOOKED AT A NUMBER
OF PRE-EXISTING CONDITIONS,
AGAIN, THE CONTROLS WERE OBESE,
DIABETES, HYPERTENSION AND
MENTAL HEALTH PROBLEMS.
THE ONE THAT DID STAND OUT AS
YOU CAN SEE AND I'M SURE PEOPLE
HAVE HEARD OF IS THE LONG COVID
GROUP HAD A HIGHER PRE-COVID INS
KENS OF HISTORY OF HAVING
ANXIETY DISORDER.
BUT NOT OTHER MOOD DISORDERS
SUCH AS DEPRESSION OR BIPOLAR.
FINALLY AS I ALLUDED TO EARLIER,
THE MAJORITY OF THESE PATIENTS
WERE NOT HOSPITALIZED, ONLY A
LITTLE OVER 11% WERE
HOSPITALIZED FOR COVID-19 AND
HAD CRITICAL ILLNESS.
THE OTHER 89% HAD MILD ILLNESS
AND WERE NEVER HOSPITALIZED.
SO THIS IS A PLOT LOOKING AT
PRECOVID RISK FACTORS FOR THE
DEVELOPMENT OF PERSISTENT
SYMPTOMS OR LONG COVID AND WE
LOOKED AT ALL OF THE -- PRETTY
MUCH EVERYTHING IN THE PREVIOUS
TABLE.
YOU CAN SEE THE ONLY TWO, AGAIN,
ANY OF THE DOTS TO THE RIGHT OF
THIS -- OF THE DOTTED LINE ARE
ASSOCIATED WITH HIGHER ODDS OF
GETTING LONG COVID, THOSE TO THE
LEFT, LOWER ODDS OF GETTING LONG
COVID.
AND THE BARS ATTACHED TO EACH
CIRCLE ARE THE 95% CONFIDENCE
INTERVALS.
SO THERE ARE ONLY TWO FEATURES
OR PRECOVID RISK FACTORS THAT
WERE SIGNIFICANTLY ASSOCIATED
WITH THE DEVELOPMENT OF LONG
COVID.
ONE IS FEMALE GENDER AS YOU CAN
SEE THE ODDS RATIO WAS 2.34 AND
THE CONFIDENCE INTERVAL DID NOT
CROSS 1.
HISTORY OF A PRIOR ANXIETY
DISORDER WITH AN ODDS RATIO OF
2.78 AND, AGAIN, CONFIDENCE
INTERVAL NOT CROSSING 1.
THIS IS A SUMMARY OF THE
SYMPTOMS REPORTED IN BOTH
GROUPS, AND REALLY THESE ARE THE
SYMPTOMS THAT WERE REPORTED IN
MORE THAN 1% OF THE COVID GROUP.
AND AS YOU CAN SEE, ONLY ONE OF
THE BARS HAS A CONTROL GROUP
COLOR ON IT.
THAT'S BECAUSE THERE WERE NO
CONTROLS THAT IN THE LAST -- IN
THE PREVIOUS 162 DAYS PRIOR TO
ENROLLMENT HAD DEVELOPED ANY OF
THESE OTHER SYMPTOMS.
SO MOST OF THIS IS FOR THE COVID
GROUP, WHICH IS IN BLUE.
YOU CAN SEE THAT THERE IS THE
MOST PROMINENT SYMPTOM WAS
FATIGUE IN 26% OF THE WHOLE
COVID COHORT, AND COGNITIVE
DYSFUNCTION, ABOUT 20%,
SHORTNESS OF BREATH IN SOMEWHERE
AROUND 18%, SO ON ALL THE WAY
DOWN.
SO NOW MOST RECOGNIZED AND
COMMON SYMPTOM IN PEOPLE THAT
PERSIST FOLLOWING ACUTE ILLNESS.
THE ONLY ONE THAT SHOWED UP IN
THE CONTROL GROUP AT ALL WAS
ANXIETY THAT DEVELOPED WITHIN
162 DAYS OF ENROLLMENT BUT IT
WAS FAR LESS IN THE CONTROL
GROUP THAN IN THE COVID GROUP.
SO I DON'T REALLY HAVE TIME IN
THIS TALK TO GO THROUGH EVERY
SINGLE TEST WE DID AND COMPARE
IT WITH CONTROLS AND THE POST
COVID GROUP AND THE POST COVID
GROUP WITH AND WITHOUT PERSIST
10 SYMPTOMS SO I'M GOING TO
SUMMARIZE THOSE FINDINGS HERE.
PARTICIPANTS IN THE COVID-19
GROUP REPORTED MORE SYMPTOMS
COMPARED TO THE CONTROL GROUP.
OBVIOUSLY AS I SHOWED YOU IN THE
PREVIOUS SLIDE.
AND AGAIN THE MOST COMMON
SYMPTOMS ARE NOW WELL-KNOWN, I
THINK, TO MOST PEOPLE.
ABNORMAL FINDINGS ON PHYSICAL
EXAM OR LABORATORY TESTING
OCCURRED WITH SIMILAR FREQUENCY
IN BOTH THE COVID-19 GROUP AND
THE CONTROL GROUPS, AND WERE NOT
ASSOCIATED WITH ANY POST-ACUTE
SEQUELAE OF COVID-19.
THAT LATTER POINT IS ILLUSTRATED
HERE FOR THE SORT OF PASC AS A
WHOLE.
AGAIN, IN ANOTHER FOREST PLOT.
ON THE LEFT IS LISTED THE
DIAGNOSTIC TESTS THAT WE AN
ANALYZED, THE ODDS RATIO OF IT
BEING ASSOCIATED WITH ANY
POST-ACUTE COVID MANIFESTATION
ARE SHOWN IN THE DOTS, IN THE
COLUMN OVER HERE.
YOU CAN SEE THAT REALLY NOTHING,
NONE OF THESE ABNORMALITIES ON
ANY OF THESE TESTS OR LABORATORY
VALUES WAS SIGNIFICANTLY
ASSOCIATED WITH POST-ACUTE
SYMPTOMS OF COVID-19.
WE THEN BROKE THIS DOWN BY
INDIVIDUAL GROUPS OF SYMPTOMS SO
WE LOOKED AT FATIGUE,
CARDIOPULMONARY SYMPTOMS, AND
NEUROCOGNITIVE SYMPTOMS, AND DID
THE SAME ANALYSIS.
AND THE RESULTS WERE EXACTLY THE
SAME AND I'LL SHOW YOU AN
EXAMPLE JUST OF THE NEUROLOGIC
SYMPTOMS.
IN THIS CASE, NEUROLOGIC
SYMPTOMS INCLUDED COGNITIVE, ANY
KIND OF SYMPTOM OF COGNITIVE
IMPAIRMENT OR HEADACHE OR
PARESTHESIAS.
AGAIN IT LOOKS VERY SIMILAR TO
THE FIRST FOREST PLOT I SHOWED
YOU IN THAT NONE OF THE TESTING
WE DID CORRELATED WITH
NEUROCOGNITIVE OR NEUROLOGIC
SYMPTOMS.
SPECIFICALLY IF YOU LOOK AT THE
ONES THAT I'VE HIGHLIGHTED, A
BIOMARKER OF BRAIN INJURY WAS
NOT ASSOCIATED WITH ANY OF THE
NEUROLOGIC SYMPTOMS.
A 6 HAD B 6-MINUTE WALK TEST ISD
MEASURE OF STRENGTH AND BALANCE
AND CARDIOPULMONARY FUNCTION.
A AGAIN DISTANCE WALKED IN
6 MINUTES WAS NO SIGNIFICANTLY
DIFFERENT IN THOSE WITH OR
WITHOUT NEUROLOGIC SYMPTOMS.
PROBABLY MOST IMPORTANTLY, NONE
OF THE NEUROCOGNITIVE TESTING IN
ANY OF THE THREE DOMAINS WAS
SIGNIFICANTLY DIFFERENT OR
SIGNIFICANTLY ASSOCIATED IN AN
ODDS RATIO OF 1.
SO TO SUMMARIZE, PARTICIPANTS
WITH PASC SELF-REPORTED -- EVEN
THOUGH WE HAD A LACK OF SORT OF
OBJECTIVE FINDINGS IN THESE
INDIVIDUALS, CERTAINLY THE
PRESENCE OF THESE SYMPTOMS HAD A
MAJOR EFFECT ON THE QUALITY OF
LIFE IN THESE INDIVIDUALS.
AND THESE PATIENTS HAD
SIGNIFICANTLY LOWER SCORES ON
BOTH THE MENTAL HEALTH AND
PHYSICAL HEALTH PORTIONS OF THE
SF36 HEALTH SURVEY.
SELF-REPORTED ANXIETY WAS ALSO
INCREASED IN THE GROUP WITH
POST-ACUTE COVID -- SEQUELAE OF
COVID.
THIS IS PROBABLY LIKELY DUE TO
WORRY AND CONCERN AND ANXIETY
ABOUT SYMPTOMS THEY WERE HAVING
THAT WERE UNEXPLAINED.
AND FINALLY, EXPLORATORY STUDIES
WE DID IN THE LABORATORY LOOKING
AT A NUMBER OF BIOMARKERS OF
INFLAMMATION IN AUTOANTIBODIES
AND VIRAL ANTIGENS, WE COULD NOT
FIND ANY EVIDENCE OF ABNORMAL
SYSTEMIC IMMUNE ACTIVATION,
AUTOIMMUNE DISEASE OR PERSISTENT
VIRAL INFECTION.
SO LIKE ANY STUDY, THIS STUDY
HAS ITS STRENGTHS AND
WEAKNESSES.
I THINK THE STRENGTHS ARE THAT
IT REQUIRE LABORATORY-CONFIRMED
DEFINITE SARS-COV-2 INFECTION SO
WE ARE EVALUATING PATIENTS WHO
DID FOR SURE HAVE SARS-COV-2
INFECTIONS.
THE CONCURRENT ENROLLMENT OF
CONCURRENT CONTROL GROUP THAT
WAS SIMILAR TO THE COVID-19
GROUP IN AGE AND COMORBIDITIES
AND DEMOGRAPHIC CHARACTERISTICS
BUT HAD NO HISTORY OF OR
SEROLOGIC EVIDENCE OF PRIOR
SARS-COV-2 INFECTION WAS VERY
IMPORTANT BECAUSE WHEN YOU DO
ALL THIS DIAGNOSTIC TESTING IN
PEOPLE WHO DON'T REALLY HAVE
SYMPTOMS, WE DID CARDIOPULMONARY
TESTING IN PEOPLE WHO HAD NO
SYMPTOMS AND PEOPLE WHO HAD
SYMPTOMS OUTSIDE THE
CARDIORESPIRATORY SYSTEM, SAME
FOR NEUROCOGNITIVE TESTING,
EVERYBODY GOT THE SAME BATTERY
OF TESTS.
YOU'LL PICK UP SORT OF ALL MINOR
ABNORMALITIES THAT YOU'RE NOT
GOING TO KNOW WHETHER THESE ARE
DUE TO THE UNDERLYING INFECTION
OR JUST THE VARIABILITY OF THE
TESTING, ESPECIALLY WHEN YOU DO
SO MANY DIAGNOSTIC TESTS ON
PEOPLE, ESPECIALLY THE CONTROL
GROUP WHO DON'T HAVE AN
INDICATION FOR THOSE TESTS.
FINALLY, WE DID IN AN ORGANIZED
WAY PROTOCOL-DEFINED
PRESPECIFIED DIAGNOSTIC
EVALUATIONS ON ALL PARTICIPANTS,
INCLUDING CONTROLS, THOSE
WITH -- WHO HAD COVID AND DID
NOT HAVE ANY RESIDUAL SYMPTOMS
AND THOSE WHO HAD RESIDUAL
SYMPTOMS, THEY ALL GOT THE SAME
WORKUP.
SO LIMITATIONS.
ONE, AT LEAST AT THE TIME FOR
THIS PAPER AND TO A LESSER
EXTENT I HOPE NOW, IT IS A
RELATIVELY SMALL SAMPLE SIZE,
BUT AGAIN, IT'S HARD TO DO ALL
THIS DIAGNOSTIC TESTING AT ONE
CENTER IN ONE CLINIC ON A LARGE
NUMBER OF PATIENTS.
MOST -- AND AGAIN, MOST AS I'VE
MENTIONED, MOST OF THE
PARTICIPANTS IN THIS STUDY,
APPROXIMATELY 90% HAD MILD TO
MODERATE ACUTE ILLNESS THAT
DIDN'T REQUIRE HOSPITALIZATION,
SO THESE FINDINGS DON'T
NECESSARILY APPLY TO PEOPLE
WHOSE ACUTE ILLNESS WAS SEVERE
AND REQUIRED INTENSIVE CARE
TREATMENT.
AND FINALLY, AS I ALSO MENTIONED
AND ALLUDED TO, THE PREVALENCE
OF PASC THAT WE FOUND IN THIS
INITIAL COHORT WHICH WAS 55%
ALMOST CERTAINLY REPRESENTS A
MARKET OVERESTIMATION.
AS I THINK INDIVIDUALS WHO DO
SUFFER FROM POST COVID SYMPTOMS
WERE PROBABLY MORE MOTIVATED TO
ENROLL IN THE STUDY IN THE HOPES
WE WOULD FIND AN EXPLANATION FOR
THEIR SYMPTOMS.
SO THIS IS THE CURRENT STATUS OF
THE PROTOCOL AS OF A FEW WEEKS
AGO.
SO OUR TOTAL ENROLLMENT IS NOW
UP TO 530.
IN THE CONTROL GROUP, WE NOS NOW
HAVE 246 CONTROLS AND IN THE
COVID-19 GROUP, 284.
THE BREAKDOWN AS IT STANDS RIGHT
NOW IS, AGAIN, ABOUT 50/50
HAVING POST COVID SYNDROME AND
THE OTHER 50% HAVING NO RESIDUAL
SYMPTOMS.
SO WE'RE JUST NOW STARTING TO
LOOK AT THE ONE-YEAR DATA.
THERE'S 247 OF THE COVID-19
COHORT THAT HAVE COMPLETED THEIR
ONE-YEAR FOLLOW-UP.
AT LEAST THEIR ONE-YEAR
FOLLOW-UP AND SOME HAVE
COMPLETED MORE THAN THAT.
AND THIS LOOKS AT THE -- WHAT
HAPPENS TO THE SAME SYMPTOMS I
SHOWED YOU ON AN EARLIER SLIDE
BETWEEN BASELINE AND MONTH 12.
AND YOU CAN SEE WITH FATIGUE,
THERE'S WHAT I THOUGHT WAS A
RATHER SURPRISING RESOLUTION OF
FATIGUE IN THE PATIENTS -- NO
LONGER HAD IT AT ONE YEAR.
THE COGNITIVE SYMPTOMS WERE NOT
QUITE AS IMPRESSIVE A DROP BUT
VIRTUALLY EVERY SYMPTOM WITH THE
EXCEPTION OF ANXIETY WAS
DECREASED AT THE ONE-YEAR
FOLLOW-UP.
AND BY DECREASED, I MEAN THE
SYMPTOMS WERE GONE.
THEY SAID THEY WERE BETTER, THEY
STILL GOT COUNTED AS HAVING
FATIGUE, IT HAD TO COMPLETELY
RESOLVE TO BE PUT IN THE GREEN
BAR, OR A CONSIDERED RESULT.
SO DURING THE LAST YEAR AND A
HALF, SORT OF AN INTERESTING AND
I THINK A UNIQUE OPPORTUNITY HAS
COME ALONG IN THAT MEMBERS OF
OUR CONTROL GROUP STARTING ABOUT
IN DECEMBER OF '21, WHEN THE
OMICRON VARIANT SORT OF HIT THIS
AREA AND BECAME THE DO DOMINANT
VARIANT AND HAS REMAINED THE
DOMINANT VARIANT IN THIS AREA,
HALF OF OUR CONTROL GROUP HAS
NOW BECOME INFECTED WITH -- AT
LEAST ONCE WITH SARS-COV-2.
THESE ARE PEOPLE WHO AGAIN HAD
ONE OR MORE VISITS AS CONTROLS
WHO WERE NOT INFECTED BECAUSE WE
CHECK SEROLOGIES AT EVERY VISIT
AND LOOK FOR SEROCONVERSION BUT
THESE PEOPLE HAD SYMPTOMATIC --
THIS OFFERS A UNIQUE OPPORTUNITY
SO YOU HAVE THE IDEAL SORT OF
CONTROL COHORT.
YOU HAVE A GROUP OF INDIVIDUALS
WHO HAD EXTENSIVE EVALUATION
PRIOR TO BECOMING INFECTED WITH
SARS-COV-2, AND ALL THESE PEOPLE
AGREED TO REMAIN ON THE PROTOCOL
AND CAN CONTINUE UNDERGOING
THESE SAME MANIFESTATIONS, SO
THEY'RE THE PERFECT CONTROL
GROUP AND IT GIVES YOU THE MOST
ACCURATE ESTIMATE OF PREVALENCE
OF LONG COVID, HOW MANY PEOPLE
THAT GET ACUTE COVID DEVELOP
PERSISTENT -- OR CONTINUE ON TO
HAVE PERSISTENT SYMPTOMS, SINCE
YOU KNOW THE COHORT BEFORE AND
AFTERWARDS, SO THERE'S NO BIAS
AS FAR AS REFERRAL BIAS OR
SELF-REFERRAL BIAS OR THINGS
LIKE THAT.
SO WHEN WE LOOKED AT THIS
COHORT, AND AGAIN, ALL THESE
INDIVIDUALS, NONE OF THESE
INDIVIDUALS REQUIRED
HOSPITALIZATION.
THEY ALL HAD MILD TO MODERATE
ILLNESS.
NONE OF THE INFECTED CONTROLS.
SO IF WE LOOK AT THE INCIDENCE
OF PO POST-ACUTE SEQUELAE OF CO,
ONLY ONE INDIVIDUAL OUT OF THE
134 DEVELOPED -- OR HAD
PERSISTENT SYMPTOMS FOLLOWING
INFECTION.
THE OTHER 133 COMPLETELY
RECOVERED AND HAVE NO LONG COVID
SYMPTOMS.
SO THAT WAS REALLY A STRIKING
FINDING AND I THINK THAT TELLS
YOU THAT THIS IS A MORE ACCURATE
WAY OF DETERMINING PREVALENCE
THAN JUST OPEN-ENDED SELF
REFERRAL OR PHYSICIAN REFERRAL.
AND I THINK IT GIVES YOU AN IDEA
OF WHAT THE CURRENT PICTURE OF
LONG COVID IS NOW AND WILL BE IN
THE FUTURE.
WHETHER IT'S AS LOW AS 1% OR
LESS, THE SAMPLE SIZE IS TOO
SMALL TO TELL BUT THIS SHOWS YOU
THE BASELINE CHARACTERISTICS I
WAS TRYING TO FIGURE OUT WHY
THERE'S ANYTHING IN THE
DEMOGRAPHICS OF THIS -- OF THE
INFECTED CONTROLS THAT WAS
DIFFERENT AND THAT MIGHT EXPLAIN
THIS HUGE DIFFERENCE.
SO THIS TABLE JUST COMPARES THE
ORIGINAL COHORT TO THE RIGHT,
THE 189 THAT I JUST DISCUSSED,
WITH THE 134 INFECTED CONTROLS
WHO GOT INFECTED AFTER ONE OR
MORE PROTOCOL VISITS.
SO THEY REALLY LOOKED VERY
SIMILAR AS FAR AS ALL THE
DEMOGRAPHICS, THE PRECOVID
CONDITIONS, PRECOMORBIDITIES,
BUT THE BIG DIFFERENCE IS SHOWN
AT THE BOTTOM, WHICH FIRST OF
ALL IS THAT ONLY TWO OF THE
INFECTED CONTROLS WERE INFECTED
PRIOR TO DECEMBER 2021, THAT
WOULD HAVE BEEN IN THE ALPHA OR
DELTA VARIANT STAGE, SO THE VAST
MAJORITY WERE INFECTED WITH
OMICRON VARIANTS.
SECOND, IF YOU LOOK AT THE
VACCINATION RATES, IN THE
INITIAL COHORT OF 189, ONLY ONE
OF THOSE INDIVIDUALS HAD BEEN
VACCINATED PRIOR TO CONTRACTING
COVID.
THAT'S BECAUSE MAINLY VACCINES
WEREN'T AVAILABLE DURING THAT
FIRST YEAR OF THE STUDY FOR MOST
INDIVIDUALS.
IN SHARP CONTRAST TO THAT IS
ONLY ONE INDIVIDUAL IN THE
INFECTED CONTROL GROUP WAS NOT
VACCINATED PRIOR TO CONTROL --
SO VACCINATION RATE WAS 99%, AND
THAT'S RECEIVING AT LEAST TWO
VACCINES AND ONE BOOSTER, AT
LEAST ONE BOOSTER.
SO THERE'S SIGNIFICANT
DIFFERENCE IN THE INCIDENCE OF
POST-ACUTE SEQUELAE OF COVID
SEEING THESE INFECTED CONTROLS
IS PROBABLY LARGELY RELATED TO A
HIGH VACCINATION RATE AND
PERHAPS THE OMICRON VARIANT AND
THE FACT THAT THERE'S NO
REFERRAL BIAS IN THIS
POPULATION.
SO THE STUDY IS ONGOING.
WE STILL ARE ENROLLING PATIENTS.
THESE ARE SORT OF LISTED SORT OF
WHAT'S CURRENTLY GOING ON AND
WHAT SOME OF THE GOALS ARE.
SO WE'RE GOING TO CONTINUE TO
FOLLOW THE PREVALENCE OF PASC
OVER TIME.
WE'RE LOOKING AT LONGITUDAL
FOLLOW-UP, NEUROCOGNITIVE
FUNCTION AND SEE IF THERE'S ANY
CHANGE PAST ONE YEAR.
ONE YEAR AND BEYOND.
WE'RE LOOKING AT THE EFFECT OF
REINFECTION OF THE COVID-19
GROUP ON PERSISTENT SYMPTOMS
DUE -- LONG COVID SYMPTOMS AND
PEOPLE WHO HAVE THEM GET WORSE
AFTER RE-INFECTION.
UP TO THIS POINT, AS OF TODAY,
41% OF THE ENTIRE COVID CORE
HORT HAS EXPERIENCED ONE OR MORE
REINFECTIONS AND WE'RE IN THE
PROCESS OF ANALYZING HOW THAT
IMPACTS REPORTED SYMPTOMS THAT
THEY HAVE OR DON'T HAVE.
AND WE'RE LOOKING AT DOING
ADDITIONAL BIOMARKER STUDIES
LOOKING AT MORE BIOMARKERS.
IN FACT, WE'RE JUST FINISHING A
SET OF EXPERIMENTS INVOLVING
SEFERLG THOSEVERAL THOUSAND SAMM
THE ENTIRE COHORT LOOKING AT
EVERY CYTOKINE THAT IS REPORTED
HAVING BEEN ASSOCIATED IN OTHER
PUBLICATIONS WITH LONG COVID.
WE'RE ALSO GOING TO ANALYZE THAT
NOT JUST AS A WHOLE GROUP, BUT
BREAK IT DOWN BY GENDER, GIVEN
THE GENDER DIFFERENCES IN LONG
COVID SYMPTOMS.
WE'RE STARTING TO LOOK MORE AND
MORE AT VIRAL PERSISTENCE
LOOKING AT BOTH PLASMA
NUCLEOCAPSID AND SPIKE PROTEIN
LEVELS.
-- SHOW NOBODY'S POSITIVE FOR
THAT IN ANY GROUP, INCLUDING
CONTROLS OR NON-CONTROLS.
SPIKE PROTEIN LEVELS, THERE ARE
TWO MAIN ASSAYS BEING USED AND
WE'VE SENT BLINDED SAMPLES TO
TWO CABINETRIES THAT ARE LABORAS
ASSAY, TWO SAYING MARKEDLY
DISCREPANT.
STILL UP IN THE AIR WHAT THAT'S
REFERRING TO THERE.
AND WE'VE STOPPED RECRUITING
PEOPLE WHO HAVE HAD COVID IN THE
LAST YEAR AND BEEN FOCUSING ON
RECRUITING ONLY COVID-NEGATIVE
CONTROLS, AS FAR AS WE CAN TELL,
COVID-NEGATIVE CONTROLS, WITH
THE IDEA THEY'RE ALL GOING TO
CONTRACT SARS-COV-2 INFECTION,
AND THAT WILL BE, I THINK, A
VERY VALUABLE COHORT TO ENLARGE
AND TO STUDY TO GET A TRUE LOOK
AT WHAT THE PREVALENCE OF LONG
COVID IS IN 2023-2024 IN A
HIGHLY VACCINATED POPULATION.
SO THAT'S THE END OF MY TALK.
[APPLAUSE]
>> I HAVE ONE QUESTION.
CAN YOU HEAR?
>> BARELY.
>> HAVING FINALLY CONTRACTED
COVID ABOUT SIX WEEKS AGO, I'M
CURIOUS IF YOU HAVE DATA ON THE
CONTROLS, WHETHER THEY HAD
ACCESS TO ANTIVIRAL THERAPY LIKE
PAXLOVID.
>> I'M SORRY, I MISSED THE LAST
PART.
>> YOUR THOUGHT ON WHETHER OR
NOT THE CONTROLS HAD -- IF YOU
HAVE DATA ON WHETHER OR NOT THEY
RECEIVED ANTIVIRAL THERAPY.
PAXLOVID.
>> OH, PAXLOVID.
YEAH, WE RECORD -- OH, ACTUALLY
MOST OF THEM DIDN'T.
GET
PAXLOVID.
I DON'T KNOW, IT'S NOT -- MOST
OF THE REASONS -- WE RECORD THAT
DATA, BUT MOST OF THE PEOPLE SAY
I JUST DIDN'T FEEL SICK ENOUGH
TO GET IT.
SOME PEOPLE STARTED TAKING IT
AND DIDN'T LIKE THE SIDE
EFFECTS.
SOME PEOPLE HAD DRUG
INTERACTIONS THAT WERE HARD TO
GET AROUND LIKE WITH
ANTICOAGULANTS AND STUFF.
SO I THINK THE USE OF PAXLOVID,
AT LEAST MY EXPERIENCE ON THIS
STUDY, IS NOT VERY HIGH.
I THINK IT'S GOING TO BE EVEN
LESS NOW IF YOU HAVE TO PAY THE
INSURANCE CO-PAY FOR IT, WHICH
AT LEAST FOR MY INSURANCE, NIH
INSURANCE COVERAGE IS ABOUT $400
FOR A COURSE.
THAT'S THE CO-PAY.
>> I WAS VERY LUCKY MY INSURANCE
COVERED IT.
HOW ABOUT THE ONE PATIENT WHO
DEVELOPED PASC, DO YOU KNOW IF
THAT ONE GOT --
>> I DON'T RECALL THAT THAT
INDIVIDUAL GOT -- BUT I DO KNOW
THAT ALL OF HER SYMPTOMS THAT
SHE HAD OF PASC CONCENTRATION
IMPAIRMENT AND FATIGUE WERE
PRESENT AS A CONTROL.
SHE JUST FELT THAT THEY WORSENED
AFTER THE INFECTION.
SO BY OUR DEFINITION, WE COUNTED
THAT AS IN THE LONG COVID GROUP.
[APPLAUSE]
THESE ARE TOUGH ACTS TO FOLLOW
WHEN YOU COME UP HERE.
SO OUR LATEBREAKING SESSION IS
THREE 10-MINUTE TALKS AND WE'RE
GOING TO BE LED OFF BY AGOSTINA
CASAMENTO-MORAN FROM JOHNS
HOPKINS, UNDERSTANDING THE
BEHAVIORAL FEATURES OF FA TEEK
IN LONG COVID.
AGOST?
>> GOOD AFTERNOON, EVERYBODY.
THANK YOU FOR GIVING ME THE
OPPORTUNITY TO PRESENT TODAY AND
SHARE PART OF OUR WORK, WHICH IS
AIMING TO UNDERSTAND THE
BEHAVIORAL FEATURES OF FATIGUE
IN LONG COVID.
BUT BEFORE I START, I WOULD LIKE
TO HIGHLIGHT THAT THE WORK THAT
I'M SHARING TODAY RESULTS FROM A
STRONG COLLABORATION WITH OTHERS
AS WELL AS THE HOPE REGISTRY AT
JOHNS HOPKINS.
TOGETHER WE HAVE WORKED
COLLABORATIVELY TO MAKE SURE
THAT OUR WORK IS INCLUSIVE, IT
TAKES INTO CONSIDERATION BOTH
THE SCIENTIFIC AND CLINICAL
PERSPECTIVE, AND THAT WE CAN
QUICKLY TRANSLATE WHAT WE LEARN
BOTH TO THE CLINIC AND THE
COMMUNITY.
SO FOR TODAY'S TALK, I WOULD
LIKE TO FIRST GIVE YOU A BRIEF
OVERVIEW ABOUT COVID FATIGUE.
I WILL SHARE OTHER FEATURES OF
FATIGUE WE'RE FINDING AT
BASELINE AND FINISH WITH A BRIEF
TAKE-HOME MESSAGE AND A QUICK
OVERVIEW OF WHAT ARE OUR NEXT
STEPS.
SO AS WE ALL KNOW, DEBILITATING
FATIGUE IS THE MOST COMMON
SYMPTOM IF LONG COVID.
IN LONG COVID.
IN ADDITION, 1 IN 4 INDIVIDUALS
WITH LONG COVID WILL MEET THE
DIAGNOSIS CRITERIA FOR ME/CFS,
WHICH IS IN ITSELF A CONDITION
THAT IS CHARACTERIZED BY
DEBILITATING FATIGUE.
HOWEVER, THE EXACT CLINICAL
PRESENTATION OF FATIGUE IN LONG
COVID AND ITS MECHANISMS REMAINS
UNKNOWN.
BUT BEFORE TRYING TO UNDERSTAND
FATIGUE IN LONG COVID, WE NEED
TO TAKE A STEP BACK AND ASK
OURSELF WHY DO WE HAVE SUCH A
LIMITED UNDERSTANDING OF FATIGUE
IN GENERAL?
AND THIS IS EVEN THOUGH FATIGUE
IS ONE OF THE MOST COMMON AND
DEBILITATING SYMPTOMS ACROSS THE
HEALTHCARE SYSTEM.
BECAUSE FATIGUE HAS A BROAD
CLINICAL PRESENTATION ACROSS
INDIVIDUALS AND ILLNESSES, IT
HAS BEEN BROADLY DEFINED AS --
AWARENESS, INCREASE OF -- OR
EXHAUSTION.
IT IS THIS IMPRECISE DEFINITION
AND THE ABSENCE OF QAWBT TAITIVE
METHODS TO DISTINGUISH BETWEEN
ASPECTS OF FATIGUE WHICH LIMITS
OUR ABILITY TO DEEP LE
UNDERSTAND IT AND HINDERS THE
DEVELOPMENT OF EVIDENCE-BASED
TREATMENT.
SO TO UNDERSTAND FATIGUE IN LONG
COVID, WE HAVE DEVELOPED AN
EXPERIMENTAL APPROACH THAT
ALLOWS US TO QUANTITATIVELY
DESCRIBE THREE FEATURES OF
FATIGUE.
WE USE FATIGUE RATINGS TO
UNDERSTAND THE FEELINGS OF
TIREDNESS, AND EFFORT ASSESSMENT
TASK TO UNDERSTAND FATIGUE
PERCEPTION AND DECISION-MAKING
TASK -- LET ME WALK YOU THROUGH
THESE THREE METRICS IN MORE
DETAIL.
SO TO UNDERSTAND, WE ASK
INDIVIDUALS TO RATE THE LEVEL OF
TIREDNESS THAT THEY FEEL BY
MOVING THE CURSOR IN A COMPUTER
SCREEN.
THIS IS A SUBJECTIVE SELF-REPORT
METRIC, AND OUR WORKING
HYPOTHESIS REFLECTS AN EFFECTIVE
RESPONSE TO HOMEOSTASIS.
SO UNDERSTAND EFFORT PERCEPTION,
WE USE AN EFFORT ASSESSMENT TASK
IN WHICH WE ASK INDIVIDUALS TO
EXERT A -- TARGET FORCE AND THEN
RETROSPECTIVELY ASSESS HOW MUCH
EFFORT THEY FELT TO HAVE
EXERTED.
THIS IS A HYBRID METRIC BECAUSE
WE'RE ASKING PARTICIPANTS TO
SUBJECTIVELY ASSESS AND
OBJECTIVELY EXERT THE FORCE, AND
OUR WORKING HYPOTHESIS IS THAT
IT REFLECTS A SENSORY MOTOR
UNDERSTANDING OF THE EXERTED
EFFORT.
LASTLY, TO UNDERSTAND
INDIVIDUALS' WILLINGNESS TO
EXERT EFFORT, WE USE AN EFFORT
DECISION-MAKING -- TO MAKE A
CHOICE TO EITHER EXERT A CERTAIN
AMOUNT FOR SURE OR TAKE A
GAMBLE, IN WHICH THEY CAN HAVE A
50/50 CHANCE OF EXERTING A
HIGHER AMOUNT OR NO EFFORT AT
ALL.
THIS METRIC IS THE MOST
OBJECTIVE METRIC THAT WE HAVE
BECAUSE PARTICIPANTS UNDERSTAND
WHAT THEY ARE DOING BUT THEY
DON'T KNOW WHY WE ARE DOING IT.
AND OUR WORKING HYPOTHESIS IS IT
REFLECTS INDIVIDUALS' DECISION
TO ENGAGE IN ACTION AS A
BEHAVIORAL STRATEGY THAT COULD
ALLOW US TO ACT OR REST IN ORDER
TO RECOVERY.
SO OUR GOAL IS TO USE THESE
THREE QUANTITATIVE METRICS TO
CHARACTERIZE FATIGUE IN LONG
COVID.
SO WHAT DID WE FIND?
SO FIRST WE HAD 34 LONG COVID
PARTICIPANTS AND 34 HEALTHY AGE,
SEX, RACE AND FITNESS MATCHED
CONTROLS.
THIS IS A BIG TABLE WITH A
SUBSET OF MY LONG COVID
PARTICIPANTS, BUT THE GOAL HERE
IS TO SHOW YOU THEY'RE PRIMARILY
WOMEN, THAT THEY HAVE ALL
REPORTED THAT THE PERCEIVED
PHYSICAL AND COGNITIVE STATUS IS
LOWER THAN THEIR PRECOVID
ESTIMATE.
AND THAT THEY ALL REPORT FATIGUE
BEING ONE OF THE MOST COMMON AND
DEBILITATING SYMPTOMS THAT THEY
EXPERIENCE.
SO WHAT DID WE FIND
EXPERIMENTALLY?
SO LOOKING AT FEELINGS OF
TIREDNESS, NOT SURPRISINGLY, WE
SEE THAT INDIVIDUALS WITH LONG
COVID DEPICTED IN BLACK
EXPERIENCED HIGHER FATIGUE
RATINGS THAN HEALTHY CONTROLS.
IMPORTANTLY, THIS INITIAL METRIC
RELATES TO PERCEIVED PHYSICAL
STATUS AND THE NUMBER OF
SYMPTOMS.
SO ON THE Y AXIS, YOU HAVE
PERCEIVED PHYSICAL STATUS AS A
FUNCTION OF FATIGUE RATINGS,
THOSE WHO REPORT HIGHER FATIGUE
ARE ALSO THE ONES WHO ARE
REPORTING LOWER PERCEIVED
PHYSICAL STATUS.
THE SAME TREND YOU CAN SEE NOW
WITH HAVING THE NUMBER OF
SYMPTOMS OR THE SYMPTOM COUNT ON
THE Y AXIS, WHICH WE ASSESS WITH
A VERY COMPREHENSIVE CHECKLIST
IN WHICH WE TRY TO CHARACTERIZE
HOW IS THE FATIGUE
MANIFESTING -- THE DISEASE
MANIFESTING IN THESE
INDIVIDUALS.
I THINK THESE RESULTS SPEAK TO
THE IDEA THAT THIS METRIC IS --
COULD INDEED BE CAPTURING AN
EFFECTIVE RESPONSE TO SOME LEVEL
OF BODY DISHOMEOSTASIS.
NEXT, LOOKING AT EFFORT
ASSESSMENT, BUT PARTICULARLY THE
EXERT COMPONENT, WHAT WE SEE IS
SIMILAR MODEL CONTROL BETWEEN
THE GROUPS.
SO WHAT YOU HAVE IS EXERTED
FORCE ON THE Y AXIS AS A
FUNCTION OF THE TARGET FORCE.
YOU HAVE LONG COVID IN BLACK,
HEALTHY CONTROLS IN GREY.
AND YOU CAN SEE THAT BOTH GROUPS
ARE COMPLETELY OVERLAPPING.
HOWEVER, DESPITE SIMILAR MOTOR
CONTROL BETWEEN THE GROUPS,
LOOKING NOW AT THE ASSESSED
COMPONENT OF THE TASK, WHAT WE
SEE IS HEIGHTENED EFFORT
PERCEPTION IN LONG COVID.
SO NOW YOU HAVE EFFORT
PERCEPTION ON THE Y AXIS AS A
FUNCTION OF THE TARGET FORCE AND
NOW YOU CAN SEE THAT INDIVIDUALS
WITH LONG COVID DISASSOCIATE
FROM THE HEALTHY COUNTERPART AND
SHOW A HEIGHTENED ASSESSMENT OF
EFFORT.
SUGGESTING POTENTIALLY THAT IN
THIS POPULATION, THERE IS SOME
ALTERATIONS THAT CHANGE THE
SENSORY MOTOR UNDERSTANDING OF
WHAT'S THE EFFORT THAT THEY ARE
ACTUALLY EXERTING.
LASTLY, LOOKING AT THE EFFORT
BASED DECISION, THIS REFLECTS
THE ACCEPTANCE RATE OF THE FLIP
OPTION.
SUCH THAT THE WARMER THE COLOR,
THE MORE LIKELY YOU ARE TO
ACCESS THE FLIP OPTION, THE
COOLER THE COLORS, THE LESS
LIKELY THAT YOU ARE TO ACCEPT
THE FLIP OPTION.
AND WHAT WE SEE IS THAT NOT
SURPRISINGLY, IN HEALTHY
CONTROLS, THE THE LOWER THE
VALUE OF THE FLIP OPTION ARE NOT
LIKELY WE ARE TO ACCEPT IT.
THIS IS PARTICULARLY TRUE WHEN
WE ARE PRESENTED WITH HIGHER
VALUES OF THE SURE OPTION,
SHIFTING FROM LEFT TO RIGHT.
HOWEVER, THIS PATTERN IS NOT AS
CLEAR IN LONG COVID.
SO A WAY FOR US TO QUANTIFY THE
DIFFERENCES BETWEEN THE GROUPS
IS TO SUBTRACT THESE TWO
MATRICES AND SEE WHAT IS THE
DIFFERENCE IN DECISIONS TO
ENGAGE BETWEEN THE GROUPS.
AND THIS IS WHAT I'M SHOWING YOU
HERE.
THIS IS THE SAME HEAT MAP, BUT
THIS TIME THE WARMER THE COLOR
REFLECTS A HIGHER LIKELIHOOD OF
LONG COVID PARTICIPANTS CHOOSING
THE FLIP OPTION RED THAN THE
HEALTHY COUNTERPARTS.
THE INDIVIDUALS WITH LONG COVIDD
HAVE A MUCH RISKIER BASE TO MAKE
DECISION.
THESE INDIVIDUALS ARE NORMALLY
WILLING TO EXERT EFFORT TO
COMPARED TO THE STIGMA THAT YOU
FEEL FAT BECAUSE YOU'RE LAZY,
BUT ALSO MAYBE THEY ARE SO
DESPERATE TO GET THE ZERO OPTION
THAT THEY NEED TO REST, THAT
THEY ARE WILLING TO TAKE THAT
GAMBLE.
SO AS A SUMMARY, OUR DATA
SUGGESTS THAT INDIVIDUALS WITH
LONG COVID EXHIBIT HIGHER -- AND
RISKIER BASED DECISION-MAKING.
BUT IF THERE IS ONE THING THAT I
WOULD LIKE ALL OF US TO REMEMBER
OR TO TAKE FROM THIS TALK IS
THAT IF WE REALLY WANT TO
UNDERSTAND FATIGUE, WE NEED TO
USE A BATTERY OF BEHAVIORAL
TASKS THAT WILL ALLOW US TO
CAPTURE THE MULTIDISCIPLINARY
NATURE OF FATIGUE, NOT ONLY IN
LONG COVID AND MESOPOTAMIA BUT O
OTHER CONDITIONS.
SO TO CONCLUDE, I SHOW YOU ONLY
BASELINE DATA.
OUR GOAL IS TO -- ACTUALLY --
WORKING ON UNDERSTANDING THE
NEUROMUSCULAR MECHANISMS OF
THESE DATA, AND WE'RE GOING TO
BE USING OTHER NEUROIMAGING AND
PHYSIOLOGICAL TECHNIQUES TO
REALLY GET AT THE MECHANISMS.
BUT ALSO, MY NEXT PROJECT WILL
BE AIMING TO CHARACTERIZE
FATIGUE AND ME C NISMS DURING PT
EXERTIONAL MALAISE, I REALLY
BELIEVE TO UNDERSTAND WHAT'S
HAPPENING IN LONG COVID WE NEED
TO GO AFTER THEM.
THE IDEA IS TO LOOK AT THESE
METRICS DURING AND IMMEDIATELY
AFTER REPEATING A SUBMAXIMAL
EXERTION -- AND AFTER TWO DAYS
AND SO FORTH, WORK WE HAVE BEEN
WORKING VERY CLOSELY WITH ALLA
IN TRYING TO CAPTURE IT.
SO WITH THAT, I THANK YOU FOR
YOUR ATTENTION, AND I'M HAPPY TO
TAKE ANY QUESTIONS.
[APPLAUSE]
>> THANK YOU, AGOST.
OUR NEXT SPEAKER IS FROM
COLUMBIA, COMPREHENSIVE PLASMA
METABOLOMICS ANALYSIS WITH
EXERCISE TOLERANCE TEST.
>> HI.
MY NAME IS XIAOYU CHE, AS
TONIGHT PROFESSOR OF
BIOSTATISTICS FOR THE CENTER FOR
INFECTION IMMUNITY AT COLUMBIA
UNIVERSITY.
AND TODAY I'LL BE PRESENT DATA
FROM A COMPREHENSIVE PLASMA
METABOLOMICS ANALYSIS IN
MESOPOTAME/CFSWITH EXERCISE TOL.
TWO SITES, CLINIC IN NEW YORK
CITY AND STANFORD UNIVERSITY
SCHOOL OF MEDICINE.
THERE WERE 47 ONE TO ONE MATCHED
CASE CONTROL PAIRS.
THE PLASMA SAMPLES WERE
COLLECTED AT TWO TIME POINTS.
THERE IS IMMEDIATELY BEFORE AND
24 HOURS AFTER THE ETT.
KNOWN PARTICIPANTS WERE REQUIRED
TO GO TO 12-HOUR FASTING BEFORE
BLOOD DRAW.
THE METABOLOMICS ASSAYS WERE
PERFORMED AT DR. OLIVER FINN'S
METABOMIBG CENTER AT U.C. DAVIS
AND GENERATED DAY TAI FOR 935
ANNOTATED METABOLITES FROM FOUR
SEPARATE PANELS.
WE COMPARED LEVELS OF
METABOLITES FOR THE
DIFFERENCES -- THE BETWEEN-GROUP
DIFFERENCES AT TWO TIME POINTS,
AND ALSO THE WITHIN-GROUP
TRAJECTORIES IN CASES AND
CONTROLS, AS WELL AS
INTERACTIONS WHICH WILL INDICATE
A CROSSOVER EFFECT.
WE RECENTLY PUBLISHED A PAPER ON
THE UTILITY OF BAYESIAN
INFERENCE IN HUMAN ME TACK LOW
MIX DATA ANALYSIS AND SHOW THAT
EXHIBIT GRATING DATA FROM
SIMILAR STUDY DESIGN AS PRIOR
INFORMATION CAN SIGNIFICANTLY
IMPROVE THE INTERPRETABILITY.
AND, THEREFORE, WHERE REQUIRED
DATA -- INDEPENDENT STUDY WITH A
SIMILAR STUDY DESIGN FROM
CORNELL UNIVERSITY INDEED
DR. MAUREEN HANSON'S RECENT
PUBLICATION.
THE DIFFERENCE IS THEY CONDUCTED
TWO EXERCISE TESTS ON TWO
CONSECUTIVE DAYS, WHERE WE ONLY
CONDUCTED ONE EXERCISE TEST.
BUT OUR PRE-ETT TIME POINT
CORRESPONDED TO THEIR D1 PRE AND
OUR POST TIME POINT CORRESPONDED
TO THEIR D2 PRE.
MATCHING FOR METABOLITES WERE
NOT IDEAL.
ONLY 220 METABOLITES WERE
MATCHED.
BETWEEN THE TWO STUDIES,
INCLUDING 60% OF PRIMARY
METABOLITES IN OUR ASSAY, 37% OF
BIOGENIC AMINES.
THE LIPIDS AND OXYLIPINS WERE
PROTEIN MATCHED.
IT WAS STILL SUCCESSFULLY
PERFORMED, INTEGRATING CORNELL'S
DATA ON THIS 220 METABOLITES
MOSTLY ESSENTIAL COMPOUNDS.
SORE THE RESULTS, FIRST WE FOUND
ELEVATED LEVELS AT BOTH PRE AND
POST ETT TIME POINTS.
IT IS RECOGNIZED BY THE --
ADJUST THE P VALUE AND BAYESIAN
ANALYSIS NOT INCLUDING DATA FROM
OTHER STUDIES AS WELL AS
COMBINED ANALYSIS INCORPORATING
DATA.
ALSO THE PLASMA LEVELS OF PRO WE
UPREGULATED AT THE POST-ETT TIME
POINT.
SO AROUND A QUARTER OF THE
RESIDENT BACTERIA SPECIES IN
HUMAN GUT PRODUCE BETA -- OF
CHRONIC ACID.
THE PROPIONIC ACID IS A SHORT
CHAIN FATTY ACID PRODUCED BY GUT
BACTERIA.
SO THESE DATA MAY PROVIDE ACTUAL
EVIDENCE OF THE GUT MICROBIOTA
DYSBIOSIS IN T IN ME/CFS PRESEND
PREVIOUSLY IN THE MORNING.
SO ONE OF THE KEY FINDINGS IN
THE METABOLOMICS ANALYSIS WE
FOUND IS IN THE LEVELS OF --
ACID.
HERE THE LEVELS IN ME/CFS
DECREASED FROM BEFORE TO AFTER
EXERCISE WHERE THE LEVELS IN
CONTROLS -- NO, THE LEVELS IN
ME/CFS INCREASED FROM BEFORE TO
AFTER EXERCISE, WHILE THE LEVELS
AND CONTROLS MARGINALLY
DECREASED.
SO HERE WE HAVE THE LEVELS OF
PHOSPHATE DECREASED FROM BEFORE
TO AFTER EXERCISE IN HEALTHY
CONTROLS, BUT NO CHANGE IN THE
ME/CFS.
SO THIS DATA TOGETHER SHOWS THAT
THE FIRST CONTROLS ARE UTILIZ
UTILIZING - CITRIC ACID TO PRODE
MOLECULES, WHILE THIS PUNKS IS
IMPAIRED LEADING TO ACCUMULATION
OF SUCH AN ACID.
THE PHOSPHATE DYSREGULATION MAY
HAVE MANY IMPLICATIONS BUT MOST
ARE INVOLVED IN ENERGY
METABOLISM, INCLUDING GENERATION
AND CONSUMPTION OF ATP MOLECULES
AND THE GLYCOLYSIS AND OXIDATIVE
PHOSPHORYLATION.
WE ALSO FOUND DYSREGULATION IN
THE RATIOS WHERE THEY WERE
ELEVATED IN ME/CFS BUT DECREASED
IN RESPONSE TO ETT.
THIS IS A KEY INDEX TO ASSESS
THE METABOLIC ACTIVITY IN THE
UREA CYCLE.
A JAPANESE STUDY -- IT ALSO
CONNECTS WITH THE ENERGY
METABOLISM BY SHARING SOME
INTERMEDIATES WITH THE TC CYCLE.
THEY ALSO FOUND EVIDENCE OF THE
IMPAIRED UREA CYCLE IN PLASMA
AND URA METABOLOMICS.
ANOTHER RATIO WAS DOWN REGULATEE
BUT INCREASED IN RESPONSE TO
EXERCISE.
AND THAT INDICATES ABNORMALITIES
IN THE PATHWAY AND TRYPTOPHAN
METABOLISM.
AND THAT CAN INFLUENCE
MITOCHONDRIAL FUNCTIONING AND
ALSO INDUCE COGNITIVE IMPAIRMENT
IN ADDITION, THERE ARE ALSO
LINKS TO INFLAMMATION.
THE CHEMICAL ENRICHMENT ANALYSIS
ALSO REVEALED SOME ALTERED
CHEMICAL CLUSTERS.
FIRST, DERIVED FROM ACIDS, AND
FUNCTION AS INFLAMMATORY
REGULATORS WERE REDUCED IN
ME/CFS BEFORE EXERCISE.
AND TERPENES, MAINLY THE
ANTI-INFLAMMATORY LINALOU WERE
ALSO DOWN THE -- IN ME/CFS.
NEXT, ELEVATED IN ME/CFS BEFORE
AND AFTER EXERCISE AND
ELEVATIONS WERE MORE SIGNIFICANT
AT A POST-ETT TIME POINT.
THESE COMPOUNDS ARE LIPIDS THAT
SERVE AS ENERGY SOURCE THAT CAN
RELEASE FREE FATTY ACIDS.
THE ELEVATIONS CAN ALSO
CONTRIBUTE TO ELEVATION.
LASTLY, LEVELS OF CARNITINES
WERE REDUCED IN ME/CFS AFTER
EXERCISE.
CARNITINES ARE CRITICAL BECAUSE
THEY'RE RESPONSIBLE FOR THE
TRANSPORTATION OF FREE FATTY
ACIDS INTO MITOCHONDRIA FOR
LATER OXIDATION.
WE ALSO FOUND SOME UNIQUE
METABOLIC PHENOTYPES IN
SUBGROUPS OF ME/CFS.
IN PATIENTS WITH LESS THAN THREE
YEARS OF ILLNESS DURATION, A
GROUP OF POS FOE LIPIDS, WERE
EITHER ELEVATED AFTER EXERCISE
OR INCREASED FROM BEFORE TO
AFTER EXERCISE.
SO THEIR DYSREGULATIONS WILL
INDICATE PEROXISOMAL
DYSFUNCTION.
ALSO THE CROSSTALK BETWEEN THEM
IS CRITICAL FOR MAINTAINING THE
ENERGY HOMEOSTASIS.
WE FIRST REVIEWED PEROXISOMAL
DYSFUNCTIONS IN -- ABUNDANT
NUMBER OF LIPID MEDIATORS WERE
ALL REDUCED IN FEMALE ME/CFS
PATIENTS YOUNGER THAN 45
COMPARED TO THEIR CORRESPONDING
CONTROLS.
SO DR. LIPKIN PRESENTED DATA
FROM THE TRUE CULTURE ASSAY IN
THE SAME COHORT THAT SHOW THAT
CYTOKINE RESPONSE ENTEROTOXIN
TYPE B WERE ELEVATED IN FEMALE
M.E. CFS AND CORRELATE WITH
ESTRADIOL LEVELS.
HERE WE FOUND FURTHER EVIDENCE
THAT AGE IS AN IMPORTANT FACTOR
THAT MAY CONTRIBUTE TO THE
SUBGROUPS OF ME/CFS, AT LEAST IN
FEMALES.
AND THESE SUBGROUPS HAVE UNIQUE
IMMUNE AND INFLAMMATORY
PROFILES.
AND WE HAVE MORE PROFOUND
EVIDENCE IN THE PLASMA
PROTEOMICS THAT SUPPORT THIS
SUBGROUPING.
SO TO SUM UP, WE KER CHARACTERIE
THE METABOLIC PROFILES IN ME/CFS
FOLLOWING EXERCISE TOLERANCE
TEST SHOWS ABNORMALITY IN THE --
THE KI CHIMERA PATHWAY WAS ALSO
IMPAIRED AND CAN COMPROMISE
COGNITIVE FUNCTIONING.
CARNITINES WERE DEPLETED IN
ME/CFS AFTER EXERCISE, WHICH
INDICATE A LOSS OF CAPABILITY OF
TRANSPORTING FREE FATTY ACIDS
INTO MITOCHONDRIA FOR BETA
OXIDATION.
TRIGLYCERIDES AND DIGLIS RIDES S
ARE RESPONSIBLE FOR RELEASING
THESE FREE FATTY ACIDS AND THEY
WERE UPREGULATED IN ME/CFS.
TOGETHER THEY FORM A EXR
COMPREHENSIVE MODEL.
WE WILL INCORPORATE THE
PROTEOMICS DATA GENERATED FROM
THE SEROLOGIC PANEL FOR OUR
UPCOMING PUBLICATION.
AND OUR CENTER WILL ALSO
CONTRIBUTE TO IT.
SO LASTLY, THE WORK WAS FUNDED
BY NIH AND CHRONIC FATIGUE
INITIATIVE.
I WANT TO ACKNOWLEDGE DR. OLIVER
FINN'S GROUP AT U.C. DAVIS FOR
THE PERFORMANCE OF THE
METABOLOMICS ANALYSIS AND
SPECIAL THANKS TO THE DOCTORS
FOR SHARING THEIR DATA WITH US
FOR THE BAYESIAN ANALYSIS.
THANK YOU.
[APPLAUSE]
>> OUR NEXT SPEAKER IS JESSICA
MAYA FROM CORNELL, WHO'S GOING
TO TELL US ABOUT INVESTIGATING
T-CELL POPULATIONS FOR IMMUNE
CELL DYSFUNCTION IN ME/CFS.
>> THANK YOU SO MUCH FOR
INVITING ME TO BE HERE AND
PRESENTING MY WORK.
I'LL GO AHEAD AND GET STARTED.
SO TO BEGIN, I'LL INTRODUCE THE
IMMUNE CELL POPULATIONS UNDER
INVESTIGATION IN MY STUDY, WHERE
IN YOUR BLOOD, YOU HAVE YOUR
WHITE BLOOD CELLS THAT CONTAIN
YOUR IMMUNE CELLS LIKE
PERIPHERAL BLOOD CELLS.
THIS CONTAINS THE CELLS I WORK
WITH.
IN PARTICULAR, THIS INCLUDES CDR
CYTOTOXIC T CELLS AS WELL AS CD.
NOW THESE T CELLS CAN BE FURTHER
DIVIDED INTO THEIR STAGE OF
DIFFERENTIATION, SUCH ACINI EVE
CELLS THAT SURVEY THE BODY FOR
INFECTIONS, THE POST INFECTION
EFFECTOR OR HELPER CELLS THAT
CAN BE CYTOTOXIC, AND THEN
FINALLY MEMORY CELLS THAT STICK
AROUND, PROTECT THE BODY IF
THESE CELLS REENCOUNTER THAT
INFECTION LATER ON.
OFTEN EXAMINED PBMCs
COLLECTIVELY BUT CONSIDERING THE
DIVERSE CELL TYPES WITHIN THIS
GROUP, EACH WITH UNIQUE
METABOLISMS, FUNCTIONS AND
CYTOKINE PREFERENCES, IT'S
CRUCIAL TO ISOLATE IMMUNE CELLS
TO SUBSETS FOR ACCURATE
IDENTIFICATION OF ANY
ABNORMALITIES.
OTHERWISE CHANGES COULD BE
OBSCURED WHEN LOOKING AT THE
ENTIRE CELL POPULATION.
NOW PREVIOUSLY WE'VE SHOWN THAT
ME/CFS SITE TOXIC CD8 T CELLS
HAVE DECREASED GLYCOLYSIS,
DECREASED MITOCHONDRIAL MEMBRANE
POTENTIAL AS WELL AS
INCREASED -- IN IMMUNOLOGY
THERE'S MORE LIGHT BEING SHED ON
THE IMPORTANCE OF METABOLISM AS
WELL AS FUEL USAGE IN THESE CELL
TYPES SO THAT THEY CAN FUNCTION
PROPERLY.
AND BY FUNCTION, I MEAN HOW
RESPONSIVE ARE THEY TO
INFECTIONS, AND HOW WELL CAN
THEY FIGHT OFF ANY IMMUNE
CHALLENGES.
AND WHILE THIS WORK IS NOT THE
FOCUS OF TODAY'S TALK, THESE
METABOLIC CHANGES DID LEAD ME TO
INVESTIGATE WHAT THESE
ABNORMALITIES COULD TELL US
ABOUT ME/CFS T-CELL FUNCTION.
SPECIFICALLY, A PHENOMENON
CALLED T-CELL EXHAUSTION.
AND SO NORMALLY WHEN A T-CELL --
WHEN A CELL ENCOUNTERS AN
INFECTED CELL, IT WILL ENGAGE
COSTIMULATORY RECEPTORS TO BEGIN
A SIGNALING CASCADE FOR EFFECTOR
FUNCTION.
HOWEVER, WHEN PD-1, WHICH IS A
MAJOR REGULATOR OF T-CELL
EXHAUSTION, IS ENGAGED ON A CELL
SURFACE, ITS SIGNALING WILL
DEPHOSPHORYLATE EFFECTOR
MOLECULES AND AS A RESULT, CAUSE
A DECREASE IN T-CELL
PROLIFERATION, SURVIVAL,
CYTOKINE PRODUCTION, AND PROTEIN
SYNTHESIS.
AND NOTABLY METABOLICALLY,
EXHAUSTED T CELLS ARE
CHARACTERIZED BY THE SAME
DYNAMICS THAT WE'VE REPORTED IN
ME/CFS T CELLS.
HOWEVER, IDENTIFYING AND
CONFIRMING AN EXHAUSTED STAY IN
ME/CFS HAS BEEN CHALLENGING DUE
TO LIMITATIONS IN SAMPLE
COLLECTION AS WELL AS VIRUS
SPECIFICITY.
HOWEVER, A NOTABLE STUDY FROM
2020 ELEGANTLY CHARACTERIZED
T-CELL EXHAUSTION INTO FOUR
DISTINCT DIFFERENTIATION STAGES.
STARTING WITH TWO PROGENITOR
STAGES.
NEXT DIFFERENTIATING INTO AN
INTERMEDIATE EXHAUSTIVE STATE,
AND THEN FINALLY DIFFERENTIATING
TO A TERMINAL STAGE.
NOW THE RESEARCHERS
CHARACTERIZED THESE PD-1
POSITIVE CELLS THAT WERE
EXHAUSTED BASED ON THE PRESENCE
OR ABSENCE OF MARKERS SUCH AS
CD69, AS WELL AS TRANSCRIPTION
FACTORS LIKE TOX, T-BET, TCF1.
DWTWO OF THESE STAGES ARE SPECIC
TO CIRCULATING CELLS WHICH IS
WHAT I WORK WITH, AND THEY HAVE
DISTINCT FEATURES COMPARED TO
HEALTHY, NON-EXHAUSTED PD-1
POSITIVE CELLS.
SO THIS CELL PHENOTYPING IS PART
OF THE BASIS OF MY STUDY TO THEN
ANSWER THE QUESTION, ARE ME/CFS
T CELLS IN AN EXHAUSTED STATE?
AND SO FOR THE STUDY, WE HAVE 15
PATIENTS AND 14 AGE MATCHED
HEALTHY SEDENTARY CONTROL
FEMALES, WHERE PATIENT ILLNESS
DURATION VARIED FROM 2 TO 30
YEARS, AND PARTICIPANTS PROVIDED
DETAILS ON THEIR ME/CFS
PRESENTATION AS WELL AS SYMPTOM
SEVERITY.
SO FOR EXAMPLE, THE LOWER BELL
ACTIVITY SCALE YOU SEE AT THE
BOTTOM IN THE PATIENT COHORT
HIGHLIGHTS MORE SEVERE HEALTH
IMPAIRMENTS COMPARED TO THE
HEALTHY CONTROL COHORT.
NOW OUR STUDY IS ALSO UNIQUE
BECAUSE WE ALSO ASKED ALL
PARTICIPANTS TO PERFORM THE
TWO-DAY CARDIOPULMONARY EXERCISE
TEST THAT WAS JUST MENTIONED IN
THE LAST TALK, AND THIS IS
TYPICALLY USED AS A DIAGNOSTIC
TOOL TO INDUCE THE HALLMARK POST
EXERTIONAL MALAISE STATE IN
INDIVIDUALS WITH ME/CFS.
AND SO THIS WAS ALSO DONE IN
THIS ATTEMPT TO KIND OF
STANDARDIZE OUR DISEASE STAILT N
OUR COHORT, SO WE COLLECTED
WHOLE BLOOD FOLLOWING THE
TWO-DAY CPE IT THE AND FROM
THERE ISOLATED PBMCs TO USE
MAGNETIC BEAD ISOLATION TO
SEPARATE OUT CD8 POSITIVE T
CELLS.
FROM THERE I EMPLOYED FLOW
CYTOMETRY TO ASSESS MARKERS
LINKED TO THE PHENOTYPES I
MENTIONED EARLIER, AND I ALSO
EXAMINED TRANSCRIPTION FACTORS
SUCH AS TOX, WHICH IS KNOWN TO
DRIVE T-CELL EXHAUSTION IN THE
CONTEXT OF PD-1 POSITIVE CELLS,
AS WELL AS TCF1 WHICH SUPPORTS
THE PROGENITOR STATE IN
CIRCULATING T-CELL EXHAUSTION,
AND THEN TBET, WHICH AGAIN IN
THE CONTEXT OF AN EXHAUSTED
T-CELL STATE CAN MAINTAIN A
BALANCE AMONG VARIOUS T-CELL
EXHAUSTED STAGES IN TISSUES
VERSUS CIRCULATION, AND ALSO
REGULATES THIS TRANSITION FROM
INTERMEDIATE TO LATE STAGES OF
EXHAUSTION.
AND SO HERE I'M SHOWING YOU THE
GATING STRATEGY USED TO DETECT
THESE EXHAUSTION MARKERS WHERE I
ANALYZED THESE MARKERS FOR THE
FREQUENCY OF POSITIVE
POPULATIONS IN TOTAL CELLS.
INDICATED BY THE BLACK BAR FOR
EACH MARKER.
AND NOW WITHIN THE PD-1 POSITIVE
CELLS, I AGAIN LOOKED AT ALL
THESE MARKERS SINCE WE'VE SEEN
TRANSCRIPTION FACTORS ARE
DISTINCT IN PD-1 POSITIVE
EXHAUSTED T CELLS COMPARED TO
PD-1 POSITIVE NORMAL HEALTHY
CELLS.
AND IT'S WITHIN THESE PD-1
POSITIVE CELLS THAT I THEN
DEFINE THE TWO EXHAUSTED
PHENOTYPES I CAN DETECT IN
CIRCULATION.
SO THEN FINALLY, I ALSO LOOKED
AT ALL OF THESE MARKERS AND
PHENOTYPES WITHIN SUBSETS OF
POPULATIONS TO IDENTIFY ANY
SUBPOPULATIONS WITH ALTERED
FREQUENCIES OF THESE INHIBITORY
RECEPTORS OR TRANSCRIPTION
FACTORS THAT WERE OTHERWISE
CONCEALED WITHIN OVERALL
CD8 T-CELL POPULATION ANALYSES.
THIS IS ALSO TO IDENTIFY ANY
SPECIFIC SUBSETS RESPONSIBLE FOR
OVERALL T-CELL CHANGES.
SO NOW STARTING WITH TOTAL
CD8 POSITIVE T CELLS, I SAW NO
DIFFERENCE IN THE TOTAL
FREQUENCY OF THE HALLMARK
EXHAUSTION MARKER PD-1, BETWEEN
PATIENTS AND CONTROLS FOLLOWING
THE TWO-DAY CPET.
BUT ONCE I ANALYZED CD1 POSITIVE
T CELLS I BEGAN TO NOTICE THE
DIFFERENCES.
SPECIFICALLY THIS ASSAY SHO
SHOWED -- IN TOTAL CD8 T CELLS
OF ME/CFS PATIENTS COMPARED TO
HEALTHY CONTROLS.
I WAS ALSO ABLE TO DETECT THE
RELATED CIRCULATING PROGENITOR
EXHAUSTED T-CELL PHENOTYPE AT
HIGHER PROPORTIONS IN TOTAL
CD8 POSITIVE ME/CFS T CELLS AS
WELL.
NOW, THIS PROGENITOR STAGE OF
QUIESCENT EXHAUSTED T CELLS
MAINTAINS T-CELL EXHAUSTION
DURING CHRONIC VIRAL INFECTIONS.
AND THIS IS THE STAGE OF
EXHAUSTION THAT CAN ACTUALLY BE
RESTORED TO PROPER FUNCTION BY
TREATMENT WITH PD-1 BLOCKADE
THERAPY.
AND SO THEN I ALSO FOUND A
SIGNIFICANTLY HIGHER FREQUENCY
OF THE EXHAUSTED IPT IMMEDIATE
CELL PHENOTYPE IN ME/CFS CELLS
COMPARED TO HEALTHY CONTROL
CELLS AS WELL.
AND SO ALL OF THESE
TRANSCRIPTIONALLY DIFFERENT
ME/CFS CD8 T CELLS INDICATE THAT
INDIVIDUALS WITH ME/CFS MAY HAVE
THESE MORE DISREGULATED
EXHAUSTED T CELLS THAN THE
HEALTHY SEDENTARY CONTROLS THAT
WE COMPARED THEM TO FOLLOWING
EXERCISE.
JUST TO GO THROUGH A FEW OF THE
EFFECTOR SUBSETS, I THEN SAW AN
INCREASE IN EARLY DIFFERENTIATED
T CELLS.
CLA SIBLY TOX IS NOT ESSENTIAL
FOR THE ESTABLISHMENT OF
EFFECTOR OR MEMORY CD8 POSITIVE
T CELLS, BUT THIS TRANSCRIPTION
FACTOR PLAYS A CRUCIAL ROLE IN
T-CELL EXHAUSTION BECAUSE IN THE
ABSENCE OF TOX EXHAUSTED T CELLS
ARE SIMPLY NOT PRODUCED.
I ALSO HERE OBSERVED A
REMARKABLY HIGHER FREQUENCY OF
THE INTERMEDIATE EXHAUSTED
T-CELL PHENOTYPE WITHIN THE
INTERMEDIATE POPULATION COMPARED
TO THE HEALTHY CONTROL GROUP.
THIS POPULATION SEEMS TO BE THE
LARGEST CONTRIBUTOR OF THIS
EXHAUSTED PHENOTYPE IN ME/CFS T
CELLS.
NOW, IN LATE EFFECTOR T-CELL
POPULATIONS, A DISTINCTIVE
PATTERN BEGINS TO EMERGE WHICH
IS THIS LOWER FREQUENCY OF T-BET
POSITIVE CELLS IN TOTAL EFFECTOR
POPULATIONS.
NOW, T-BET IS PIVOTAL NOT ONLY
IN EXHAUSTED CELLS BUT IN
GENERAL.
IT'S KNOWN FOR ITS ROLE IN
REGULATING THE EXPRESSION OF
GENES THAT BASICALLY ENCODE
EFFECTOR MOLECULES.
SO THESE RESULTS ALIGN WITH
PRIOR ME/CFS LITERATURE
REPORTING THE CYTOTOXIC IMMUNE
RESPONSE IN ME/CFS.
AKITION DIGSALLY, TOX POSITIVE
CELLS WERE OBSERVED AT HIGHER
PROPORTIONS IN TERMINALLY
DIFFERENTIATED POPULATIONS.
INTERESTING BECAUSE THIS
TRANSCRIPTION FACTOR MAINTAINS
THE EXHAUSTED T-CELL RESPONSE
BUT IT DOES SO IN PART BY
INHIBITING CLASSIC CD8 T-CELL
TERMINAL DIFFERENTIATION.
AND THIS IS IN AN ATTEMPT TO
PROTECT AGAINST T-CELL MEDIATED
IMMUNOPATHOLOGY.
SO THEN FINALLY, I CONTINUE TO
SEE THESE ELEVATED EXHAUSTED
CELL PHENOTYPE FREQUENCIES IN
LATE EFFECTOR AND PARTICULARLY
IN TERMINAL ME/CFS T CELLS,
COMPARED TO HEALTHY CONTROLS.
ALTHOUGH IT'S NOT AT THE SAME
HIGH PROPORTIONS AS WHAT WE SAW
IN THE PREVIOUS SLIDE IN THE
EARLY DIFFERENTIATED T-CELL
POPULATION.
AND SO THEN IN CONCLUSION, MU
STUDY REVEALS THE PRESENCE OF
THIS DISREGULATED IMMUNE CELL
STATE IDENTIFIED BY AN EXHAUSTED
T-CELL PHENOTYPE AND MULTIPLE
ME/CFS SUBSETS.
INDICATING A SUPPRESSED IMMUNE
RESPONSE IN THIS ILLNESS THAT
SUPPORTS THE IDEA OF A CHRONIC
VIRAL INFECTION IN THIS DISEASE.
AND OUR FINDINGS ARE PROMISING.
IT'S IMPORTANT TO NOTE THAT
T-CELL EXHAUSTION WHICH IS SEEN
IN VARIOUS MODELS INCLUDING
CANCER AND OTHER CHRONIC VIRAL
DISEASES HAS SHOWN REVERSIBILITY
WITH PD-1 BLOCKADE THERAPY,
RESULTING IN INCREASED CELL
PROLIFERATION AND FUNCTION.
AND AS THERE'S CURRENTLY NO
FDA-APPROVED TREATMENT FOR
ME/CFS, INVESTIGATING EXHAUSTION
AS A POTENTIAL MECHANISM AND
IDENTIFYING THERAPEUTIC TARGETS
HOLDS SUBSTANTIAL PROMISE FOR
INDIVIDUALS THAT ARE AFFECTED BY
THIS DISEASE.
AND SO WITH THAT, I'D LIKE TO
THANK MY LAB, THE CLINICIANS, MY
MENTORS, INCLUDING MY PI,
DR. MAUREEN HANSON, AND MY
FUNDING SOURCES AND RESOURCE
FACILITIES AT CORNELL.
THANK YOU.
[APPLAUSE]
>> ACTUALLY CAN I ASK YOU A
QUESTION?
>> SURE.
>> DO YOU THINK IF YOU USE THE
PD-1 THERAPY, WOULD IT BE
SOMETHING THAT WOULD HAVE TO BE
DONE CONTINUALLY, OR COULD BE
ONE TIME?
>> SO HE WAS ASKING ABOUT HOW
REALISTIC THE PD-1 BLOCKADE
THERAPY WOULD BE IN THE CONTEXT
OF ME/CFS.
SO IT'S CURRENTLY BEING USED AS
A CANCER THERAPY.
IT HASN'T BEEN APPROVED FOR
CHRONIC VIRAL INFECTIONS.
THERE HAVE BEEN A FEW STUDIES
WITH LIKE HIV THAT THEY'VE USED
IT IN COMBINATION AS CLINICAL
TRIALS AGAIN WITH ANTIVIRALS
THAT ARE SPECIFIC TO HIV WHERE
THEY'RE FLUSHING OUT THE
RESERVOIRS AND THEN DOING A
LOWER DOSE OF PD-1 BLOCKADE
THERAPY TO TRY TO GET AT THOSE
CELLS THAT ARE TYPICALLY HIDDEN.
SO IT WOULD HAVE TO BE SOMETHING
WHERE ONCE WE UNDERSTAND THE
MECHANISM, WE COULD DIRECT IT.
BASED ON WHAT ELSE WE KNOW ABOUT
THE DISEASE.
>> IT WOULDN'T BE ONE --
>> IT WOULDN'T BE WITH.
>> THANK YOU.
>> SO OUR NEXT SESSION IS
ACTUALLY METABOLISM OF ME/CFS
AND LONG COVID, AND WE HAVE
THREE SPEAKERS, AND THE
MODERATOR IS DR. KARL-JOHAN
TRONSTAD ACTUALLY A SPEAKER IN
THE SESSION, WHICH IS WHY I'M
INTRODUCING FOLKS.
THE FIRST SPEAKER IS PAUL HWANG
FROM NHLBI WHO'S GOING TO TELL
US ABOUT HIS THOUGHTS ABOUT A
PAPER THAT HE RECENTLY PUBLISHED
AND THEN SOME ADDITIONAL
THINKING ABOUT ACTUALLY
SOMETHING DR. KOROSHETZ
MENTIONED THIS MORNING, WASF3
MAY MEDIATE BIOENERGETIC
DEFICIENCY OF ME/CFS.
PAUL?
>> THANK YOU.
THANKS VERY MUCH, JOE AND OTHER
ORGANIZING MEMBERS FOR THIS
INVITATION, OPPORTUNITY TO
PRESENT OUR WORK.
IT'S ALSO IMPORTANT FOR ME TO
THANK MEMBERS OF MY LABORATORY,
ESPECIALLY THOSE THAT DID MUCH
OF THE WORK THAT I'LL BE SHOWING
YOU.
SO WHAT I'D LIKE TO DO TODAY IS
SHARE WITH YOU A SHORT STORY
THAT WE'VE BEEN WORKING ON FOR
THE PAST FEW YEARS IN WHICH
WE'VE TRIED TO DETERMINE THE
MECHANISM FOR THE LACK OF ENERGY
IN THE SKELETAL MUSCLE OF
PATIENTS WITH CHRONIC FATIGUE
SYNDROME.
SO THIS PROJECT STARTS WITH A
PATIENT WHO ARE ACTUALLY IS A
PROJECT WE KIND OF STUMBLED UPON
BECAUSE OF A VERY PERSISTENT BUT
PLEASANT PATIENT WHO SHOWED UP
WITH THE SYMPTOM OF FATIGUE.
SO OUR LAB HAS BEEN WORKING ON
AN EARLY ONSET CANCER DISORDER
CAUSED BY INHERITED MUTATIONS OF
P53, WHICH IS ARGUABLY THE MOST
IMPORTANT TUMOR SUPPRESSOR GENE
IN THE HUMAN GENOME.
AND WE HAD LOOKED AT LI-FRAUMENI
SYNDROME BOTH IN IT'S FORMS AND
WE HAD REPORTED A NUMBER OF
YEARS AGO THAT INDIVIDUALS WITH
LI-FRAUMENI SYNDROME ACTUALLY
HAVE INCREASED MITOCHONDRIAL
METABOLISM.
THE PATIENT HAD SEEN THIS WORK
ON THE WEB AND CONTACTED ME AND
SAID, I HATE TO DO THIS TO YOU,
BUT I'M THE EXACT OPPOSITE OF
WHAT YOU REPORTED, WHICH IS --
WE HAD REPORTED THAT P53
PROMOTES AEROBIC EXERCISE AND
ALL THAT, IN MOUSE MODEL IT
DOUBLES THE CAPACITY OF MICE.
BUT SHE'S THE EXACT OPPOSITE.
AND HAS BEEN FATIGUED FOR MANY
YEARS.
SO THIS IS THE CASE OF A
38-YEAR-OLD WOMAN WITH
LI-FRAUMENI SYNDROME WHO
PRESENTED WITH FATIGUE AGAIN
SINCE TEENAGE YEARS SINCE HAVING
A BOUT OF MONONUCLEOSIS, SHE
RECALLS.
SHE HAD EXTENSIVE CLINICAL
WORKUP OVER THE YEARS AND REALLY
IT WAS UNREMARKABLE IN TERMS OF
DIAGNOSIS AND SHE ACTUALLY ALSO
HAD A MITOCHONDRIAL DISEASE
WORKUP WHICH SEQUENCING WHICH
SHOWED NO MUTATIONS.
SO I THINK IN THIS AUDIENCE I
DON'T HAVE TO SAY MUCH ABOUT
ME/CFS, BY MAINLY THAT MANY
DIFFERENT MECHANISMS HAVE BEEN
PROPOSE AND THERE'S A HEAVY
FOCUS ON IMMUNE MECHANISM IN
THIS SESSION.
BUT THERE'S ALSO BEEN REPORTS OF
MITOCHONDRIAL DYSFUNCTION.
IT'S CLEAR THAT THERE'S
SOMETHING WRONG WITH THE
MITOCHONDRIA IN THESE PATIENTS,
BUT NO SPECIFIC GENE HAD BEEN
IDENTIFIED.
IN ANY EVENT, WE INVITED THE
PATIENT TO COME TO THE NIH AND
WE STUDIED HER.
AND WE DID THIS NONINVASIVE
EXERCISE TEST CALLED A P31MR
SPECTROSCOPY.
IT'S ACTUALLY A PHOSPHOCREATINE
DEPLETION TEST WHERE YOU DO THIS
KIND OF MILD FOOT EXERCISE TEST.
I'M HAVING TO LOOK UP HERE
BECAUSE I CAN'T SEE THE POINT ON
THE SCREEN HERE.
BUT WE DO THIS MILD EXERCISE
TEST WITH A FOOT PEDAL ON A
FIXED WEIGHT HERE AND YOU DO
KIND OF LIKE A REALTIME MRI
SCAN, AND YOU'RE IMAGING THE
LEVELS OF THIS VERY IMPORTANT
CHEMICAL CALLED PHOSPHOCREATINE
THAT'S THE ENERGY MOLECULE THAT
CELLS USE FOR MUSCLE
CONTRACTION.
AND WHAT YOU DO IS A MILD
EXERCISE FOR A FIXED PERIOD OF
TIME, YOU STOP EXERCISING, AND
THEN YOU LOOK AT THE RECOVERY OF
THIS ENERGY MOLECULE WHICH GETS
DEPLETED WITH EXERCISE.
AND YOU CAN DO A CALCULATION
LOOKING FOR THE TIME CONSTANT OF
RECOVERY OF PHOSPHOCREATINE, AND
THAT HAS BEEN SHOWN BY OTHER
RESEARCHERS THAT CAN BE A MARKER
OF -- A NONINVASIVE MARKER OF
MITOCHONDRIAL OXIDATIVE
PHOSPHORYLATION WHICH IS WHAT
MAKES ATP TO MAKE ENERGY FOR THE
CELLS TO USE.
AND WHAT WE SAW WAS RATHER
SURPRISING.
THIS IS SO THE PATIENT WITH
FATIGUE IS PATIENT S1, S STANDS
FOR SIBLING 1.
AND SHE HAD A VERY PROLONGED
RECOVERY TIME CONSTANT OF
80 SECONDS.
WE'VE NEVER SEEN ANYTHING THAT
PROLONGED.
NORMAL RANGE IS ABOUT 36 TO
40 SECONDS RECOVERY TIME
CONSTANT.
WE REPEATED THAT SIX MONTHS
LATER.
IT WAS PRETTY CONSTANT.
IT WAS 80 SECONDS.
WE ALSO INVITED THE PATIENT'S
BROTHER, SIBLING 2, S STANDS FOR
SIBLING 2, WHO ALSO HAD
LI-FRAUMENI SYNDROME, THE SAME
MUTATION, P53 MUTATION, BUT HE
DIDN'T HAVE FATIGUE SYMPTOMS.
AND WE FOUND THAT HIS RECOVERY
TIME CONSTANT WAS 30 SECONDS.
AND THAT'S ACTUALLY A LITTLE BIT
FAST, AND THAT'S EXACTLY WHAT
WE'RE SEEING IN OTHER
LI-FRAUMENI SYNDROME PATIENTS,
THAT IS THEY HAVE INCREASED
MITOCHONDRIAL -- SO IT APPEARED
THAT THE MUTATIONAL P53 DID NOT
SEEM TO DIRECTLY CORRELATE WITH
THIS TIME CONSTANT.
SO SOMETHING ELSE WAS HAPPENING.
THIS IS AGAIN RATHER PROFOUND,
SO WE'RE VERY CURIOUS AND WE
WANTED TO STUDY HER FURTHER.
SO WE TOOK SMALL SKIN BIOPSIES
FROM BOTH THE PATIENT AND HER
BROTHER AND MADE FIBROBLAST
CELLS AND JUST DID A SIMPLE
OXYGEN CONSUMPTION TEST TO LOOK
AT MITOCHONDRIAL RESPIRATION.
AGAIN WE SAW THAT THE PATIENT IS
IN RED, SHE HAD DIMINISHED
OXYGEN CONSUMPTION WITH
MITOCHONDRIAL ACTIVITY, BOTH IN
ITS BASAL AND STIMULATED STATE
IN THE UNCOUPLED STATE, WHILE
THE BROTHER, THE CONTROL, S2,
HAD NORMAL LEVELS OF OXYGEN
CONSUMPTION AND MITOCHONDRIAL
FUNCTION.
SO AT THIS POINT, I WILL
SUMMARIZE OUR WORK BY SAYING
THAT BY FOLLOWING RETROGRADE
ABERRANT SIGNALING INVOLVING P53
AND P38, WHICH IS JUST, AGAIN,
REGULATORY MOLECULES IN THE CE
CELL, WE TRACE THIS BACK TO
INCREASED LEVELS OF WA WASF3
EXPRESSION.
IT STANDS FOR WISKOTT-ALDRICH
SYNDROME PROTEIN FAMILY MEMBER
3.
THIS WAS A FAMILY MEMBER OF THE
GENE THAT MUTATED IN THAT
CONDITION.
AND WHAT WAS INTERESTING WAS
THAT THIS GENE HAD ACTUALLY BEEN
IDENTIFIED AS ONE OF THE TOP
CANDIDATE GENES IN ME/CFS IN A
BIOINFORMATICS STUDY PUBLISHED
PROBABLY OVER 10 YEARS AGO, AND
THIS WAS BASED ON PROTEOMICS SNP
AND GENE ANALYSIS, BUT NOT MUCH
MORE HAD BEEN DONE WITH WASF3.
HOWEVER, WASF3 IS A WELL-KNOWN
PROTEIN.
IT IS KNOWN TO BE AN ACTIN
INTERACTING PROTEIN, IT HELPS
POLYMERIZE ACTIN.
AND ALSO SERVES AS A SCAFFOLD
FOR PROTEIN COMPLEXES.
AND IT'S BEEN HIGHLY STUDIED IN
THE CELL MIGRATION FIELD AND IS
THOUGHT TO BE IMPORTANT FOR
METASTASIS, CANCER CELLS ABLE TO
MOVE AROUND.
SO WE DECIDE TO STUDY THIS
PROTEIN FURTHER, AND ONE OF THE
FIRST EXPERIMENTS WE DID WAS TO
SEE WHAT HAPPENS IF YOU KNOCK
DOWN -- AGAIN, WE FOUND HIGH
LEVELS OF WASF3.
WE CAN DO THAT SIMPLY BY DOING A
KNOCK DOWN EXPERIMENT USING THE
PATIENT'S CELLS, AND YOU CAN SEE
THAT WHEN WE KNOCK DOWN WASF3
PROTEIN USING SH RNA, THE
MITOCHONDRIAL RESPIRATION IN THE
PATIENT'S SKIN GUY SKIN FIBROBS
IMPROVED, SO IT HAD THE ABILITY
TO CONSUME OXYGEN BUT SOMETHING
WAS SUPPRESSING IT.
WHAT WAS ALSO INTERESTING WAS
THAT THE RESPIRATORY COMPLEX
4 PROTEIN, JUST LOOKING AT COX-1
AND COX-2 SUBUNIT PROTEINS, THE
PROTEIN LEVELS ACTUALLY ALSO
IMPROVED, SUGGESTING THAT WASF3
ARE SOMEHOW DOWNREGULATING THIS
COX, WHICH IS AGAIN ESSENTIAL
FOR RESPIRATION, AND I'LL SHOW
YOU HERE IN THE NEXT SLIDE THAT
WHEN WE DO THE CONVERSE
EXPERIMENT, SO NOW YOU
OVEREXPRESS WASF3 IN A C2C12
MOUSE MYOBLAST LIKE THE SKELETAL
MUSCLE CELLS IN TISSUE CULTURE,
SO WE WERE ABLE TO INTRODUCE
THIS PROTEIN, EXPRESS IT AT
HIGHER LEVELS, AND WHAT YOU CAN
SEE HERE IS THAT COMPARED TO
CONTROL, WHEN YOU EXPRESS WASF3
YOU CAN SUPPRESS OXYGEN
CONSUMPTION.
ASSOCIATED WITH THAT WE SO YOU
DOWN REGULATION WITH THE COMPLEX
FOUR SUBUNITS, COX-1 AND COX-5.
SOME OF THE OTHER SUBUNITS FROM
OTHER COMPLEXES SUCH AS COMPLEX
5 WHICH IS THE ATP SYNTHASE
COMPLEX 3 DID NOT APPEAR TO
CHANGE MUCH, COMPLEX
1 ESPECIALLY AND COMPLEX 2 IS
PROBABLY JUST A COMPENSATORY
INCREASE AND THAT'S PRETTY
WELL-KNOWN -- HYDROGENASE.
SO WE ARE VERY INTRIGUED BY
THESE FINDINGS AND WE WANTED TO
LOOK FURTHER INTO THE MECHANISM.
AND ONE OF THE OTHER THINGS WE
DID WAS WE OVEREXPRESSED WASF3
AGAIN IN THE C2C12 MYOBLASTS, TO
SEE IF WAS IF 3 LOCALIZES THE
MITOCHONDRIA.
THERE WAS SOME INDICATION IT
DOES BUT WE WANTED TO SEE IT
OURSELVES.
SO WE AGAIN TRANSFECTED C2C12
MYOBLASTS WITH THE GENEWATO
EXPRESS IT.
THE MITOCHONDRIAL FRACTION
ENRICHED FOR WA WAS IF3.
THERE'S AN UPPER BAND AND LOWER
BAND.
AND YOU CAN SEE THAT THE LOWER
BAND APPEARS TO BE WHAT
LOCALIZES THE MITOCHONDRIA.
AND EMPIRICALLY, WE TREATED THIS
CELL WITH ALKALINE PHOSPHATASE,
WHICH IS -- PHOSPHATE GROUPS
FROM PROTEINS.
AND YOU CAN SEE THAT THE BAND
SHIFTS FROM THIS LOW MOLECULAR
WEIGHT IN THE MITOCHONDRIA TO A
HIGHER MOLECULAR WEIGHT,
INDICATING TO US THAT, PERHAPS,
THE WASF3 FOUND IN THE
MITOCHONDRIA AT LEAST IN THE
C2C12 IS PHOSPHORYLATED AND
POTENTIALLY INDICATING THAT'S
MAYBE HOW IT'S TARGETED.
THESE ARE ONGOING STUDIES.
WE ALSO WONDERED ABOUT THE
MECHANISM AND HOW WASF3 DOWN
REGULATES THOSE COX RESPIRATORY
COMPLEX 4 PROTEINS.
BECAUSE IT PLAYS AN IMPORTANT
ROLE IN SCAFFOLDING AND HELPING
PROTEINS COMPLEX INTERACT, WE
WONDERED THE EFFECT OF
MITOCHONDRIAL SUPER --
RESPIRATORY COMPLEXES ARE KNOWN
TO FUNCTION BY CLUSTERING
TOGETHER COMPLEX 1, 2, 3, 4 AND
IS THOUGHT TO PROMOTE MORE
EFFICIENT ELECTRON TRANSFER AND
MITOCHONDRIAL RESPIRATION.
WE PERFORMED DENATURING OF BLUE
NATIVE GELS -- TO INCREASE THE
WASF3 -- AND YOU CAN SEE HERE,
THESE ARE REALLY LARGE COMPLEKS.
720 KILODALTON PROTEIN COMPLEX,
YOU CAN SEE OVEREXPRESSED --
IT'S KNOWN FROM THE SUPER
COMPLEX FIELD THAT THE 720
CORRESPONDS TO THE COMPLEX
3 DIMER SO WE'RE TALKING ABOUT
RESPIRATORY COMPLEX 3 WHICH IS
FORM BID MULTIPLE PROTEINS NOW
FORMING A DIMER AND INTERACTING
WITH COMPLEX 4, SO IT'S ACTUALLY
A HETEROOLIGOMER COMPLEX.
WHAT WE CAN SEE HERE IS THAT
WHEN YOU OVEREXPRESS WASF3, THIS
720 KILL DALTON APPEARS TO
DECREASE BUT IMPORTANTLY, IT'S
THE ACTIVITY OF COMPLEX 4 U 4 YU
CAN SEE THE ACTIVITY IS LOWER.
THAT SUGGESTS AGAIN WHAT YOU SAW
WITH OXYGEN CONSUMPTION, IT'S
REALLY EQUIVALENT OF OXYGEN
CONJUNCTION IN GEL CHEMICAL
REACTION SHOWN HERE.
SO AGAIN WE'RE SEEING COMPLEX
4 ACTIVITY DECREASE WHERE
COMPLEX 1 ACTIVITY DOESN'T SEEM
TO CHANGE VERY MUCH.
SO AGAIN SOMETHING IS POINTING
TO COMPLEX 4 AS BEING
DESTABILIZED.
THIS IS ACTUALLY VERY
INTERESTING BECAUSE THE COMPLEX
3 DIMER IS KNOWN TO BE VERY
IMPORTANT FOR HELPING STABILIZE
COMPLEX 46789 WITHOUT THIS
COMPLEX 3 DIMER FORMATION,
COMPLEX 4 GETS DESTABILIZED AND
DEGRADED, SUGGESTING MAYBE THAT
MIGHT BE THE MECHANISM BY WHICH
COX -- THE INITIAL WESTERN BLOTS
I SHOWED YOU WAS LOWER.
SO WE WONDERED -- WE MADE A
TRANSGENIC MOUSE AND WHAT WE
FOUND WAS RATHER DRAMATIC, ITS
EXERCISE CAPACITY ON A TREADMILL
WAS DRAMATICALLY REDUCED BY
ABOUT 50%, ABOUT HALF OF WHAT
ITS WILD TYPE LITTER MATES WERE
CAPABLE OF DOING, SO YOU'RE
SUPPRESSING EXERCISE CAPACITY.
ALSO ISOLATED SKELETAL MUSCLE
FROM THESE MICE AND WE'RE ABLE
TO SHOW DECREASED MITOCHONDRIAL
RESPIRATION, ALBEIT NOT AS
DRAMATIC AS 50% BUT IN VIVO IT'S
HARD TO TELL WHAT THE CORRELATES
ARE OF EXERCISE FUNCTION.
WE ALSO LOOKED AT EXPRESSION OF
WASF3 PROTEIN IN DIFFERENT
TISSUES.
WE WERE ABLE TO OVEREXPRESS
WASF3 PROTEIN HERE IN THE
TRANSGENIC MOUSE COMPARED TO
WILD TYPE MICE THERE.
YOU CAN SEE THERE ARE DIFFERENT
BASAL LEVELS OF WASF3 EVIDENT IN
DIFFERENT TISSUES, IT ACTUALLY
EXPRESSES A LOT OF WASF.
AND THAT MAY HAVE SOMETHING TO
DO WITH THE ACTIN.
ACTIN IS VERY IMPORTANT IN THE
BRAIN FOR NEURONAL STRUCTURE,
CELL STRUCTURE.
BUT IN ANY EVENT, YOU CAN SEE
THAT DIFFERENT LEVELS.
IN THE LIVER WE CAN OVEREXPRESS,
THE REASON IS UNCLEAR, BUT WHAT
IS CLEAR HERE IS WE CAN
OVEREXPRESS IT IN SKELETAL
MUSCLE AND THE MICE HAVE THIS
PHENOTYPE.
JUST LOOKING AT THE OTHER
COMPLEXES, AGAIN, YOU DON'T SEE
MUCH CHANGE IN COMPLEX 1.
COMPLEX 2 AS WELL AS COMPLEX 3.
BUT AGAIN, YOU SEE THAT THE
COMPLEX 4 SUBUNITS, COX-1,
COX-2, 5 AND 17, ARE ALL
DIMINISHED.
AND AGAIN, THE ATPASE THAT
ACTUALLY MAKES THE ATP IS
UNCHANGED.
SO AGAIN, THERE'S THIS --
WITHOUT THAT, YOU CAN'T RESPIRE.
SO HAVING OBSERVED THIS IN A
SINGLE PATIENT, IT'S IMPORTANT
TO SEE IF THIS MIGHT ALSO APPLY
TO OTHER PATIENTS, SO WE ARE
VERY FORTUNATE TO BE HERE AT NIH
TO BE ABLE TO COLLABORATE WITH
AVI NATH, WHO ACTUALLY GAVE A
TALK JUST A LITTLE BIT EARLIER
AND BRYANT WALLIT.
THEY HAD DONE THIS ME/CFS STUDY
WHERE THEY COLLECTED PATIENT
SAMPLES AND THEY ACTUALLY HAD
TAKEN NEEDLE BIOPSIES OF
SKELETAL MUSCLE OF ME/CFS
PATIENTS AND STORED THEM AWAY.
WE WERE ACTUALLY ABLE TO CHECK
FOR LEVELS IN A SUBSET OF
PATIENTS THAT THEY HAD COLLECTED
SAMPLES, SO THIS WAS ACTUALLY --
THIS IS JUST REPRESENTATIVE OF
HALF THE SAMPLES, SO THERE WERE
ACTUALLY 10 HEALTHY VOLUNTEERS,
CONTROLS AND 14 ME/CFS PATIENTS,
SO THIS IS REALLY JUST HALF.
BUT GENERALLY WE WERE ABLE TO
SHOW THAT THERE WAS
DIFFERENT DEGREES OF EXPRESSION
OF WASF3 PROTEIN BUT THEY TENDED
TO BE HIGHER IN THE ME/CFS
PATIENTS.
AGAIN HETEROGENEOUS COMPARED TO
CONTROLS.
CONTROLS VERSUS ME/CFS PATIENTS.
AND THIS IS JUST LOOKING AT THE
COMPLEX 4-G SUBUNITS AND A
CORRELATION BETWEEN WASF AND THE
SIGNIFICANT CORRELATION BETWEEN
WASF3 AND COMPLEX 4 SUBUNITS,
QUANTIFICATION OF THE DATA.
SO WHAT REGULATES WASF3, WHY IS
WASF3 INCREASED IN THE SAMPLES
AT LEAST THAT WE'VE LOOKED AT SO
FAR?
THERE WAS SOME INDICATION IN THE
WASF3 FIELD, AGAIN, IT'S A WELL
STUDIED PROTEIN IN THE CELL
MOTILITY AND ACTIN FIELD, AND
THE CANCER FIELD.
AND WASF3 CAN BE INDUCED BY ER
STRESS, AND WE TESTED IN THE
CELLS, ACTUALLY IT WAS SHOWN TO
BE BIP, A CHAPERONE PROTEIN THAT
STABILIZES PROTEIN FOLDING THAT
WAS ACTUALLY INVOLVED IN THAT
PROCESS, MIGHT ACTUALLY REGULATE
WASF3, SO WE TREATED SOME HUMAN
MYOBLASTS WITH TWO DIFFERENT
CHEMICALS THAT ARE KNOWN TO
INDUCE ER STRESS.
AND YOU CAN SEE THAT
WASF3 PROTEINS COMPARED TO
UNTREATED CONTROL WAS INDUCED BY
ER STRESS, AND IN PARALLEL, YOU
CAN SEE THE COMPLEX 4 SUBUNITS
ARE DECREASED.
AND PERK AND BIP ARE CHAPERONE
PROTEIN, JUST ER STRESS MARKERS.
SO YOU CAN SEE ASSOCIATED WITH
INCREASE IN ER STRESS, THERE WAS
A PARALLEL INCREASE IN
WASF3 WITH A DOWN REGULATION OF
RESPIRATORY COMPLEX.
WE ALSO USED LIPOPOLYSACCHARIDE
WHICH IS AN ENDO TOXIN, ALSO
KNOWN TO INDUCE ER STRESS, AND
SO WE TREATED MICE WITH THIS AND
YOU CAN SEE THAT WASF -- I
SHOULD ALSO MENTION THAT IT'S A
MODEL OF SEPSIS.
SEPSIS IS WELL-KNOWN TO BE
ASSOCIATED WITH FATIGUE AS WELL.
WE SAW WASF3 INDUCED IN THIS
PROTEIN OVER TIME, AND AGAIN,
THERE'S DECREASE IN COMPLEX 4,
INCREASE IN THE ER STRESS
MARKERS.
WE WENT BACK TO THE PATIENT'S
CELLS, THE FIBROBLASTS, AND WE
COMPARED THE BROTHER CONTROL
SUBJECT TO THE PATIENT S1 AT
BASELINE, YOU CAN SEE THAT THE
PATIENT'S CELL, GUY PRO BLASTS
HAS HIGHER PERK, AGAIN A MARKER
OF ER STRESS.
AND WE TRIED TO REVERSE THE ER
STRESS USING A NUMBER OF
DIFFERENT ER STRESS INHIBITORS.
ONE OF THEM IS TUDCA FOR
PATIENTS WITH BILE OR LIVER
DISORDERS, AND WE USE A MUCH
MORE POTENT ER STRESS INHIBITOR,
IT'S ACTUALLY A PHOSPHATASE
INHIBITOR, SALUBRINAL.
WE TREATED THE CELLS AND -- IN
THE PATIENT CELL, AND YOU CAN
SEE WE WERE ABLE TO DOWN
REGULATE THE ER STRESS MARKER,
AND ASSOCIATED WITH THAT WAS A
DOWN REGULATION OF WASF38
PROTEIN, AGAIN, MUCH MORE
POTENTLY WITH THE SALUBRINAL, A
HIGHLY POTENT DRUG ACTUALLY TO
THE LEVEL OF THE CONTROL LEVEL.
CONTROL PATIENT CELL LEVEL.
MOST IMPORTANTLY, WE WERE ABLE
TO SHOW USING THE SALUBRINAL,
WHICH AGAIN IS VERY SPECIFIC FOR
ER STRESS, WE BELIEVE, MORE
SPECIFIC THAN TUD.
C A, WE WERE ABLE TO IMPROVE THE
PATIENT'S BASAL RESPIRATION HE
HERE, WE HAD RECOVERY OF OXYGEN
CONSUMPTION IN THE PATIENT CELLS
WHEN WE DOWNREGULATED ER STRESS,
SUGGESTING PERHAPS THAT THAT'S A
STRATEGY THAT COULD BE USED TO
IMPROVE MITOCHONDRIAL FUNCTION,
AT LEAST IN THE PATIENT'S CELLS,
IT'S SUGGESTING THAT.
SO I'D LIKE TO SUMMARIZE BY
SAYING WE'VE IDENTIFIED WASF3 IN
A SINGLE PATIENT WHO HAPPENED TO
HAVE LI-FRAUMENI SYNDROME.
WE WERE INTRIGUED BY HER
MITOCHONDRIAL DYSFUNCTION AND
FOLLOWED UP ON THAT.
WE BELIEVE THAT WASF3 IS
SOMEHOW -- ACTUALLY I DIDN'T
SHOW YOU THE DATA HEE BUT WE
ACTUALLY HAVE EVIDENCE THAT
WASF3 PROTEIN ITSELF IS IN
PHYSICAL PROXIMITY TO A COUPLE
OF SUBUNITS OF THE COMPLEX 3,
RATHER SPECIFIC INTERACTION
GOING ON, AND THAT WHAT WE THINK
IS HAPPENING IS THAT WASF3 IS
PREVENTING WHEN IT BINDS THE
COMPLEX, IT'S PREVENTING COMPLEX
4 SUBUNITS FROM -- DESTABILIZES
COMPLEX 4 PROTEIN.
IF YOU DON'T HAVE THIS
SUPERCOMPLEX, THEN YOUR
EFFICIENCY OF RESPIRATION WOULD
BE DECREASED, AND IF YOU CAN'T
RE SPIRE, YOU CAN'T MAKE ATP AND
PERHAPS THAT CAN CONTRIBUTE TO
THE FATIGUE AND ENERGY
DEFICIENCY IN CHRONIC FATIGUE
SYNDROME.
SO I'D LIKE TO COMPLETE JUST BY
ACKNOWLEDGING AGAIN PEOPLE WHO
DID ALL THE WORK.
MY LAB MEMBERS, THE PATIENT WHO
MADE THIS STUDY POSSIBLE.
WITHOUT PATIENTS, PERSISTENT
PATIENTS, IT WOULD BE DIFFICULT
TO DISCOVERY, AND ALSO THE MANY
COLLABORATORS WHO HELPED US WITH
THIS STUDY, ESPECIALLY BRIAN
WALITT AND AVI NATH WHO AGAIN
HELPED US WITH THE SAMPLES AND
GAVE US GREAT ADVICE.
SO THAT'S IT.
THANK YOU.
[APPLAUSE]
>> HELLO.
FRANCISCO FROM SAN DIEGO.
QUESTION.
IN YOUR OVEREXPRESSING MICE, IF
YOU DO A SECOND TREADMILL TEST,
DO THEY DEVELOP LIKE A POST
EXERTIONAL MALAISE?
>> THAT'S A GREAT QUESTION.
THE QUESTION IS WHETHER -- IF
YOU EXERCISE TEST THE MICE,
AGAIN, DO THEY -- I GUESS IS
THERE A CHANGE, RIGHT?
WE ACTUALLY DEPARTMENT DO THAT,
BUT THAT'S A VERY, YOU KNOW,
INTERESTING POINT.
BUT WE DIDN'T DO THAT.
I MEAN, IT WAS A VERY DRAMATIC
DECREASE.
WE'RE JUST PROVING THAT -- WE'RE
JUST DEMONSTRATING THAT IF YOU
OVEREXPRESS IT IN VIVO, YOU CAN
HAVE AN IN VIVO PHYSIOLOGIC
PHENOTYPE.
THANKS.
>> ONE CORNELL QUESTION.
[LAUGHTER]
>> OKAY.
I WAS WONDERING IF YOUR CONTROLS
FOR THE SKELETAL MUSCLE BIOPSY
WERE SEDENTARY.
AND WERE THE CONTROLS SEDENTARY
THAT YOU WERE COMPARING THE
LEVELS OF WASF3 TO THE PATIENTS
WHO ARE SEDENTARY?
AND THE POINT BEING IS, IS IT
POSSIBLE THAT THERE'S A
DIFFERENCE IN WASF33 LEVELS IN
PEOPLE WHO ARE SEDENTARY VERSUS
PEOPLE WHO ARE ACTIVE?
>> THAT'S A GREAT POINT.
THAT'S A GREAT POINT.
THE QUESTION IS, DID WE CONTROL
FOR LEVEL OF ACTIVITY IN THE
HEALTHY VOLUNTEER MUSCLE
SAMPLES.
I ACTUALLY APOLOGIZE BUT I DON'T
KNOW THE ANSWER TO THAT.
I'M SURE BRIAN HAS THE ANSWER TO
THAT BECAUSE THEY TOOK A VERY
COMPREHENSIVE SURVEY OF THESE
PATIENTS SO I'M SURE THEY HAVE
THE ACTIVITY LEVELS OF THE
PATIENTS, BUT THAT'S A GOOD
QUESTION.
AND I THINK THE IMPORTANT
QUESTION IS DOES IT ALSO CHANGE
WITH EXERCISE, RIGHT, AS THE
PREVIOUS PERSON ASKED THE
QUESTION ABOUT WHAT HAPPENS
AFTER EXERCISE, DOES IT GET
WORSE.
BUT WE REALLY DON'T KNOW DOES IT
CHANGE WITH EXERCISE ACTIVITY.
I WOULD SUSPECT THAT IF YOU DO
ENDURANCE EXERCISE THAT THERE
WILL BE CHANGES IN ER STRESS
LEVELS IN SKELETAL MUSCLE.
SO I WOULD IMAGINE THAT THERE
WOULD BE ADAPTATIONS THAT MIGHT
CHANGE.
SO I THINK IT'S A GOOD QUESTION,
IMPORTANT QUESTION.
>> RELATED TO THAT, WAS THERE A
SEX DIFFERENCE IN THE PATIENTS
AND CONTROLS AND IS THERE ANY
EVIDENCE ABOUT MALES VERSUS
FEMALES ABOUT HAVING MORE OR
LESS WASF3.
>> OH, IT'S SO HARD TO HEAR FROM
UP HERE.
OH.
I THINK THERE ARE MORE WOMEN
SAMPLES BUT THERE ARE MALE
SAMPLES AS WELL.
WE ACTUALLY TRY TO BALANCE THAT
AS WELL.
BUT I'M PRETTY SURE IT'S
DEFINITELY MORE WOMEN THAN MEN.
>> SORRY I HAD TO CUT YOU OFF,
JEFF.
MAYBE YOU CAN ASK DURING THE
PANEL DISCUSSION.
WE'LL MOVE TO OUR NEXT SPEAKER,
METABOLIC INSIGHTS INTO ME/CFS,
PHENOTYPES AND UNDERLYING
MECHANISMS.
KARL-JOHAN TRONSTAD FROM
UNIVERSITY OF BERGEN.
PROBABLY TRAVELED THE FURTHEST
TO COME.
>> THANK YOU, AND THANK YOU FOR
THE INVITATION TO COME.
IT'S VERY GOOD TO BE HERE AND
LISTEN TO THE TALKS.
NIH IS INSTRUMENTAL IN INSPIRING
RESEARCH ALL OVER THE WORLD, I
THINK, EVEN IN SMALL CORNERS OF
THE WORLD.
WHERE I CAME FROM, COME FROM.
SO I'M GOING TO TALK ABOUT
METABOLIC STUDIES IN ME/CFS, AND
SOME OF THE THINGS WE HAVE BEEN
WORKING ON, BUT FIRST I'LL
INTRODUCE TO THE GROUP WE ARE
WORKING IN.
I WILL JUST HOLD THE POINTER.
AND I'M WORKING IN A
TRANSLATIONAL RESEARCH GROUP IN
BERGEN, IN NORWAY.
ANI COME FROM THE UNIVERSITY IN
THE DEPARTMENT OF BIOMEDICINE AT
THE UNIVERSITY OF BERGEN AND
COLLABORATE CLOSELY WITH THE
CLINIC.
TOGETHER WE INVESTIGATE
MECHANISMS AND DIFFERENCES
BETWEEN HEALTHY AND ME/CFS
PATIENTS.
THERE'S A BIOBANK -- WHICH WE
USE AS A RESOURCE FOR THESE
STUDIES.
SO THE HYPOTHESIS WE ARE
ADDRESSING IS THAT M.E. IS DUE
TO AN ACQUIRED IMMUNE SYSTEM
DEFECT THAT CAN BE CAUSED BY
AUTOIMMUNITY.
PROBABLY IN A SUBGROUP OF
PATIENTS.
AND BASED ON THIS HYPOTHESIS, MY
PARTNERS AT THE CLINIC, THEY ARE
TRYING TO TEST DIFFERENT
THERAPIES TO REBOOT PARTS OF THE
IMMUNE SYSTEM.
TO SEE IF THAT HAS BENEFICIAL
EFFECT.
NOW, THIS HISTORY, THE HISTORY
OF THIS RESEARCH STARTED AROUND
2007 WHERE MY TWO MAIN
COLLEAGUES AT THE CLINIC ARE
WORKING IN THE CANCER WORLD AND
THEY TREAT CANCER PATIENTS,
CANCER PATIENTS THAT HAD M.E.
FOR SEVERAL YEARS BEFORE THEY
GOT THEIR CANCER TREATMENT, AND
THEN THEY OBSERVED THAT SOME OF
THESE PATIENTS BECAME BETTER
AFTER THE CANCER TREATMENT.
SO THEN THEY GOT THIS IDEA OF --
MAYBE THIS COULD BE SOME TYPE OF
AN AUTOIMMUNE MECHANISM.
AND THEY HAVE DONE SEVERAL
CLINICAL TRIALS TO TEST IMMUNE
MODULATING TREATMENTS IN THESE
PATIENT GROUPS AND THEY HAVE
ESTABLISHED THE BIOBANK AND ALSO
DONE OBSERVATIONAL STUDIES
RELATED TO THIS.
SO THE STATUS IS THAT THERE
MIGHT BE A SUBGROUP OF PATIENTS
THAT MAY BENEFIT FROM THIS.
BUT MORE EVIDENCE IS NEEDED.
NOW WE CAME IN AROUND 2015 AND
CONTRIBUTED IN THE MECHANISTIC
INVESTIGATIONS.
ALSO THE COMPREHENSIVE BLOOD
SAMPLE ANALYSIS THAT HAS BEEN
DONE UNDER THE BIOBANK SAMPLES.
TWO OF THE MAJOR CLINICAL TRIALS
TRIALS, THERE WERE MANY LEARNING
LESSONS AND MANY SAMPLE FROM
THAT STUDY WHICH HAS BEEN VERY
USEFUL AFTERWARDS.
THIS WAS A MULTICENTER RCT AND
IT NEGATIVE.
THE CYCLOME TRIAL DRUG WAS HARD
FOR THE PATIENT TS TO 50 THROUGH
THIS AND IT WAS AN OPEN LABEL
STUDY.
MORE THAN HALF OF THE PATIENTS
GOT CLINICAL BENEFIT FROM THIS
TREATMENT.
THE S.DUE TO SIDE EFFECTS, THISG
WILL NOT BE CONTINUED FOR
TESTING.
NOW BASED ON THESE OBSERVATIONS
AND THE OTHER ACTIVITY GOING ON,
WE HAVE THIS WORKING HYPOTHESIS.
IT'S ON THE IMMUNE DYSREGULATION
BEHIND THAT CAUSES AN EFFECTOR
MECHANISM, AND WE FIND VASCULAR
DYSREGULATION TO BE A POSSIBLE
AND LIKELY EFFECTOR MECHANISM.
AND THEN YOU HAVE ADAPTATION OF
CHANGES AFTERWARDS.
WE DIVIDED IN THREE STEPS TO TRY
TO KIND OF FIND THE PAT THAT PAT
MIGHT BE ASSOCIATED THROUGH
THESE THREE STEPS.
THERE YOU ALSO FIND SOME
SUGGESTIONS FOR THERAPEUTIC
STRATEGIES AND WHERE TO GO -- WE
COULD GO.
SO CURRENTLY THEY'RE TESTING
PLASMA CELL DIRECTED TREATMENT
IN A PILOT STUDY.
MAYBE THAT CAN BE A POSSIBLE
STRATEGY.
NOW, WHEN IT COMES TO THE STATUS
OF METABOLISM IN ME/CFS, STUDIES
HAVE FOUND CHANGES IN BLOOD
BIOCHEMISTRY AND THERE ARE MANY
THEORIES AND HYPOTHESES
DISCUSSED, BUT WE INTERPRET --
TO KEEP IT SIMPLE, WE INTERPRET
THESE FINDINGS AS INDICATIONS --
THERE ARE MANY FINDINGS, MANY
INDICATIONS OF ENERGY STRESS IN
THOSE FINDINGS.
AND WE ALSO THINK THERE IS
EVIDENCE OF HYPOXIA.
THIS HAS BEEN, OF COURSE, A
PARADIGM IN THE FIELD AS WELL,
THAT TISSUE HYPOXIA IS A
CHARACTER OF THIS PATIENT GROUP.
BUT THERE HAVE NOT BEEN TARA TAO
REALLY SHOW THIS IN MOST
PATIENTS.
WE THINK THERE ARE METABOLIC
SUBGROUPS THAT CAN ALSO BE OF
CLINICAL INTEREST, BUT WE NEED
MORE CLINICAL OR COMPREHENSIVE
STUDIES TO REALLY GET INTO THE
MOLECULAR ARCHITECTURE, AND
MAYBE FIND BIOMARKERS AND MAYBE
TARGETS FOR TREATMENT.
DIFFERENT MORE PRECISE
SUBGROUPS.
SO I WILL GO INTO THIS TISSUE
HYPOXIA TOPIC.
SO WE HAVE SOME INDICATIONS, AND
I THINK I DON'T NEED TO USE TIME
CONVINCING YOU THAT TISSUE
HYPOXIA IS IMPORTANT.
COMING AFTER ME, HE WILL TALK
MORE ABOUT THIS BUT THEY HAVE
CONTRIBUTED SOME OF THE MOST
IMPORTANT FINDINGS LIKELY THAT
THIS IS A VERY LIKELY EFFECT.
NOW, THIS IS DUE -- THIS LEADS
TO REDUCED OXYGEN OR A VASCULAR
EFFECT CAN LEAD TO REDUCED
OXYGEN DELIVERY ANDS BE
RESPONSIBLE FOR THE LACTATE
OVERPRODUCTION THAT THE PATIENTS
TALK ABOUT AND WE HAVE BEEN
ALSO -- OR SOME GROUPS -- THIS
STUDY FROM OSLO WHERE YOU SEE
THE RED LINES SHOWING AN EARLY
ELEVATION OF LACTATE IN PATIENTS
DURING THE TEST.
ALSO THESE EFFECTS CAN BE
RESPONSIBLE AT LEAST PARTLY FOR
THE PHYSICAL IMPAIRMENT AND
SYMPTOMS IN THE PATIENTS.
AND I WILL TAKE YOU BACK TO THE
CORE WHEN IT COMES TO ENERGY
METABOLISM AND WHAT KIND OF
EFFECTS TISSUE HYPOXIA WE WILL D
TO OR MAY LEAD TO OR EVEN A
PARTIAL ACTIVATION OF THIS
HYPOXIA M PRA.
SO HERE WE HAVE THE MAIN ACCESS
OF ENERGY METABOLISM IN THE
CELL.
WITH GLUCOSE BEING CONVERTED TO
PYRUVATE, IMPORTED INTO THE
MITOCHONDRIA AND CONVERTED TO
ACETYL COA, THEN YOU HAVE THE
TCA CYCLE, AND OXIDATIVE
PHOSPHORYLATION SYSTEM, WHICH
THEN ARE RESPONSIBLE FOR MAKING
ALL THAT ATP FROM THE
MITOCHONDRIAL FUNCTION.
NOW, WHAT HAPPENS IF WE HAVE
SOME ELEVATION OF -- OR
AMPLIFIED EFFECTS OF HYPOXIA?
SO TYPICALLY THIS LEADS TO
INCREASED GLYCOLYSIS.
AND INCREASED PRODUCTION OF
PYRUVATE, THIS IS WHERE NOW THE
CELL GETS MOST OF ITS ENERGY.
BUT SINCE WE HAVE A LACK OF
OXYGEN, THE MITOCHONDRIAL
MACHINERY WHICH WILL BE TURNED
OFF, OR IF YOU HAVE A CONDIT
CONDITION -- OF OXYGEN, WE CAN
THINK MAYBE MITOCHONDRIA ARE
PARTLY TURNED OFF.
NOW, WHAT ARE THE CONSEQUENCES
OF THIS?
THERE WILL BE METABOLIC
COMPROMISES.
THERE WILL BE MORE LACTATE,
THERE WILL BE A STRUGGLE FOR ATP
AND THIS CAN BE AMPLIFIED BY
ACTIVITY.
AND THIS IS SOMETHING THAT WE
EASILY CAN RELATE TO WHEN IT
COMES TO THE PATIENTS.
THE POSSIBLE CAUSES CAN THEN BE
THAT THERE IS LESS BLOOD TO THE
TISSUE, LESS PERFUSION.
AS I MENTIONED.
BUT IT CAN ALSO BE DUE TO
MITOCHONDRIAL DEFECTS, WHICH CAN
BE, FOR INSTANCE, GENETIC IN
MITOCHONDRIAL DISEASE AND
CONDITIONS LIKE THAT, BUT ALSO
IN SOME ACQUIRED METABOLIC
DISEASE, NOT ONLY ACQUIRED BUT
ALSO DIABETES AND OTHER
CONDITIONS, THIS SYSTEM CAN BE
ACTIVATED.
AND THEN THE NEGATIVE
PHYSIOLOGICAL IMPACT INVOLVES
BOTH LOWERED ANAEROBIC
THRESHOLD, EXERCISE INTOLERANCE,
AND MAYBE POST EXERTION MALAISE,
WHICH IS THE THING WE KNOW LESS
OF IN THIS CONTEXT.
NOW YOU HAVE THIS ACTIVATED
PROGRAM FOR -- ACTIVATED BECAUSE
THERE IS A LACK OF OXYGEN.
AND THIS CREATES A CONDITION OF
ENERGY STRESS, WHICH THE BODY
CAN TRY TO MITIGATE BY
ACTIVATING METABOLIC
ADAPTATIONS.
AND THIS CAN BE LONG TERM
ADAPTATIONS, AND THEY ARE
INHERENT PROGRAMS TO TRY TO
RESCUE THE SITUATION.
BUT THESE ARE ALSO ACTIVATED IN
DIFFERENT CONTEXTS.
SO THIS MAY LOOK VERY COMPLEX,
BUT IT'S IMPORTANT TO KNOW THAT
THIS IS CONTEXT-DEPENDENT
PATHWAYS WE ARE TALKING ABOUT.
SO THE PURPOSE OF THESE
ADAPTATIONS ARE TO RESCUE AND
MAINTAIN SUPPLY.
IN MOST CONTEXT DEPENDENT
PROGRAMS AND EXERCISE, IT
TYPICALLY INVOLVES FUEL
SWITCHING FROM GLUCOSE TO
ANOTHER OXIDATIVE -- OXIDIZED
FUEL, AND THIS ALSO HAS A
SYSTEMIC IMPACT.
IT'S NOT ONLY IN THE TISH EUM TE
WHERE YOU MAY FIND AMPLIFIED
HYPOXIA EFFECT BUT ALSO IN OTHER
ORGAN SYSTEMS.
SO THIS EFFECT OF HYPOXIA AND
STRESS ACTIVATES ALTERNATIVE
PATHWAYS, AND IT MAY, IN THE
CONTEXT OF ME/CFS, IT MAY SERVE
TO MITIGATE EFFECTS ON SYMPTOMS
AND TRY TO BE A POSITIVE
INFLUENCE ON THE CONDITION.
NOW, IN MOLECULAR TERMS, WHAT
HAPPENS HERE IS THAT THE LACK OF
OXYGEN, IT OF COURSE INHIBITS
MITOCHONDRIAL RESPIRATION
DIRECTLY BY INHIBITING
PHOSPHORYLATION SYSTEM, IN
ADDITION, IT ACTIVATES
TRANSCRIPTION FACTOR CALLED
HYPOXIA INDUCED FACTOR 1 ALPHA
WHICH REGULATES BOTH
ANGIOGENESIS BUT ALSO STEPS IN
THIS MAIN ENERGY PATHWAY.
AND THIS OCCURS THROUGH GENETIC
REGULATION.
SO HIF1 ALPHA TARGETS SPECIFIC
GENES WITH A RESPONSE ELEMENT IN
THE PROMOTER REGION, THEN YOU
HAVE INCREASED EXPRESSION OF
THESE DIFFERENT GENES.
WHERE SO IN OUR STUDY IN 2016,
THAT ONE TARGET, OR THAT THE
ACTIVITY OF THE PYRUVATE
HYDROGENASE SEEM TO BE INHIBITED
AND WE FOUND INCREASED
EXPRESSION OF SEVERAL PROTEINS
THAT HAVE AN INHIBITORY EFFECT
ON THIS ENZYME, AND THERE WERE
INCREASED EXPRESSION OF THIS IN
THE PATIENTS.
AND ONE OF THESE IS THE PD
PDK1 PART OF IT, WHICH IS A
TARGET OF HIF1 ALPHA.
SO THIS IS AN INDICATION THAT
THERE MAY BE AMPLIFIED HYPOXIA
EFFECT IN THE PATIENTS.
NOW, IN THIS CONTEXT, IT IS ALSO
POSSIBLE ACTUALLY THAT THERE WAS
A THREE PROTEIN, COULD BE A
MEDIATOR HERE, AND IT SUGGESTS
IT WAS VERY INTERESTING TO
LISTEN TO JUST THE PRESENTATION
OF DR.HWANG AND REALLY SHOWS
MOLECULAR MECHANISM WHEREBY --
WHICH CAN REALLY EXPLAIN PARTS
OF THE MECHANISM INVOLVED IN
ME/CFS PATIENTS.
NOW THIS WAS A -- ALSO HAS
RESPONSE ELEMENT FOR HIF1 ALPHA
IN THE PROMOTED REGION, SO THIS
IS A SUGGESTION THAT MAYBE, IF
THERE IS A CONDITION OF HYPOXIA
IN THE PATIENTS' MUSCLES, THIS
COULD ALSO EXPLAIN WHY WASF3 SIN
CREASED IN THE PATIENTS.
BUT THIS HAS NOT BEEN
INVESTIGATED YET.
BUT IT COULD BE AN ALTERNATIVE
MECHANISM BUT THAT SAID,
WASF3 BEING A MEDIATOR TO
INHIBIT OXIDATIVE
PHOSPHORYLATION IN THE CONTEXT
OF HYPOXIA MAKES PERFECT SENSE
AS WELL, AND IT CAN EXPLAIN
MAYBE SOME OF THE EFFECTS.
I THINK FINDINGS LIKE THESE ARE
PARTICULARLY IMPORTANT, SINCE WE
HAVE SO FEW MOLECULAR TARGETS TO
REALLY TRANSLATE INTO THE IN
VITRO SETTING AND START STUDYING
THE MOLECULAR MECHANISMS
INVOLVED IN ME/CFS.
BECAUSE SUCH KIND OF DISCOVERIES
MAKES US ABLE TO DEVELOP IN
VITRO MECHANISTIC MODELS, AND
MAYBE -- EVEN PAUL AND HIS GROUP
MADE ANIMALS, AND WE ARE LACKING
ALSO ANIMAL MODELS IN THIS FIELD
THAT IN A -- MANNER REFLECTS THE
DISEASE MECHANISM.
BUT SUCH FINDING REALLY GIVES
HOPE THAT WE WILL BE ABLE TO
MAKE GOOD MECHANISTIC MODELS SO
WE CAN DO MECHANISTIC STUDIES.
NOW, HERE ARE SOME OF THE
EFFECTS OF THE ADAPTATION GOING
ON, UPON AMPLIFIED HYPOXIA.
TYPICALLY, GLYCOLYSIS WILL BE
DECREASED BY THIS INFLUENCE AND
THIS OCCURS PARTLY BECAUSE OF
PDH INHIBITION BY DIFFERENT
PATHWAYS.
THE PURPOSE IN THIS CASE IS TO
PROMOTE ALTERNATIVE FUELING BY
FATTY AND AMINO ACIDS THAT CAN
FUEL INTO THE TCA CYCLE AND
PROVIDE A FUEL FOR OXIDATIVE
PHOSPHORYLATION AS WELL.
BUT THIS, OSKT, OCCURS NOW IN
THE PRESENCE OF OXYGEN.
SO THIS CAN BE ACTIVATED IN
DIFFERENT CO CONTEXTS AND ALSO N
DIFFERENT CELL TYPES, AND SOME
OF THE FACTORS THAT CAN
CONTRIBUTE TO THIS HAVE SOME OF
THOSE THAT ARE MOST KNOWN, THEY
ARE KNOWN ENERGY SENSOR AND
METABOLIC REGULATOR, THEY ARE
KNOWN TARGETS FOR DIFFERENT
KINDS OF DRUGS AND TREATMENTS.
IN DIFFERENT CONTEXTS.
SO THEIR MAIN TASK IS TO RESTORE
ATP, CONSERVE GLUCOSE AND TO
PROVIDE ALTERNATIVE FUELING.
WHAT'S RELEVANT ALSO HERE IS
THERE CAN HAPPEN DEREGULATION IN
THE SYSTEM.
WHICH CAN CONTRIBUTE TO THINGS
LIKE DYSLIPIDEMIA AND INSULIN
RESISTANCE.
AND THIS ON TOP OF THE MECHANISM
OF ME/CFS CAN LEAD TO FURTHER
IMPAIRMENT OR NEGATIVE EFFECTS.
WE KNOW THAT SOME OF THESE
REGULATORY ELEMENTS ARE RELEVANT
ALSO IN ME/CFS.
AND I'M SUING SHOWING YOU AN EE
HERE, INCREASED EXPRESSION OF BD
K1 IN THE PATIENTS, WE ALSO
FOUND INCREASED EXPRESSION OF
PDK4, WHICH IS TYPICALLY A
FACTOR THAT'S ACTIVATED WHEN
FATTY ACID OXIDATION IS HIGH,
YOU HAVE AN ALTERNATIVE
FUELING OF THE SYSTEM.
SO THIS IS TYPICALLY AN ADAPTIVE
RESPONSE.
SO IN THE PATIENTS, THIS SEEMS
ACTIVATED AT THE SAME TIME, BOTH
THE HYPOXIC RESPONSE AND
ADAPTATION.
AND WE LACKED FURTHER INTO THE
METABOLIC -- IN ME/CFS AND IN
COMPREHENSIVE METABOLOMICS
STUDY, WE MENTIONED I WE FOUND 9
SIGNIFICANT DIFFERENCES BETWEEN
THE TWO GROUPS.
WE DID SEE DATA HETEROGENEITY,
AND WE USED THIS ACTUALLY AS A
RESOURCE TO CLUSTER THREE
SUBSETS OF PATIENTS.
WE CALL THEM METABOLIC
PHENOTYPES, AND ESPECIALLY IT
POINTED TO AMINO ACIDS AND
LIPIDS AND WHAT WE INTERPRETED
AS PATTERNS OF ENERGY STRESS
BECAUSE OF THIS ALTERNATIVE
METABOLISM.
I ARE NOT WILL NOT GO IN DETAILD
SEE UNIQUE UNIFORM EFFECT IN THE
GROUPS, WE SEE, FOR INSTANCE,
THE HEALTHY CONTROLS COMPARED TO
THE TOTAL M.E. GROUP, THERE WAS
AN ELEVATION IN GLYCEROL, AND WE
DID SEE SIMILAR LEVELS IN THE
THREE DIFFERENT SUBSETS.
GLYCEROL IS ACTUALLY COMING FROM
DS -- OF FATTY ACIDS FROM
TRIGLYCERIDES.
SO YOU HAVE MOBILIZATION OF FAT
AND THE RELEASE OF FREE FATTY
ACIDS IN BLOOD TO BE USIZ UTILID
FOR ENERGY PURPOSES.
SO MOBILIZATION IN ALL THE THREE
SUBSETS.
HERE IS ANOTHER EXAMPLE, WE DID
SEE HERE THAT THERE WAS A SMALL
INCREASE IN THE TOTAL M.E.
GROUP, BUT THERE WERE ALSO A
LARGE SPREAD IN THIS GROUP.
AND WHEN WE SUBDIVIDED BASED ON
THE DIFFERENT -- THREE DIFFERENT
GROUPS OF PATIENTS OR SUBGROUPS,
WE SAW THAT THIS WAS
PARTICULARLY DUE TO ELEVATION IN
ONE OF THE SUBSETS.
SO THIS METABOLITE,
3 HYDROXYBUTYRATE, IS THE SAME
AS -- IT'S A KETONE BODY, AND
THIS IS ACTIVATED OR ELEVATED
TYPICALLY UNDER ENERGY STARVED
CONDITIONS.
ANOTHER OBSERVATION WAS THAT
THESE THREE METABOLIC SUBSETS
WERE ALSO DIFFERENT WHEN IT CAME
TO THE PHYSICAL FUNCTION SCORE,
THE SF36 PHYSICAL FUNCTION
SCORE.
SO WHAT WE CALL THE MEM
MEM2 METABOTYPE SEEMED WORSE
COMPARED TO OTHER ONES.
SO THE METABOLIC PHENOTYPE SEEMS
TO BE A FUNCTIONAL EFFECT ON THE
PATIENTS.
WE DON'T KNOW, REALLY, IF IT'S
THE HEN AND THE EGG AND, YEAH,
WHICH IS THE -- ONE.
BUT IT IS INTERESTING TO SEE
THAT IT HAS CLINICAL IMPACT.
AND HERE THE CONCLUSION FROM
THAT STUDY.
WE DID SEE COMMON FEATURES OF
ENERGY STRAIN IN THE PATIENTS.
WE THINK THAT COULD BE DUE TO
TISSUE HYPOXIA OR AT LEAST SOME
UNDERLYING ENERGY STRESS AND IT
IS EXERTION-SENSITIVE.
THEN WE DID SEE CONTEXTUAL
DEFECTS, WHERE WE THINK MIRRORS
METABOTYPES, ONE SIMILAR TO
FASTING WITH HIGH FATTY ACIDS
AND HIGH KETONE BODIES.
THEY ARE STILL EXTREME LIE HIGH,
THERE IS A BIOLOGICAL SHIFT.
AND THE SAME FOR METABOTYPE
2 WHICH HAD SIMILARITY TO THIS
LIPIDEMIA WITH HIGH DRY GLIS
RIDES AND THEN YOU HAVE M3 WHICH
WAS SOMETHING IN BETWEEN AND
ALSO MORE SIMILAR TO THE
CONTROL.
SO HOW IS THIS CONNECTED AND HOW
IS IT CONECTED TO THE OTHER
FINDINGS SUPPORTING THAT THERE ?
WE STILL HAVE MUCH TO DO IN THAT
SENSE.
WE THINK THAT -- WE DON'T REALLY
KNOW IF IT IMPACTS OXYGEN
DELIVERY OR UPTAKE IN THE
TISSUES.
WE DON'T REALLY KNOW HOW THIS IS
EXACERBATED BY EXERTION, BUT
YOU'RE BEGINNING TO GET MUCH
KNOWLEDGE -- DAVID WILL TALK
ABOUT AFTERWARDS.
WHEN IT COMES TO POST EXERTION
MALAISE, THERE ARE STUDIES FROM
CORNELL AND OTHER GROUPS THAT
ARE DOING THAT, SO THAT'S VERY
GOOD BECAUSE THIS HAS BEEN A
BLACK HOLE FOR SO MANY YEARS.
AND WE ALSO NEED TO LOOK INTO
WHAT ARE THE LINKS TO THE IMMUNE
SYSTEM DYSREGULATION.
AND WHEN IT COMES TO SIMILARITY
WITH LONG COVID, THE GERMAN
ASSOCIATION A COUPLE YEARS AGO
MADE THIS NICE OVERVIEW OF
REPLICATED FINDINGS WHICH POINTS
TO SEVERAL OF THE KEY ELEMENTS
THAT HAVE BEEN MENTIONED SEVERAL
TIMES ALREADY.
SO I'VE NOT LOOKED INTO THE
EXACT REPLICATION IN THIS THING,
BUT I THINK MORE COMPREHENSIVE
STUDIES, THERE IS SO MUCH GOING
ON NOW IN THE LONG COVID FIELD
AND ALSO WE HAVE SOME DATASET
FROM THE M.E. FIELD, BUT WE NEED
LARGER STUDIES ALSO IN THE M.E.
FIELD, I THINK TO REALLY BE ABLE
TO LOOK INTO THE SUBGROUPS OF
PATIENTS AND TRYING TO
UNDERSTAND THE UNDERLYING
MECHANISMS.
WE KNOW ALSO LITTLE ABOUT THE
METABOLIC LANDSCAPE OF POST
EXERTIONAL MALAISE FROM
MAUREEN'S GROUP, THEY HAVE DONE
SEVERAL INTERESTING STUDIES, AND
COULD IT BE THAT THERE ARE SOME
TOXIC EFFECTS OR TOXIC FACTORS
THAT ARE RELEASED UNDER THIS
EXERCISE TESTING.
WE KNOW THAT TRAINING ITSELF
CREATES WAVES OF PROGRAMS THAT
ARE ACTIVATED GENE REGULATION
PROGRAMS AND THEN YOU HAVE A
GRADUAL ADAPTATION OF THE
METABOLISM IN THE MUSCLE WHICH
IS POSITIVE, BUT WE ALSO KNOW
THAT EXCESSIVE TRAINING CAN LEAD
TO MITOCHONDRIAL IMPAIRMENT,
THERE CAN BE SOME TOXIC FACTORS
RELEASED UNDER THESE CONDITIONS.
SEVERAL GROUPS HAVE ALSO SEEN,
INCLUDING OURSELF IN THIS STUDY,
WE SAW THAT IF WE COUNTED
HEALTHY MUSCLE CELLS IN THE
PRESENCE OF SERUM FROM PATIENTS,
WE COULD SEE SOMETHING THAT
RESEMBLES ENERGY STRESS IN THE
PATIENTS.
WE DID SEE BOTH INCREASED OXYGEN
CONSUMPTION AND INCREASED
LACTATE PRODUCTION UNDER THESE
OPINIONS.
SO THERE ARE SOME ACTIVE FACTORS
IN THE BLOOD OF THE PATIENTS.
WE DON'T REALLY KNOW IF IT'S IN
COCKTAIL EFFECT OR IF IT'S -- IF
THERE ARE SINGLE FACTORS THAT
ARE RESPONSIBLE FOR THESE KIND
OF EFFECTS.
AND SOME SPECULATION WHEN IT
COMES TO BIOMARKERS AND
TREATMENTS.
IF WE HAVE A KIND OF A MAP LIKE
THIS, WE CAN LOOK INTO WHAT CAN
BE DONE, SO IN HIS GROUP, THEY
CALL IT A TREATABLE
NEUROVASCULAR DYSREGULATION, AND
THIS OF COURSE WILL REPAIR THE
HYPOXIA EFFECTS.
WHERE ADAPTATION OF PROGRAMS CAN
BE ACTIVATED BY DIFFERENT
THERAPIES OR SUPPLEMENTS OR
STRATEGIES, BUT THEY ARE NOT
ALWAYS POSSIBLE TO DO.
FOR INSTANCE, WE NOPE THAT
PHYSICAL ACTIVITY IS POSITIVE
FOR THIS SITE, BUT THIS IS OF
COURSE NOT ALWAYS POSSIBLE TO
DO.
BUT IF WE HAVE A MAP WITH THE
RESPONSIBLE FACTORS LIKE THIS,
WE CAN KIND OF TRY TO BE
SPECIFIC WHEN WE MAKE HYPOTHESES
AND ALSO USE MODEL SYSTEM THAT
HAS ALREADY BEEN CREATED IN THE
LABORATORIES AROUND, BECAUSE
THEN YOU CAN REALLY LOOK INTO
THE MECHANISMS.
SO WE THINK STILL THAT IT IS A
VIABLE APPROACH TO TRY TO
CORRECT EFFECTS IN THE IMMUNE
SYSTEM, BUT IT IS -- ADD
CHALLENGE AS WELL SINCE WE DON'T
HAVE THE OBJECTIVE BIOMARKERS
FOR THE CONDITION AND ALSO FOR .
THIS IS A CHALLENGE, OF COURSE,
IN THE ENTIRE FIELD.
AND ALSO WE WILL HAVE TO WORK
HARD TO FIND THE MISSING LINKS
IN THE MECHANISM AND THAT
INCLUDES DEEP IMMUNE
CHARACTERIZATION AND
CHARACTERIZATION OF SUBGROUPS AS
WELL, DEFINED POSSIBLE
SUBGROUPS.
SO I WILL END THIS BY THANKING
MY GROUP AT BERGEN AND OUR
COLLEAGUES, AND THANK YOU FOR
LISTENING.
[APPLAUSE]
>> HI.
ALLAN CASH.
I'M WITH TERRA BIOLOGICAL SO I'M
FROM INDUSTRY HERE.
OOO!
[LAUGHTER]
HAVE YOU MEASURED HYPOXABLE
INDUCIBLE FACTOR IN THESE
PATIENTS?
HAVE YOU SEEN AN INCREASE IN
ME/CFS PATIENTS?
>> THE SHORT QUESTION, SO HOW DE
WE SEEN AN INCREASE IN
HIF1 ALPHA IN M.E. PATIENTS?
THE SHORT ANSWER IS NO.
AND THE REASON FOR THIS IS THAT
THIS WILL HAVE TO BE MEASURED IN
THE MUSCLE TISSUE OR TISSUE
WHERE YOU EXPECT THE HYPOXIC
EFFECT.
IT'S ACTUALLY REGULATED -- IT'S
CONTINUOUSLY EXPRESSED IN THE
PRESENCE OF OXYGEN IS DEGRADED
BUT IF OXYGEN DISAPPEARED, IT'S
STABILIZED.
SO IT'S QUITE QUICKLY STABILIZED
TO AN ACTIVE FORM.
BUT YOU DON'T FIND IT USUALLY IN
BLOOD CELLS CIRCULATING,
ACTIVATED.
SO YOU NEED THE TISSUE OR
SOMETHING.
>> AND SO FOLLOW-ON, ANOTHER WAY
INSTEAD OF USING OXYGEN TO BREAK
DOWN HIGH HYPOXABLE INDUCIBLE
FACTOR 1 ALPHA IS TO USE O
OXYLOACETATE, SHOWING INCREASING
THOSE LEVELS BREAKS DOWN
HIF1 ALPHA, AND IN CLINICAL
TRIALS, OXYLOACETATE TAKES
REDUCTIONS IN FATIGUE IN LONG
COVID AND CHRONIC FATIGUE
SYNDROME.
SO THAT WOULD SUPPORT YOUR
THEORY HERE.
>> SO IF YOU INJECT
OXYLOACETATE?
>> OR YOU CAN TAKE IT ORALLY.
>> ORALLY AS WELL, OKAY.
I DON'T KNOW ABOUT THAT.
I KNOW IN CANCER CELLS, IF YOU
HAVE DEFECT, A T CYCLE DEFECT,
YOU GET AN ACCUMULATION AND THIS
ACTUALLY ACTIVATES THE HYPOXIA
INDUCIBLE FACTOR.
YOU GET KIND AFTER SAW DOUGH
HYPOXIA.
BUT THIS OCCURS INVIED S. SIDE E
CELLS.
SO IT CAN BE DIFFERENT.
>> IN CANCER CELLS, THE WARBURG
EFFECT DOES THE SAME THING BY
INCREASING LACTATE LEVELS.
>> THIS IS DONE -- THE MECHANISM
OF THE WARBURG EFFECT IN THOSE
CELLS.
>> YES.
AND IN THE LAST THREE YEARS,
OXYLOACETATE HAS BEEN SHOWN TO
REVERSE THE WARBURG EFFECT.
>> YEAH.
>> APOLOGIZE, THERE WILL BE A
PANEL DISCUSSION, WE MIGHT
RETURN TO SOME OF THE THEMES.
THE LAST SPEAKER IN THIS SESSION
IS -- ACTUALLY HIS WORK WAS JUST
REFERENCED, DAVID SYSTROM.
NEUROVASCULAR DYSREGULATION
DURING EXERCISE IN ME/CFS.
SO LOOK FORWARD TO HEARING YOUR
WORK.
>> THANK YOU FOR THE IN INVITATN
AND I THINK EVEN I KNOW HOW TO
PLUG IN AN HDMI CABLE WITHOUT
HELP.
ALL RIGHT.
SO I WAS ACTUALLY HERE,
DR. BREEN, IN 2019.
I SAT IN FRONT OF RON TOMPKINS
OVER ON THE OTHER SIDE, AND IT
WAS AN AMAZING SESSION.
AND A LITTLE WATER UNDER THE
BRIDGE SINCE THEN, I GUESS,
CALLED A PANDEMIC.
SO IT'S A PLEASURE TO COME BACK
AND GIVE YOU GUYS A LITTLE
UPDATE ON WHAT WE'VE BEEN DOING
IN BOSTON, WATCHING THE PATRIOTS
GO DOWN IN SMOKE.
IT'S THERE.
SUCCESS.
PATIENCE IS A VIRTUE.
SO WHAT I HOPE TO CONVINCE SOME
OF YOU IN THE AUDIENCE OVER THE
NEXT 20, 25 MINUTES IS THAT
THERE IS SYSTEMIC VASCULAR
DYSREGULATION DURING EXERCISE
THAT'S AT PLAY IN BOTH ME/CFS
AND IN LONG COVID.
AND THERE ARE MANY WAYS TO
ATTACK THIS.
WE'VE GOT ONE PARTICULAR TOOL
THAT I'D LIKE TO INTRODUCE,
THOSE OF YOU WHO DON'T KNOW
ABOUT IT, THE INVASIVE
CARDIOPULMONARY EXERCISE TEST,
WHICH REALLY GIVES US A DEEP
DIVE INTO THE PATHOPHYSIOLOGY
DURING ACUTE EXERCISE.
A LITTLE BIT OF HISTORY HERE
FIRST JUST FOR FUN.
I WENT BACK A LITTLE WHILE AGO
AND LOOKED FOR EVIDENCE THAT
WE'VE BEEN HERE BEFORE, AND WE
IN FACT HAVE BEEN HERE BEFORE,
ACTUALLY EVEN BEFORE THE SPANISH
FLU, THE RUSSIAN FLU, DESCRIBED
AFTERWARDS SOMETHING SIMILAR TO
ME/CFS, AND AFTER THE SPANISH
FLU FOR ABOUT A DECADE, THERE
WERE -- THERE WAS ABOUT A DECADE
WORTH OF PAPERS WRITTEN, MOSTLY
CASE REPORTS THROUGH EUROPE OF
AN INTERESTING ENTITY CALLED
THIS ENCEPHALITIS LETH ARGICA.
THIS FELLOW, AN AUSTRIAN
ANATOMIST SCRIBED IT FIRST.
HE MET A LOT OF PUSHBACK.
DOES THIS SOUND FAMILIAR?
IT WAS CALLED POST-INFLUENZAL
HYSTERIA.
IT WAS ACTUALLY REVISITED IN A
REVIEW ARTICLE JUST RECENTLY, IF
YOU'RE INTERESTED.
THERE WAS ANOTHER PLACE, I WANT
TO GIVE YOU A LITTLE BIT OF
HISTORY ABOUT -- IT WAS A PLACE
EVEN THE DOCTOR IN THE FRONT ROW
WAS TOO YOUNG TO KNOW IN PERSON,
IT WAS THIS PLACE.
THE HARVARD FATIGUE LAB.
THEY MISSED THE BOAT, HOWEVER,
ON THE ME/CFS EQUIVALENT.
WHAT THEY WERE DOING WAS TRYING
TO TRAIN THE WORKERS OF THE
WORLD TO BE MORE PRODUCTIVE, AND
THE DEAN OF THE BUSINESS SCHOOL
AND THE MEDICAL SCHOOL GOT
TOGETHER AND STUDIED NORMAL
HUMAN EXERCISE PHYSIOLOGY.
MANY OF THE BASIC TENETS HAVE
WITHSTOOD THE TEST OF TIME HERE.
FLASH FORWARD A LITTLE BIT TO
THE BRIGHAM AND WOMEN'S HOSPITAL
WHERE I AM.
I DON'T KNOW WHERE THE QUESTION
MARK ENDS, DR. BREEN, BUT WE'LL
KEEP GOING FOR A WHILE YET.
SO WE'RE DOING SOME OF THE SAME
TESTING THEY DID BACK IN THE
DAY.
AND MORE RECENTLY, ABOUT HOF OF
OUR PATIENTS EITHER HAVE LONG
COVID OR ME/CFS.
THIS TEST WAS ORIGINALLY
DEVELOPED TO DETERMINE WHAT AILS
A PATIENT WITH HEART OR LUNG
DISEASE.
I'LL GIVE YOU JUST A LITTLE
MOVIE OF THIS, THIS GENTLEMAN
AGREED TO BE FILMED.
WE'VE GOT A FEW THINGS TO POINT
OUT.
WE'VE GOT A MOUTHPIECE IN PLACE.
IT'S CONNECT TODAY A METABOLIC
CART.
THAT'S THE NON-INNOVATIVE
PORTION.
IT'S QIE QUITE USEFUL.
THIS WAS DONE IN NEW YORK.
THE CATHETERS GIVE US SOME
ADDITIONAL INFORMATION.
THERE'S A PULMONARY ARTERY
CATHETER IN THIS GENTLEMAN'S
JUGULAR VEIN, THE TIP IS IN THE
PULMONARY ARTERY WHERE WE
MEASURE PRESSURE AND MIXED
VENOUS BLOOD GASES AND LACTATE
AND BIOMARKERS.
THEN IN HIS LEFT WRIST, CAN YOU
SEE RADIAL ARTERY CATHETER, WE
MEASURE ARTERIAL BLOOD GASES AND
LACTATE AND OTHER BIOMARKERS.
AND THIS IS WHAT WE END UP
MEASURING THAT'S IMPORTANT,
ESPECIALLY TO ME/CFS AND LONG
COVID.
TIME HO MO HONORED THINGS SHOWN.
THE VO2 IS WAY TO MEASURE HOW
IMPAIRED YOUR PATIENT IS, THE
CO2 OUTPUT AT THE MOUTH IS QUITE
USEFUL IN DETECTING METABOLISM.
MINUTE VENTILATION IS VE.
THEN WE MEASURE A BUNCH OF
PRESSURES.
YOU'LL SEE THAT FILLING
PRESSURES ARE QUITE IMPORTANT TO
BOTH M.E. AND LONG COVID.
THE RIGHT ATRIAL PRESSURE, THE
RIGHT VENTRICULAR PRESSURE
POTENTIALLY AND THEN DOWN BELOW,
THE MEAN PULMONARY ARTERY
PLEASURE AND THE PULMONARY
CAPILLARY EDGE PRESSURE.
THOSE THINGS PROSPECTIVELY RULE
OUT THINGS LIKE PULMONARY
HYPERTENSION AND HEART FAILURE
THAT CAN PLAGUE A PATIENT INTO
ACUTE LONG COVID.
DOWN AT THE LOWER LEFT IS MIXED
VENOUS O2 CONTENT.
THE MEASUREMENT OF VO2 AND THOSE
LATTER TWO MEASUREMENTS ALLOW US
TO GET A THICK CARDIAC OUTPUT
EVERY MINUTE DURING EXERCISE.
AND THIS IS OUR ALGORITHM.
I WON'T BELABOR ALL OF THESE
LITTLE PODS, BUT UP AT THE TOP,
WE GET THIS OVERALL ASSESSMENT
OF HOW SICK THE PATIENT IS WITH
A VO2 PEAK.
WE CAN RULE OUT A PULMONARY
MECHANICAL LIMIT OVER ON THE
LEFT UPPER LEFT, THAT'S A
NONINVASIVE MARKER AND I'VE
DISCOVERED A POINTER HERE MAYBE.
THIS WOULD BE GERMANE TO A
PATIENT WHO PERHAPS HAD ACUTE
COVID, WAS ON A VENTILATOR,
THESE ARE NOT BE THE PATIENTS I
WILL BE TALKING ABOUT TODAY.
THEY WILL BE THE PATIENTS WITH
LONG COVID WITHOUT HEART AND
LUNG DISEASE DENOTED BY THAT.
THEN IF YOU FOLLOW DOWN TO THE
LEFT, WE CAN MEASURE PEAK
CARDIAC OUTPUT.
WE CAN EXPRESS THAT AS A PERCENT
PREDICTED, AND IF THERE'S A
MATCH WITH THE VO2 PEAK, WE'VE
DENOTED A CARDIAC LIMIT.
WE CAN DIFFERENTIATE LEFT FROM
RIGHT HEART DISEASE, AND WHERE
YOU'LL SEE IN A FEW MINUTES, WE
END UP WITH MOST PATIENTS, IN
FACT, ALMOST ALL PATIENTS WITH
BOTH M.E. AND LONG COVID IS
SOMETHING WE CALL PRELOAD
FAILURE, IT'S DOWN AT THE
BOTTOM, AND I'M GOING TO SMEND
SSPENDSOME TIME EXPLAINING THAT.
WAY OVER TO THE RIGHT IS
SOMETHING ELSE.
THE LAST TWO TALKS WERE
FABULOUS.
THIS IS IMPAIRED SYSTEMIC OXYGEN
EXTRACTION, MEANING THE FAILURE
TO DEPRESS THE MIXED VENOUS
OXYGEN CONTENT DYNAMICALLY
DURING EXERCISE SHOULD FALL
ABOUT THREE FOLD.
WHEN IT FAILS TO DO SO, THERE
CAN BE CIRCULATORY ABNORMALITIES
IN THE PERIPHERY THAT I'LL TALK
ABOUT, BUT I SHOULD ALSO
ACKNOWLEDGE THAT INTRINSIC
MITOCHONDRIAL DISEASE COULD DO
THE SAME.
THIS IS WHERE WE GOT INTO THE
BUSINESS ABOUT SEVEN YEARS AGO.
WE WERE GETTING REFERRALS
INCREASINGLY FREQUENTLY OF
PATIENTS WHOSE EXERCISE
INTOLERANCE INCLUDING SHORTNESS
OF BREATH, THAT'S DYSPNEA,
FATIGUE, PALPITATIONS WERE NOT
EXPLAINED BY ANY INTRINSIC HEART
OR LUNG DISEASE, SO WE FOLLOWED
THAT ALGORITHM AND MADE SOME
PRELIMINARY DISCOVERIES.
AND THE FIRST ONE WE DISCOVERED
WAS SOMETHING WE'VE COME TO CALL
PRELOAD FAILURE.
YOU'LL FIND OTHER NAMES IN THE
LITERATURE NOW.
BUT WHAT WE DETERMINED WHEN WE
COMPARED TO A NORMAL COHORT,
THESE WERE PATIENTS WHO WERE
REFERRED TO US WITH EXERCISE
INTOLERANCE WHO DID NOT HAVE ANY
HEART OR LUNG DISEASE,
EVERYTHING WAS NORMAL, THEY WERE
PROBABLY AGE 60 RATHER THAN AGE
20.
SO THEY'RE THE NORMAL COHORT.
WHAT WE DETERMINED WHEN WE RULED
OUT HEART AND LUNG DISEASE AS A
CAUSE FOR EXERCISE INTOLERANCE,
WAS THAT PRELOAD FAILURE SEEMED
TO BE CAUSAL.
SO THAT'S SHOWN OVER ON THE LEFT
SIDE, RIGHT ATRIAL PRESSURE AN
SURROGATE FOR THE LEFT ATRIAL
PRESSURE IS THE PULMONARY
CAPILLARY WEDGE PRESSURE.
TWO IMPORTANT POINTS HERE, YOU
HAVE TO HAVE THE PATIENT IN THE
UPRIGHT POSITION.
MANY IN THE AUDIENCE KNOW
GRAVITY IS THE ENEMY HERE.
SO UPRIGHT IS WHERE WE SEE THE
SIGNAL, AND AT MAXIMUM EXERCISE,
THE SIGNAL IS NOT AS WELL SEEN
IN THE RESTING STATE.
SO LOWER FILLING PRESSURES ARE
WHAT SERVE TO DIFFERENTIATE
THESE PATIENTS HEMODYNAMICALLY
VERSUS THE NORMAL CONTROLS.
OVER ON THE RIGHT, WE'VE
ATTEMPTED TO REGRESS VO2 PEAK,
AND THEN CARDIAC OUTPUT PEAK
AGAINST THOSE FILLING PRESSURES
ON BOTH SIDES OF THE HEART, AND
YOU CAN SEE THERE'S AN
ASSOCIATION.
SO WE CALL THIS PRELOAD FAILURE.
WE LEARNED IN RETROSPECT THAT
MOST OF THESE PATIENTS MET THE
OLD IOM CRITERIA FOR ME/CFS, SO
THIS IS HOW THE LUNG DOCTOR WITH
A LITTLE BIT OF SERENDIPITY GOT
INTO THIS BUSINESS.
THIS IS WHERE THEY LANDED IN OUR
ALGORITHM, THE VO2 PEAK WAS
DOWN, THE CARDIAC OUTPUT WAS
DOWN, AND THE REASON FOR IT WAS
NOT HEART, LEFT OR RIGHT-SIDED
HEART DISEASE.
IT WAS FAILURE TO PRIME THE
PUMP.
SO THIS HAS BEEN UBIQUITOUS AND
HAS WITHSTOOD THE SEVEN YEARS OF
OUR STUDY, SO MY INTERIM
ANALYSIS IS THAT IN ME/CFS,
THERE IS EVIDENCE OF SYSTEMIC
VASCULAR DYSREGULATION IN THE
FORM OF FAILURE TO VENOCONSTRICT
AND PRIME THE PUMP ON BOTH SIDES
OF THE HEART.
WE TOOK A LITTLE DEEPER DIVE
INTO THIS WITH PHILIP JOSEPH
LEADING THE CHARGE TWO YEARS
AGO, AND WE DID TWO ADDITIONAL
THINGS.
WE HAD A LARGER DATABASE, WE
LOOKED AT ABOUT 1500 PATIENTS
WHO HAD UNDERGONE THIS TYPE OF
TESTING, AND ENDED UP WITH A
COHORT OF PATIENTS WITH
WELL-DEFINED CLINICAL ME/CFS AND
ADDITIONALLY THOSE HO H WHO HAD
UNDERGONE A SKIN BIOPSY,
SOMETHING YOU HEARD ALLUDED TO
EARLIER THIS MORNING.
AND THIS IS THE NEW VASCULAR
INFORMATION WE GOT.
WE BORROWED HEAVILY FROM THE POT
IS THE LET'S TOUR, WHICH
SUGGESTS THAT IN THE UPRIGHT
TILT TABLE TEST, THERE WAS A LOW
FLOW GROUP OVER TO THE LEFT IN
THE BLUE, AND A HIGH FLOW GROUP
OVER TO THE RIGHT, IN POTS AND
WE ASKED THE QUESTION DOES THE
SAME THING HAPPEN DURING UPRIGHT
EXERCISE IN ME/CFS.
AND THE ANSWER SEEMED TO BE YES,
THE CARDIAC OUTPUT WE MEASURE,
WE'RE LOOKING AT THIS AS A SLOPE
VERSUS INCREASING METABOLISM
DURING INCREMENTAL CYCLING.
THE CARDIAC OUTPUT WE MEASURE IS
PULMONARY BLOOD FLOW.
WHAT WE KNOW IS THAT THESE
PATIENTS HAVE A LOW VO2 PEAK,
BUT THE PULMONARY BLOOD FLOW IS
VERY HIGH.
THIS IS A HALLMARK IN CARDIOLOGY
OF LEFT TO RIGHT SHUNTING, AND
WE KNOW THAT NONE OF THESE
PATIENTS HAS A HOLE IN THE HEART
AND INTRACARDIAC LEFT TO RIGHT
SHUNT.
THIS IS PERIPHERAL LEFT TO RIGHT
SHUNTING.
AS A CONSEQUENCE, WHAT WE END UP
WITH, WITH THE FIC PRINCIPAL
WHICH IS SHOWN ABOVE IS A
DEPRESSED VO2 PEAK BECAUSE OF
FAILURE TO EXTRACT OXYGEN.
WE THINK THIS IS A PERIPHERAL
VASCULAR PHENOMENON WHERE THE
INDIVIDUAL WITH ME/CFS IS
PERFUSING ORGAN SYSTEMS THAT DO
NOT NEED THE OXYGENATED BLOOD
FLOW.
THINGS LIKE THE KIDNEY, THE GUT
AND THE SKIN.
AND WE HAVE SOME ADDITIONAL
EVIDENCE OF THAT.
SO HIGH FLOW GROUP IS WHAT I
WANT TO FOCUS ON FOR A SECOND
WITH IMPAIRED SYSTEMIC
O2 EXTRACTION.
WE TOOK A LOOK AT HOW MANY OF
THESE PATIENTS HAD SMALL FIBER
NEUROPATHY BY A SINGLE EPIDERMAL
SKIN BIOPSY AT MASS GENERAL, AND
THE ANSWER WAS ABOUT 45% EITHER
HAD DEFINITE SMALL FIBER
NEUROPATHY OR PROBABLE SMALL
FIBER NEUROPATHY.
THAT 45% IS ABOUT THE SAME AS
DESCRIBED IN THE LITERATURE IN
BOTH POTS AND IN FIBROMYALGIA
VERY MUCH RELATED TO ME/CFS, OF
COURSE, WITH A LOT OF OVERLAP
WITH THE VENN DIAGRAM.
SO WE BEGAN TO BELIEVE THAT WHAT
WE WERE OBSERVING WITH THE
VASCULAR DYSREGULATION BOTH ON
THE VENOUS SIDE, FAILURE TO
VENOCONSTRICT AND ON THE
ARTERIAL SIDE, FAILURE TO DIVERT
CARDIAC OUTPUT APPROPRIATELY TO
THTHE EXERCISING MUSCLE BED WASA
VASCULAR DYSREGULATION
PRIMARILY, THEN SECONDARILY
BLOOD FLOW.
SO THIS IS WHERE WE THINK WE END
UP WITH THAT HIGH FLOW GROUP
OVER TO THE RIGHT IN ADDITION TO
THE PRELOAD FAILURE.
NOW, HOW DO I KNOW ALL THIS IS
NEUROVASCULAR DYSREGULATION?
WE BEGIN TO MAKE A CASE FOR THE
REASONS I JUST GAVE YOU.
BUT WE ATTEMPTED TO TEST THIS
WITH SOMETHING THAT WAS JUST
MENTIONED A SECOND AGO.
A DRUG THAT IS THOUGHT TO
PRIMARILY AFFECT NEUROLOGIC
TRANSMISSION.
THIS IS PYRIDOSTIGMINE,
FDA-APPROVED SO THIS IS AN
OFF-LABEL COMMENT FOR MYASTHENIA
GRAVIS FOR N ACETYLCHOLINE AT
THE END PLATE FOR THE MUSCLE
WEAKNESS, AUTOIMMUNE DISEASE, IT
RETARDS THE DEGRADATION OF
ACETYLCHOLINE.
BUT WHAT WE WERE REMINDED OF AS
WE GOT INTO THIS, WE KNEW THIS
WAS ON THE LIST OF POTS DRUGS,
WE ANECDOTALLY TRIED IT AND THEN
SYSTEMATICALLY.
WE'RE REMINDED THERE'S A
CHOLINERGIC STEP OF THE
ADRENERGIC OUTFLOW TO BLOOD
VESSELS AT THE AUTO NO NICK
GANGLION.
SO THAT IS A CHOLINERGIC STEP.
WE THINK IT MAY BE WORKING THERE
IN POTS, AND PERHAPS IN M.E.
DURING UPRIGHT EXERCISE.
SO WE DID A RANDOMIZED PLACEBO
CONTROLLED STUDY AT THE BRIGHAM,
AND IT WENT AS FOLLOWS.
THESE PATIENTS WITH M.E. WERE
REFERRED TO US FOR CLINICAL
TESTING.
WE DID THE TESTING WITH THE
LINES IN PLACE.
WE IDENTIFIED PRELOAD FAILURE,
AND THEN WE GAVE THEM A SINGLE
DOSE OF ORAL DRUG 60 MILLIGRAMS.
REMEMBER THIS IS ACUTE, A SINGLE
DOSE, THEN WE ASKED THEM TO
RELAX FOR 45 MINUTES AND THEN
PEDAL AGAIN WITH THE LINES IN
PLACE.
SO PLACEBO CONTROLLED, AND THIS
IS WHAT WE FOUND.
THE VO2 PEAK, WHEN THEY GOT
DRUG, WHICH IS OVER ON THE
GREEN, IMPROVED.
IF THEY DIDN'T GET IT AND WERE
WONDERING IF THIS WAS EARLY PEM,
THEY ACTUALLY GOT WORSE.
THE EFFECT SIZE WAS SMALL BUT
PLEASE REMEMBER SINGLE DOSE MOST
FOLKS RESPOND CLINICALLY OVER
WEEKS TO MONTHS.
AND THE REASON THE VO2 PEAK WAS
IMPROVED WAS THAT THE CARDIAC
OUTPUT WAS HIGHER IF THEY GOT
ACTIVE DRUG, AND IT WAS RELATED
TO AN IMPROVEMENT IN RIGHT
ATRIAL PRESSURES, FILLING
PRESSURES.
AGAIN, EFFECT SIZE SMALL, BUT
MAYBE A SIGNAL THAT THIS IS
IMPROVED AUTONOMIC NERVOUS
SYSTEM FUNCTION.
SO WHAT I WOULD CONCLUDE HERE
BASED ON THAT LITTLE BIT OF DATA
IS THAT IN ME/CFS, WE HAVE SOME
EVIDENCE OF NEUROVASCULAR
DYSREGULATION IN PART BECAUSE A
DRUG THAT IS THOUGHT TO
FACILITATE AUTONOMIC NERVOUS
SYSTEM FUNCTION IMPROVES THE
HEMODYNAMICS.
THIS IS POTENTIALLY A NICE
EXAMPLE OF USING A DRUG TO DO A
DEEP DIVE INTO THE
PATHOPHYSIOLOGY OF A DISEASE
WITHOUT GOOD BIOMARKERS.
SO IF A DRUG WE KNOW HOW IT
WORKS, WORKS, THEN ERGO PERHAPS
THIS IS WHAT AILS THE PATIENT AT
LEAST IN PART.
PART TO BEGIN WITH.
A LITTLE BIT ON LONG COVID.
THIS IS A SMALL STUDY.
VERY SIMILAR IN FASHION USING
THAT INVASIVE CARDIOPULMONARY
EXERCISE TEST COMPARED TO 10
NORMAL CONTROLS, WE HAD 10
PATIENTS WITH LONG COVID AT
LEAST SIX MONTHS OUT FROM THEIR
ACUTE DISEASE.
THEY HAD NO HEART OR LUNG
DISEASE.
WHAT YOU CAN SEE IS THEIR
VO2 PEAKS AS A PERCENT PREDICTED
OR ABOUT 70% AND NORMAL CONTROLS
WERE SUPER IT IS NORMAL.
PULMONARY PLEASURE MEASURED BY
THE FIC PRINCIPLE WAS ACTUALLY
THE SAME AS THE CONTROLS IN THE
NORMAL RANGE BUT AGAIN VO2 PEAK
IS DOWN AND WHAT THEY HAVE IS
SEVERE IMPAIRMENT OF SYSTEMIC
OXYGEN EXTRACTION BY A DIFFERENT
NUMBER, BUT IT'S ABOUT HALF OF
THE NORMAL SHOWN IN THAT THIRD
ROW.
AND THEY LAKELY HAD PRELOAD LIKD
ERROR, LOW FILLING PRESSURES AND
IMPAIRED OXYGEN EXTRACTION.
SO AT LEAST IN OUR EXERCISE
WORLD, THIS FORM OF LONG COVID
LOOKS FRIGHTENINGLY SIMILAR.
IT LOOKS VERY CLOSE TO WHAT
WE'VE SEEN IN ME/CFS.
THEY LAND IN THE SAME PLACE.
SO I WOULD CONCLUDE BOTH IN M.E.
AND CFS AND LONG COVID, WE MAY
HAVE SOME EVIDENCE OF
NEUROVASCULAR DYSREGULATION.
WE PUBLISHED AS A RESULT OF SOME
COMBINED EFFORTS OF THE RECOVER
PROJECT THIS REVIEW A FEW MONTHS
AGO, A COMBINED EFFORT WHERE WE
CONCLUDED THIS.
I THINK IT'S ON REASONABLY SOLID
GROUND.
THERE MAY BE SUBSETS OF BOTH
DISEASES, BUT GENERALLY
SPEAKING, THE EXERCISE PATHOPHYS
SEEMS TO BE BOTH THE SAME IN
M.E. AND LONG COVID.
A LITTLE BIT OF A CALLOUT HERE
FOR TWO THINGS.
ONE IS THAT I THINK THE PRELOAD
FAILURE THAT WE SEE AND THE
ARTERIAL ABNORMALITIES LEFT TO
RIGHT SHUNTING DO HAVE A
DIFFERENTIAL DIAGNOSIS THAT IS
WORTHY OF FURTHER INVESTIGATION,
AND SOME IN THIS ROOM ARE DOING
EXACTLY THIS.
SO I'VE TALKED TO YOU ABOUT
DYSAUTONOMIA.
THERE ARE DATA THAT SUGGEST THAT
AS A RESULT OF THESE DISEASES,
THERE'S A SUBSET OF PATIENTS
WITH HYPOVOLEMIA.
THERE ARE EMERGING DATA,
ESPECIALLY IN LONG COVID, THAT
THE ENDOTHELIUM MAY BE INFLAMED
AND MAYBE EVEN INFECTED SO
ENDOTHELIITIS IS A NEW WORD I
HAD TO LEARN TO PRO MOWNS.
THERE ARE MICRO CLOTS THAT HAVE
BEEN DESCRIBED IN BOTH DISEASES.
A LITTLE PACKETS OF BLOOD CLOTS
WITH IP FL INFLAMMATORY CYTOKINT
SOLUBLE THEREFORE NOT MEASURABLE
OUT IN THE PERIPHERY, PERHAPS
DAMAGING THE SMALL VESSELS, AND
THERE ARE EVEN RED BLOOD CELL
ABNORMALITIES, THEY'RE TOO BIG,
THEY'RE TOO STIFF, THEY DON'T
EXHIBIT ACT WITH THE ENDOTHELIUM
NORMALLY DURING EXERCISE, THEY
MAY BE AT PLAY, AND A SPECIAL
CALLOUT HERE TO THE NIH ROAD MAP
WEBINAR, WHICH WE'RE PARTWAY
THROUGH OUR CIRCULATION VERSION
OF THIS WILL BE ON JANUA
JANUARY 11TH, A PLUG, SO PLEASE
TUNE IN, AND ALL OF THESE
SUBTITLES WILL BE COVERED.
SO WHAT I WANTED TO LEAVE YOU
WITH IS WHERE WE'RE GOING NEXT.
I KNOW JOE WANTED TO ADDRESS
POTENTIAL TREATMENT TRIALS, AND
WE DON'T CLAIM TO HAVE THE
ANSWER, BUT WE ARE GOING TO
LAUNCH A TREATMENT TRIAL WI WITH
GENEROUS HELP OF OPEN MEDICINE
FOUNDATION AND LINDA WHO'S HERE
IN THE AUDIENCE AT THE BRIGHAM.
IT'S CALLED THE LIFT TRIAL, THE
LIFE IMPROVEMENT TRIAL.
IT'S DEDICATED INITIALLY ANYWAY
TO ME/CFS PATIENTS.
IT'S A SMALLER TRIAL BUT IT WILL
BE RANDOMIZED AND PLACEBO
CONTROLLED AND WE THINK WE'VE
POWERED IT AT LEAST SUFFICIENTLY
TO ANSWER SOME QUESTIONS.
THIS WILL BE A TRIAL THAT I JUST
MENTIONED VERSUS LOW DOSE
NALTREXONE, MAYBE A TOPIC FOR
THE PANEL, VERSUS THE
COMBINATION OF THE TWO, VERSUS
PLACEBO.
SO IT WILL BE A PROPER
RANDOMIZED CLINICAL TRIAL, 40
PATIENTS IN EACH ARM, THREE
MONTHS OVERALL, AND THESE ARE
THE THINGS WE'RE GOING TO
MEASURE.
WE'VE GOT THREE MAJOR
QUESTIONNAIRES, ONE THAT'S COME
OUT OF NORWAY MORE RECENTLY, AND
DSQ PEM SHORT FORM THAT WILL BE
ADMINISTERED INTERMITTENTLY.
MOST OF THE DATA WILL BE
UPLOADED WITH OUR COMPUTATIONAL
GROUP.
WE'RE GOING TO HAVE THEM ALL
WEAR ONE OF THE NEWER GARMIN
WEARABLE DEVICES WHICH IS
REPORTED TO MEASURE ALL OF THESE
THINGS YOU SEE DOWN BELOW.
WE'RE GOING TO HAVE TO MEASURE
THESE THINGS, WEAR THEM
CONTINUOUSLY FOR THE THREE
MONTHS, IN HOPES OF CAPTURING
CRASHES AND PERHAPS SEEING WHAT
THE PATHOPHYSIOLOGY IS RELATED
TO CRASHES.
WE ARE ADDITIONALLY GOING TO DO
A PHYSIOLOGIC TEST.
THIS IS A BABY EXERCISE TEST.
IT'S CALLED THE SHAPE TEST.
IT'S A METABOLIC CART DEVELOPED
BY THE MEDICAL GRAPHICS
ENGINEERS.
IT'S A 3-MINUTE STEP TEST.
IT SHOULD NOT BE TOO ONEROUS FOR
OUR PATIENTS WITH ME/CFS.
IT IS SELF-PACED.
THESE ARE OUR EXERCISE
PHYSIOLOGISTS DOING THIS, SO
DON'T BE DISMAYED BY HOW FAST
JULIE TRACIE GOES.
THEY CAN GO AS SLOW AS THEY WANT
BUT ONLY FOR THREE MINUTES AS A
CONSTANT LOAD TEST.
WE GET MANY OF THE NONINVASIVE
VARIABLES THAT WE GET FROM AN
INCREMENTAL MEDICAL GRAPHICS
TEST.
SO THAT WILL BE ADMINISTERED AT
TIME ZERO AND AT THE END OF THE
STUDY, THE THREE-MONTH STUDY.
SO THAT'S ALL I HAD TO TELL YOU
TODAY.
I HOPE I MADE SOMEWHAT OF A CASE
FOR NEUROVASCULAR DYSREGULATION
IN ME/CFS AND LONG COVID.
I HAVE A LOT OF THANKS TO GIVE.
I MENTIONED SOME FOLKS ALREADY.
PHILIP JOSEPH AND INDY SINGH,
JOHANNA AND SARRA, I'VE GOT A
COMPUTATIONAL GROUP WITH
WENZHONG, JOSHUA AN OVER THERE.
RON DAVIS AT STANFORD, HELENE
AND MAUREEN HANSON WHOM YOU'VE
HEARD A LOT ABOUT TODAY, ALL
GOING TO BE COLLABORATING ON
THIS LIFT STUDY IN THE FUTURE,
AND I THANK THEM VERY MUCH AND
YOU FOR YOUR ATTENTION.
[APPLAUSE]
>> HOW ARE WE DOING FOR TIME?
ONE QUESTION?
SURE.
AND THERE WILL BE A PANEL LATER.
YES.
>> VERY INTERESTING.
I'M LEARNING A LOT HERE.
SO YOU SAID THAT MIXED VENOUS
OXYGEN SATURATION WAS HIGHER IN
THE CSF PATIENTS CONSISTENT WITH
OXYGEN -- SO THAT SEEMS TO BE IN
CONTRAST TO THE PREVIOUS SPEAKER
WHO TALKED ABOUT OXYGEN HYPOXIA
IN TISSUES, SO I DON'T KNOW HOW
YOU CAN RECONCILE THAT.
>> OKAY.
I CAN DEFER TO YOU, IT'S HARD TO
HEAR FROM UP HERE THE QUESTION,
BUT I THINK IT SOUNDS LIKE
THERE'S THE QUESTION ABOUT
WHETHER VENOUS OXYGEN LEVELS
DURING EXERCISE ARE HIGHER OR
LOWER IN THESE DISEASES.
WE FIND PRETTY UNIFORMLY, AT
LEAST, DURING WHOLE BODY
EXERCISE AND MIXED VENOUS OXYGEN
CONTENT FROM THE TIP OF THE PA
CATHETER THAT THEY'RE
INAPPROPRIATELY HIGH.
IT'S NOT EVERYBODY, IT'S THAT
RED GROUP, THE HIGH FLOW GROUP
THAT ARE LIKE THAT.
AND THEN LIMITED NUMBER OF LONG
COVID PATIENTS HAVE THE SAME.
I WOULD JUST ADD THAT I THINK WE
ARE VERY MUCH CONCORDANT AND ONE
OTHER THING I DIDN'T TALK ABOUT
TODAY TO ANY DEGREE, THAT IS
THAT IMPAIRED OXYGEN EXTRACTION
DURING EXERCISE CAN BE
O2 SUPPLY-RELATED.
WE KNOW IT'S NOT A PROBLEM WITH
GLOBAL CARDIAC OUTPUT.
WE KNOW IT'S NOT A PROBLEM WITH
ARTERIAL OXYGEN CONTENT, BUT WE
BELIEVE THERE MAY BE AN
O2 SUPPLY PROBLEM AT THE
MICROVASCULAR LEVEL.
BUT THE OTHER THING THAT
IMPAIRED OXYGEN EXTRACTION COULD
BE RELATED TO IS INTRINSIC
SKELETAL MUSCLE MITOCHONDRIAL
DYSFUNCTION AND THE TWO MAY
COEXIST.
>> I HAD TWO QUESTIONS.
>> YES, SIR.
>> WHAT HAPPENS TO THE PULSE
RATE WITH THE DRUG?
COULD THAT HAVE AN IMPACT ON THE
FILLING?
AND THE SECOND QUESTION IS, THE
O2 CONSUMPTION DIFFERENCES AS
YOU'RE MENTIONING, YOU TALKED
ABOUT MICROVASCULAR CHANGES AS
WELL.
HOW ABOUT VENTILATION PERFUSION
MISMATCH?
>> OKAY.
LET ME ANSWER THE LATTER,
BECAUSE IT'S EASIER.
THERE IS -- WE HAVE VIRTUALLY NO
EVIDENCE, AGAIN, THE TYPES OF
PATIENTS I'VE DESCRIBED HERE
FREE OF HEART AND LUNG DISEASE.
A V/Q MISMATCH, VENTILATION
PERFUSION MISMATCH.
THE ALVEOLAR ARTERIAL OXYGEN
DIFFERENCE AT PEAK EXERCISE IS
PERFECTLY NORMAL.
AND THE PHYSIOLOGIC DEAD SPACE
TO -- IS NORMAL, THOSE ARE THE
TWO EXTREMES OF LOW AND HIGH
V/Q.
SO THEY ARE NORMAL IN THESE
PATIENTS WE'RE STUDYING, IT'S
NOT LUNG DISEASE OR PULMONARY
VASCULAR DISEASE.
SO HEART RATE IS INTERESTING,
THERE ARE A FEW PATIENTS, I
BELIEVE, AND I KNOW SOME DIFFER
ON THIS, WITH KRO KNOW TROPIC
IMCOMPETENCE IN M.E. AND LONG
COVID, BUT IT DOESN'T SEEM TO
ACUTELY OR CHRONICALLY AFFECT
IT.
RESTING HEART RATES OCCASIONALLY
AT NIGHT WITH WEARABLE DEVICES
GO LOWER ON IT, SO ONE HAS TO
BEA WEAR OF THAT ONE, BUT AT
PEAK EXERCISE, IT SEEMS NOT TO
HAVE ANY DIFFERENCE.
>> SO THE HEART RATES ARE
EQUIVALENT?
>> CORRECT.
CORRECT.
>> ON AND OFF THE DRUG?
>> YES.
>> THANKS, JOE.
>> SO WE HAVE A SHORT BREAK,
WHICH IS GOING TO BE MADE
SHORTER.
RETURN AT 4:05, JUST A BIOBREAK
SO WE CAN STAY ON TIME.
THANK YOU.
>> OKAY, I THINK WE HAVE TO
START THE SESSION.
WE HAVE 25 MINUTES FOR SOME
DISCUSSION.
AND SO THERE MIGHT BE SOME
QUESTIONS THAT HAVE ACCUMULATED.
BUT BEFORE WE OPEN THE
POSSIBILITY FOR QUESTIONS, MAYBE
WE SHOULD HAVE SOME -- IF THERE
ARE SOME SUMMARY THOUGHTS FROM
THE PANEL HERE.
SO WE HAVE BEEN THROUGH --
TOPIC OF THIS SESSION IS
METABOLISM AND METABOLIC
FUNCTION.
SO MAYBE I CAN ASK -- START BY
ASKING A QUESTION TO MY TWO
COLLEAGUES HERE, IF THEY THINK
ME/CFS IS A METABOLIC DISEASE,
OR IF WHAT WE ARE SEEING IS
SIMPLY -- OR NOT SIMPLY BECAUSE
IT'S COMPLEX, BUT IF IT IS
SOMETHING ELSE THAT CAUSES THE
METABOLIC EFFECT.
>> I THINK I'M THE LEAST
KNOWLEDGEABLE ABOUT ME/CFS
BECAUSE I'M REALLY COMPLETELY
NEW TO THE FIELD.
BUT YOU KNOW, IT SEEMS LIKE
DEFINITELY THERE'S SOME
IMMUNE -- THERE'S SO MUCH STUFF
ON THE IMMUNE SYSTEM HERE.
SO I THINK AT ONE LEVEL, AT
LEAST EVERYTHING FOR ME REVOLVES
AROUND THE MITOCHONDRIA AND THE
SUPERCOMPLEXES, SO IT SEEMS TO
ME THAT AT LEAST WHAT WE'VE
FOUND IS JUST A -- IT'S
CERTAINLY NOT THE CAUSE OF
ME/CFS, I THINK ME/CFS OBVIOUSLY
IS VERY HETEROGENEOUS AND THE
WASF GENE WE'VE IDENTIFIED I
THINK MAY EXPLAIN MAYBE IN A
SUBSET OF THE PATIENTS WITH
ME/CFS, IT COULD BE A SUBSET,
AND IS REALLY A -- SOME SORT OF
A STRESS RESPONSE OF THE CELLS,
IT'S A METABOLIC ADAPTATION,
SOMETHING TELLING THE CELL TO
TURN DOWN ITS MITOCHONDRIA, SO I
THINK IT REALLY A MEDIATOR OF
MITOCHONDRIAL FUNCTION.
FOR SOME REASON, THE CELL WANTS
TO DO THIS, AND STRESS RESPONSE
OR ADAPTIVE RESPONSE, I THINK,
THAT'S MY IMPRESSION, TO SOME
PRIMARY INSULT, WHICH I THINK
MUST HAVE SOMETHING TO DO WITH
THE IMMUNE SYSTEM.
THAT'S ALL I CAN SAY.
>> I GUESS I WOULD ECHO ALL OF
THOSE THOUGHTS.
I THINK THE THEMES THAT WE THINK
ABOUT REPEATEDLY ARE, OF COURSE,
POST INFECTIOUS AUTOIMMUNITY,
INFLAMMATION, AND WHERE THERE'S
INFLAMMATION THAT'S UNCHECKED,
ONGOING, THERE ARE OFTEN --
THERE'S METABOLISM PROBLEMS, AND
WE'VE HAD THIS DISCUSSION, KARL
AND I, ACTUALLY ON THE BUS OVER
HERE THIS MORNING, TALKING ABOUT
METABOLIC EFFECTS OF O2 SUPPLY,
WHICH MAY BE A SUSPECT, AND ITS
DEMAND, WHICH WOULD BE INTRINSIC
MITOCHONDRIAL DYSFUNCTION.
AND I BELIEVE BOTH CAN BE AT
PLAY IN ANY GIVEN PATIENT.
THEY'RE NOT MUTUALLY EXCLUSIVE.
SO O2 SUPPLY ISSUES RELATED TO
VASCULAR DYSREGULATION IN
INTRINSIC MITOCHONDRIAL PROBLEMS
CAN COEXIST, AND THEIR
TREATMENTS ARE LIKELY VERY, VERY
DIFFERENT.
ALTHOUGH THERE MAY BE A SILVER
BULLET WAY AT THE TOP OF ALL
THIS, AT LEAST GIVEN WHAT WE
KNOW RIGHT NOW, IF WE TREAT
GENETIC FORMS OF MITOCHONDRIAL
DISEASE WITH THE MYTO COCKTAIL
RECOMMENDED BY THE MITOCHONDRIAL
SOCIETY, IT'S THREE VITAMINS.
IF WE TREAT THE BLOOD FLOW
ABNORMALITIES AS YOU TALKED
ABOUT, KARL, WE BORROW HEAVILY
FROM THE POTS LITERATURE AND
CONSERVATIVE MEASURES.
AND THEY'RE NOT MUTUALLY
EXCLUSIVE.
>> SO THIS LOW ANAEROBIC
THRESHOLD, THIS VERY QUICKLY
ACTIVATED LACTATE PRODUCTION,
LACTATE WE USE AS KIND OF -- AS
VERY SIMPLE A MEASURE FOR THE
ANAEROBIC THRESHOLD.
YOU CAN MEASURE IT INDIVIDUALLY
AND EVERYBODY CAN DO IT MORE OR
LESS.
IT'S DIFFICULT TO REALLY BASE A
PATHOLOGICAL MECHANISM ON THAT
ALONE BECAUSE IT'S A PART OF THE
PROGRAM, IT'S AFFECTED BY SO
MANY FACTORS.
BUT IT CAN RESONATE A LITTLE BIT
AROUND LACTATE IN YOUR SETTING,
WHAT IT MEANS FOR THE INDIVIDUAL
PATIENTS.
>> ANAEROBIC METABOLISM, THE
THRESHOLD, THE PEAK LACTATE, THE
RECOVERY LACTATE, THEY'RE ALL --
THEY ALL CAN BE TRACED BACK TO
EITHER OF THE PROBLEMS.
O2 SUPPLY OR MITOCHONDRIAL
MACHINERY PROBLEMS.
EXOWB OR A COMBINATION OF THE
TWO.
AND I THINK AT LEAST IN OUR
WORLD, WE ROUTINELY MEASURE
LACTATING ONE HOUR AFTER OUR
INCREMENTAL EXERCISE TEST, AND
WE FIND THEM ELEVATED, SOMETIMES
AT REST BEFORE THE TEST, WHICH
IS PURPORTED TO BE AN INDEX OF
MITOCHONDRIAL DYSFUNCTION, AND
THEN MORE OFTEN ELEVATED ONE
HOUR POST.
BUT I'VE SEEN THIS IN OTHER
DISEASES AS WELL THAT HAVE
NOTHING TO DO WITH ME/CFS,
MEANING A LACTATE OF 4 MILIMOLAR
ONE HOUR AFTER EXERCISE AFTER
HEART FAILURE OR PULMONARY
HYPERTENSION, AND THEN THE OTHER
INFLUENCE IS THE PEAK LACTATE,
WHICH IS DRIVEN BY YOUR MOTHER,
AND HOW MANY FAST TWITCH MUSCLE
FIBERS YOU'VE INHERITED,
GLYCOLYTIC FIBERS, THAT'S THE
SOURCE OF MUSCLE LACTATE.
SO IF THE SPRINTER OF THE WORLD
AS WE TALKED ABOUT THIS MORNING
IS 14 MILIMOLAR AT PEAK
EXERCISE, THEY MAY BE 4 1 HOUR
POST AND IT HAS NOTHING TO DO
WITH MITOCHONDRIAL DYSFUNCTION
OR POTENTIALLY O2 DELIVERY.
SO I THINK THE LACTATES, IT'S A
BIT OF A MURKY NONSPECIFIC
BIOMARKER.
GOT SOME QUESTIONS OUT THERE.
>> WE CAN START HERE.
>> COULD I INTRODUCE ONE OTHER
VARIABLE INTO THE EQUATION,
WHICH IS THE BLOOD VOLUME,
BECAUSE WE HAVE DATA IN THE
FIELD DATING BACK TO STRAYER'S
WORK, OUR GROUP, SHOWED THE
BLOOD VOLUME TO BE LOW IN
ME/CFS, EVEN AS MUCH AS A LITER
LOW.
SO THAT GOES TO YOUR PRELOAD
FAILURE.
SO I'M WONDERING IF THERE'S JUST
NOT ENOUGH CELLS AND THERE'S NOT
ENOUGH PRELOAD, HOW MUCH OF THIS
HYPOXIA-DRIVEN HYPOTHESIS IS
BEING DRIVEN BY THAT?
AND I'M GOING TO ADD ONE MORE
QUESTION.
WHY WOULD THE DARN VOLUME BE
LOW?
THE EPO LEVELS ARE NORMAL.
THEIR ERYTH ERYTH ERYTHROPOIETE.
>> WE HEARD THE FIRST PART.
>> RIGHT, AND THE SECOND PART IS
WHAT IS DRIVING HYPOVOLEMIA.
IN THE SETTING OF A NORMAL
ERYTHERYTHROPOITEN LEVEL.
>> WHAT AS LED ME TO LEAN TOWARD
THE COMPONENT OF THE
PYRIDSTIGMINE STUDY I PRESENTED
TODAY.
NOW IN FAIRNESS, COULD THERE BE
A PATIENT WITH HYPOVOLEMIA WHOSE
PRELOAD FAILURE IS SOMEWHAT
OVERCOME, A BAND-AID, AS IT
WERE, BY IMPROVING NERVE
TRANSMISSION, MAYBE.
AND SO I WOULD SUGGEST, TUNE IN
TO THE CIRCULATION WEBINAR ON
JANUARY 11TH, WHEN WE'RE GOING
TO HAVE THAT VERY ENTITY
PRESENTED BY OUR AMSTERDAM
COLLEAGUES, HYPOVOLEMIA AS A
COMPONENT, AND I PUT IT UP THERE
AS A DIFFERENTIAL DIAGNOSIS.
SECOND PART WAS?
>> WHAT COULD DRIVE A LOW VOLUME
STAY?
>> DON'T KNOW.
THERE ARE SOME OLDER DATA THAT
SUGGEST, AND HATE TO GET INTO
DECONDITIONING BECAUSE I DO NOT
BELIEVE ALL THIS IS DECONDIT
DECONDITIONING FOR A MOMENT.
THERE ARE SOME DATA TO SUGGEST
IF YOU PUT NORMAL INDIVIDUALS OR
ATHLETES TO BED, THAT THEY DE
FACTO DEVELOP HYPOVOLEMIA.
AND THE MECHANISMS ARE PROBABLY
ABOVE MY PAY GRADE.
DON'T KNOW.
HAVING SAID THAT, A CANADIAN
NAMED DR. STRICKLAND BACK IN THE
DAY DID INVASIVE CARDIOPULMONARY
EXERCISE TESTING AND COMPARED
DECONDITIONED PATIENTS, NO M.E.,
NO LONG COVID, LONG BEFORE THAT,
TO NORMAL INDIVIDUALS AND SHOWED
THAT THE FILLING PRESSURES WITH
DECONDITIONING DURING UPRIGHT
CYCLING ARE HIGHER, NOT LOWER,
IN THE DOUGH TRAINED OR
DECONDITIONED INDIVIDUALS.
SO I THINK WE'VE GOT THE
OPPOSITE END OF THE SPECTRUM AND
RELATE NOT JUST WHAT YOU ASKED,
NANCY, BUT AN OXYGEN EXTRACTION
STORY IS NOT A FEATURE OF SIMPLE
DECONDITIONING, AND THAT'S
REALLY BEEN PUT TO BED BY
MULTIPLE PEOPLE, PETER WAGNER ON
THE WEST COAST, AND THE FOLKS
WAY BACK IN THE DAY WITH THE
BEDREST STUDY.
THE EXTRACTION PROBLEM IS NOT A
FEATURE OF DECONDITIONING.
>> THANK YOU.
>> COULD I FOLLOW UP QUICKLY ON
THAT VOLUME, SO THERE IS
EVIDENCE THAT THERE'S HYPER
VOLEMIA IN ME/CFS, OR -- YOU
MENTIONED THE PRELOAD FAILURE,
RIGHT, AND THAT COULD BE BECAUSE
OF VOLUME OR IT COULD BE BECAUSE
YOU HAVE OVERLY COMPLIANT RIGHT
SIDE --
>> AND FAILURE TO VENOCONSTRICT,
OR BOTH.
>> OR BOTH.
>> NO, THERE ARE DATA, AND UP
FORTUNATELY TO GET AT THAT
SCIENTIFICALLY, YOU NEED TO DO A
RADIOACTIVE TRACER TO LOOK AT
PLASMA VOLUME.
THERE ARE DATA, OLDER DATA ON
M.E. THAT SUGGEST A SUBSET OF
PATIENTS MAY BE HYPOVOLY MIBG.
SO IN THAT CASE, I WOULD HAVE TO
INVOKE OVERCOMING THAT WITH THE
PYRIDSTIGMINE, WHICH IS
NEUROACTIVE.
>> OKAY.
OKAY.
SO THERE'S A SMALL FIBER --
THERE IS EVIDENCE OF SMALL FIBER
DYSFUNCTION?
>> OH, YEAH.
VERY MUCH SO.
>> I WAS WONDERING WHETHER --
YOU KNOW, I'M VERY INTERESTED IN
OXYGEN HOMEOSTASIS, AND THE
OXYGEN BEING HIGH IN THE MIXED
VENOUS SATURATION, WHETHER THAT
COULD HAVE SOME EFFECT, FOR
EXAMPLE, IN THE OXYGEN SENSORS
IN THE CAROTID DO BEE BODY ANDD
THAT FEEDBACK TO YOUR PRELOAD
SYSTEM.
>> IT'S FASCINATING TO THINK
ABOUT THE CAROTID BODY'S SENSORS
ARE THE MITOCHONDRIA.
AND WHEN HIF1 ALPHA IS
ACTIVATED, THAT COULD DRIVE A
LOT OF THINGS, MAYBE EVEN
INCLUDING THE HYPERVENTILATION
THAT IS SEEN IN SOME OF THESE
FOLKS.
MAYBE A LITTLE MORE COMMON IN
LONG COVID THAN M.E., BUT
PROBABLY IN BOTH DISEASES.
YEAH.
>> FINALLY I GET TO THE MIC,
JOE.
CAN YOU HEAR?
>> BARELY.
>> BARELY?
OKAY.
I'LL TRY TO SPEAK -- IF I SPEAK
LOUDER, DOES THAT HELP?
>> A LITTLE BIT.
>> ONLY A LITTLE BIT.
OKAY.
SO MY FOUR MENTORS, PAUL, PETER,
JERRY, AND JIM WOULD BE ALL
UPSET IF I DIDN'T BRING UP FOUR
THINGS THAT NEED BE CONNECTED
HERE.
I'LL GO IN THE ORDER WE'VE
DISCUSSED THEM TODAY.
AND THE FIRST IS INFLAMMATORY
RESPONSE IN GUT LEAKINESS.
BECAUSE ONE OF THE PROBLEMS THAT
WE MIGHT BE SEEING IS THAT THE
LOW BLOOD VOLUME, NOT REALLY LOW
BLOOD VOLUME WHICH IS WHY IT'S
EPO NORMAL, HEMATOCRIT NORMAL,
DECREASING EFFECTIVE BLOOD
VOLUME AND REDUCING VENOUS
RETURN.
SECOND THING IS THAT DR. HWANG
WOULD BE GREAT TO LOOK AT
DIFFERENTIAL FIO2s, IN OTHER
WORDS, WHEN YOU'RE DOING YOUR
PNMR SPECTROSCOPY TO ALTER THE
FI02s VERY MUCH LIKE PETER
DID, BECAUSE THE SPECTRA
THAT YOU HAD ARE VERY COMPELLING
THAT O2 ENERGETICS CAPABILITIES
ARE DEPRESSED IN THE S1 --
PARDON ME -- THE S2 PATIENT, I
THINK IT WAS, BUT YOU NEED TO
SHOW THAT THAT'S INDEPENDENT OF
O2 DELIVERY, AND THE WAY TO DO
THAT, PETER NICELY SHOWED THAT
THE WAY TO DO THAT IS ALTERING
THE FI02, SO THAT YOU CAN SHOW
THAT IT'S INDEPENDENT OF
O2 DELIVERY BECAUSE WE NEED TO
KNOW THAT IT'S NOT AS DR. CY IS
ARGUING, THAT IT'S NOT BOTH THE
SUPPLY AND TISSUE DEMAND AND
DIFFUSIVE INABILITY TO GET
OXYGEN INTO THE TISSUES.
SO THOSE ARE THE THINGS -- AND I
HAVE SAID THAT ONE OF THE
PROBLEMS WE HAVE, SINCE THE
MONTREAL CONFERENCE, AND HERE
WHEN I FIRST STARTED COMING, WE
NEED TO DETERMINE IF CIRCULATION
IS DRIVING ALL OF THIS BECAUSE
IF THERE'S -- IF THE BLOOD
VOLUME EFFECTIVE CIRCULATION IS
LOW, YOU CAN'T PERFUSE TISSUES
NORMALLY AND THE INFLAMMATORY
RESPONSE RELATED TO THE GUT MAY
BE THE DRIVING IT ALL.
SO THE ONE THING WE'VE GOT TO DO
IS NORMALIZE FOR O2 SUPPLY AND
SEE THEN IF THERE'S STILL
MYOPATHIC LIMITATIONS OR IF
THERE'S OTHER PROBLEMS.
AND THOSE ARE THE DOTS THAT NEED
TO BE CONNECTED.
>> AMEN.
[LAUGHTER]
>> PAUL, HAVE YOU CHECKED
WASF3 LEVELS IN OTHER TISSUES
BESIDES SKELETAL MUSCLE?
>> IN PATIENTS?
IS THAT --
>> YEAH.
>> WE ACTUALLY DON'T HAVE ANY
OTHER TISSUES OTHER THAN IN THAT
SINGLE -- THE FIRST PATIENT WHO
WAS JUST A SKIN BIOPSY, SO IT'S
FIBROBLASTS, THAT'S WHERE WE SAW
THE WASF INDUCED.
AND THEN IT WAS THE SKELETAL
MUSCLE NEEDLE BIOPSIES FROM THE
ME/CFS PATIENTS THAT HAD BEEN
STORED.
BUT THOSE ARE USUALLY THE TWO --
WELL, I'M SURE THERE ARE OTHER
SAMPLES.
BLOOD CELLS, OBVIOUS THING.
WE'VE NOT SEEN -- WE DON'T SEE
WASF3 AT LEAST WITH USING OUR
ANTIBODIES IN MONO NUCLEAR CELLS
OR BLOOD CELLS.
WE DON'T SEE THAT.
AT LEAST ON A NORMAL BASAL
CONDITIONS.
>> SO CAN YOU GUESS WHY THERE'S
INCREASED ER STRESS, WHICH SEEMS
TO BE INCREASING WASF3?
>> SO THERE'S SOMETHING -- I
MEAN, THOSE FIBROBLASTS FROM THE
FIRST PATIENT S1, YOU KNOW,
THOSE ARE NORMAL HEALTHY GROWING
FIBROBLASTS IN TISSUE CULTURE
FAR, FAR REMOVED FROM THE
PATIENT'S BLOOD AND PLASMA AND
CYTOKINES, WHATEVER HAVE BEEN IN
THERE, BUT WE SEE THE ER STRESS
IS ACTIVATED.
SO IT'S SOMETHING -- IT COULD BE
A GENETIC -- I MEAN, IT'S
INTRINSIC TO THE FIBROBLASTS.
COMPARED TO THE BROTHER'S
FIBROBLASTS.
SO WE DON'T KNOW.
WE DON'T KNOW.
I SAID THAT WE DIDN'T THINK IT
WAS RELATED TO THE P53 MUTATION
STATUS BECAUSE, AGAIN, BOTH
SIBLINGS HAD THE SAME MUTATION.
BUT THEY COULD BE SOMETHING,
SOME INDIRECT WAY IN THE GENETIC
BACKGROUND, OBVIOUSLY THEY SHARE
50% OF THE GENOME, BUT THERE
COULD BE OTHER DIFFERENCES THAT
COULD MAKE HER CELLS SENSITIVE
TO THE P53 MUTATION BUT WE DON'T
KNOW.
>> HELLO.
I'VE BEEN GRAPPLING, LIKE
STRUGGLING TO UNDERSTAND HOW
THIS METABOLIC DYSFUNCTION OR
CARDIOVASCULAR DYSREGULATION
WOULD APPLY TO POST EXERTIONAL
MALAISE IN THE CONTEXT OF
MAXIMAL EXERTIONS, BECAUSE IN
THE C BETs, WE SEE THAT THE
MAIN DIFFERENCES OCCUR AT PEAK
EXERCISE.
YET PATIENTS CONTINUOUSLY
REPORT -- AFTER ACTIVITIES OF
DAILY LIVING.
SO COULD YOU ALL BRAINSTORM ON
HOW THESE TWO THINGS ARE
CONNECTED?
>> I HEARD PARTLY AT LEAST.
AGAIN, THE COMMENT TO SOME OF
IT, AND THEN YOU CAN REPEAT THE
QUESTION.
>> SO YOUR QUESTION WAS, HOW CAN
OXYGEN LIMITATION AND METABOLIC
EFFECTS OCCUR AT THE SAME TIME
UNDER EXERCISE?
>> NO, NO.
THE BIGGEST DIFFERENCES ARE
OCCURRING AT PEAK EXERCISE.
BUT POST EXERTIONAL MALAISE
OCCURS AFTER ACTIVITIES OF DAY
LEA LIVING.
>> OKAY.
SO --
>> I CAN TAKE A WHACK AT IT.
NO, IT'S A GOOD QUESTION.
I THINK BROADLY SPEAKING, IF WE
GOT IT RIGHT UP HERE, PEAK
EXERCISE IS KIND OF THE STRATUS
FEASTRATOSPHERE, IT IS NOT WHERE
MOST PATIENTS SPEND A MAJORITY
OF THEIR TIME YET THEY HAVE
SYMPTOMS AT REST AND AT OTHER
TIMES, AND POST EXERTIONAL
MALAISE IS OF MAJOR INTEREST.
SO WE WONDERED IF WE HAD --
THERE ARE OTHER LINES OF
EVIDENCE AND I'LL DEFER TO
OTHERS, BUT WE WONDERED IF WE
HAD A LITTLE BIT OF A SIGNAL IN
THE ACUTE PYRIDSTIGMINE
RANDOMIZED CONTROL STUDY OF
EARLY PEM, AND THAT ALL OF THE
NUMBERS THAT WE MEASURED AT PEAK
EXERCISE WERE WORSE ONE HOUR
AFTER THE PRIOR EXERCISE.
MAYBE THAT WAS THE BEGINNING.
AND MAYBE -- NOT SHOWN THERE, WE
ACTUALLY HAD EVIDENCE THAT
RESTING VO2 READ METABOLISM WAS
ELEVATED WHEN PATIENTS RECEIVED
PLACEBO.
SO WE DON'T HAVE ALL THE
CYTOKINE MEASUREMENTS TO GO WITH
THAT IN THAT PARTICULAR STUDY,
OR OTHER BIOMARKERS, BUT OUR
SPECULATION WAS THAT THE ACUTE
EXERCISE MIGHT HAVE ELICITED
INFLAMMATION AND THE BEGINNINGS
OF PEM EVEN ONE HOUR OUT, AND
THAT THAT MIGHT BE A CONNECTION.
BUT I THINK I'LL DEFER TO
OTHERS, BUT I THINK PRIME
MINISTERPEM IS WAYMORE COMPLICAE
YA, IT'S INFLAMMATION THAT'S
ONGOING AND ALL THE BAD THINGS
THAT GO WITH IT.
>> AGAIN, CAN YOU COMMENT A
LITTLE BIT ON THE METABOLIC
SIDE, BECAUSE IF IT IS TRUE THAT
THERE IS UNDERLYING STRESS, ON
ONE SIDE IT MEANS THE PROTECTION
SYSTEM IS ACTIVATED ALL THE TIME
IN THE PATIENT.
SO THIS CAN ACTUALLY HELP TO
KEEP A HEALTHY TYPE OF
METABOLISM EVEN IN REST, BUT THE
DOWNSIDE IS, OF COURSE, THAT
THIS IS AN ELEVATED ENERGY
LEVEL, SO IT MAY LEAD TO
OVERCHARGING THE SYSTEM MORE
EASILY.
SO -- AND ALSO WHEN IT COMES TO
EXERCISE, THERE IS ALSO
SOMETHING CALLED OXYGEN DEPTH
THAT YOU ACTUALLY OVERUSE SOME
OF THE OXYGEN IN THE WAY THAT
YOU CAN TELL MORE ABOUT THAT,
BUT THAT CAN ALSO TELL SOME
ELEMENTS OF THE EFFECT OF THE
EXERCISE IMMEDIATELY AFTER THE
PEAK EXERCISE.
AND MAYBE IT'S ALSO SO THAT DUE
TO METABOLIC OVERCHARGE, THE
PATIENTS ARE NOT ABLE TO REALLY
GET BACK TO THE RECOVER TYPE OF
METABOLISM SO THEY ARE ALWAYS IN
KIND OF AN ELEVATED STATE.
>> HI, MY NAME IS LOU, I'M WITH
VASSER.
I HAVE BEEN SORT OF THINKING
ABOUT THE EARLIEST SORT OF
PHASES OF METABOLISM.
I FEEL LIKE WE'RE KIND OF
LOOKING AT SORT OF LIKE FURTHER
DOWN IN THE PATHWAY, FURTHER
DOWN IN THE SIGNALING, AND I'M
CURIOUS IF THE COLLECTIVE WE
FEEL VERY STRONGLY THAT THIS IS
NOT AN OXYGEN FIXATION ISSUE OR
WHETHER OR NOT THERE'S SOME SORT
OF -- AND THIS MAY BE MORE OF A
QUESTION FOR SOME OF THE MORE
GENETIC CENTERED TALKS WE'RE
GOING TO HEAR TOMORROW, BUT
SINCE WE'RE ALL LOOKING AT SOME
VERY SPECIFIC TISSUES, I'M SORT
OF THINKING ABOUT -- I WOULD
LOVE TO HEAR YOUR THOUGHTS ON
WHETHER OR NOT THERE COULD
POTENTIALLY BE SOME SORT OF GENE
THAT'S BEING EXPRESSED FOLLOWING
A VIRAL INFECTION THAT MIGHT BE
INTERFERING WITH OXYGEN FIXATION
OR PERHAPS FURTHER DOWN THE
POTENTIAL PERFUSION OF OXYGEN
INTO TISSUES, WHETHER OR NOT IT
IS ACTUALLY BEING FIXED IN THE
CORRECT PLACES IN THE LUNGS AND
THEN BEING DISTRIBUTED AND
SOMEHOW HAVING AN ISSUE SORT OF
ACCESSING THE PROPER RECEPTORS
AND ACCESSING ATP, AND THEN SORT
OF A FOLLOW-UP QUESTION TO THAT.
THIS MIGHT BE OBVIOUS AND IT
MIGHT BE A LITTLE RIDICULOUS,
BUT I WAS WONDERING IF WE HAD
TAKEN A LOOK AT A RESIDUAL ADP
IN TISSUES, AND WHETHER OR NOT
THERE WAS JUST AN ISSUE OF
PHOSPHORYLATING ADP.
JUST SORT OF THINKING AS EARLY
AS POSSIBLE.
>> SO THE LAST QUESTION WAS
ABOUT THE -- IF THE LEVEL OF ADP
WAS CHANGED IN PATIENTS.
AND THE FIRST JUST AS I RECALL
WERE IF THERE WERE ANY SPECIFIC
GENES ASSOCIATED WITH THE OXYGEN
FIXATION THAT HAS BEEN FOUND.
I DON'T KNOW ANYTHING ABOUT THE
FIRST QUESTION, THE GENES.
DOES ANYONE KNOW?
NO.
WHEN IT COMES TO AD P AND ATP, I
THINK THAT HAS PROBABLY NOT BEEN
MENTIONED, AND I'M ALSO A LITTLE
BIT SKEPTIC ABOUT THOSE KINDS OF
MEASUREMENTS IN TISSUES IN
PATIENTS BECAUSE THIS IS SO
DIFFICULT MEASUREMENTS FROM
TAKING THE BIOPSY TO DOING THE
MEASUREMENTS AND REALLY MAKE --
IT DEPENDS ON SO MANY FACTORS.
I THINK THIS IS THE MOST VITAL
SYSTEM IN THE CELLS AND IN THE
TISSUES TO KEEP AND MAINTAIN A
STABLE ATP LEVEL, SO THE BODY
WILL DO WHATEVER IT CAN TO
REALLY MAINTAIN THOSE LEVELS AND
INCREASE THEM IF NECESSAR NECES.
THERE HAS BEEN FOUND SOME -- SO
I THINK TRYING TO SUPPORT THE
ENERGY PRODUCTION SYSTEM SEEMS
TO WORK FOR SOME PATIENT BY
TAKING SUPPLEMENTS AND THINGS
LIKE THAT AND EVEN ADJUST THEIR
DIET, AND THIS IS TYPICALLY TO
ACTIVATE SPECIFIC PART OF THE
ADAPTATION OF PROGRAMS.
BUT DIRECT RELATION TO THE
ACTUAL ATP LEVEL, I INK THIS
THAT'S A DIFFICULT ONE.
JUST TO REMEMBER ONE GENE THAT
WAS NOT ASSOCIATED WITH THE --
WITH ENERGY PRODUCTION OR OXYGEN
FIXATION, BUT WE DO KNOW THAT IN
ONE OF THE CLINICAL TRIALS IN
BERGEN, THEY FOUND A SPECIFIC --
WITH HLA MUTATION, OR GENE
VARIANT, AND IT SEEMS TO BE
ASSOCIATED ALSO WITH A
THERAPEUTIC EFFECT.
AND THESE VARIANTS, THEY ARE
FOUND TO BE MORE FREQUENT IN
M.E. POPULATION IN BIGGER
STUDIES.
SO THERE ARE SOME GENES THAT ARE
ASSOCIATED BUT NOT DIRECTLY WITH
THE OXYGEN FIXATION.
THIS WAS MORE WITH THE POSSIBLE
UNDERLYING AUTOIMMUNE MECHANISM.
>> I HAVE TO BRING US TO A CLOSE
ACTUALLY.
>> CAN I ASK ONE IMPORTANT
QUESTION?
>> ACTUALLY WE HAVE TO -- SORRY.
IF YOU HAVE ANY FINAL COMMENTS?
, THAT WOULD BE GREAT.
OTHERWISE I'D LIKE TO THANK OUR
PANELISTS FOR ANSWERING
ADDITIONAL QUESTIONS IN THEIR
TIME TODAY.
>> THANKS, JOE.
>.
[APPLAUSE]
>> THANKS FOR HARNGING IN THERE.
WE'RE GOING TO TALK ABOUT THE
PROCESS WE'VE BEEN UNDERGOING
FOR THE ME/CFS RESEARCH ROAD
MAP.
IN 2019, 2018 TO 2019, THERE WAS
A WORKING GROUP OF NINDS
ADVISORY COUNCIL THAT TOOK A
LOOK AT WHAT WAS HAPPENING
ACROSS THE LANDSCAPE OF RESEARCH
ON ME/CFS.
THE REPORT THAT CAME FROM THAT
WORKING GROUP OF COUNCIL MADE
NUMEROUS RECOMMENDATIONS,
PRIMARILY AROUND INFRASTRUCTURE,
WORKFORCE DEVELOPMENT, THE NEED
FOR ADDITIONAL CLINICIANS IN THE
FIELD, AND ONE OF THE
RECOMMENDATIONS THAT WAS MADE
WAS TO DO A STRATEGIC PLANNING
PROCESS FOR RESEARCH ON ME/CFS.
SO THAT REPORT WAS DELIVERED IN
SEPTEMBER 2019.
WE BEGAN WORKING TO DEVELOP A
PLAN TO START AND INITIATE THE
RESEARCH ROAD MAP PROCESS, AND
THEN SARS-COV-2 CAME ALONG.
AND WE TALKED TO MANY PEOPLE IN
THE FIELD, CLINICIANS WERE
ABSOLUTELY SWAMPED IN THE
HOSPITALS, RESEARCHERS WERE
TRYING TO FIGURE OUT HOW TO KEEP
THINGS GOING IN THEIR LAB.
IT JUST WAS NOT THE TIME TO
START A PROCESS LIKE THIS.
SO WE PUT IT ON HOLD AND
RESTARTED THE PROCESS IN THE
FALL OF '22 AND LAUNCHED --
ACTUALLY LAUNCHED THE WHOLE
PROCESS IN FEBRUARY OF '23.
SO THE CHARGE TO THE WORKING
GROUP OF COUNCIL IS TO DEVELOP A
RESEARCH ROAD MAP TO PROVIDE
SCIENTIFIC GUIDANCE TO THE NINDS
COUNCIL ON HOW TO BEST ADVANCE
RESEARCH ON ME/CFS.
CONSISTENT WITH THE CHARGE, THE
WORKING GROUP WILL ASSESS
CURRENT ME/CFS RESEARCH
ACTIVITIES AND IDENTIFY
OPPORTUNITIES AND GAPS IN ME/CFS
RESEARCH TO IDENTIFY TARGETS FOR
THE DEVELOPMENT OF TREATMENTS.
SO THAT'S REALLY KEY HERE IN
WHAT ALL OF THE WORK THAT WE'VE
BEEN DOING IS TO REALLY, NUMBER
ONE, ASSESS THE FIELD BUT NUMBER
TWO, THINK FORWARD AS TO HOW CAN
WE ACCELERATE THE RESEARCH TO
REALLY MOVE TOWARD TREATMENT
TRIALS AND DEVELOPMENT OF
TREATMENTS FOR ME/CFS.
SO YOU SAW A VERSION OF THIS
SLIDE THIS MORNING, WHEN
DR. KOROSHETZ SPOKE, WE HAVE
ACTUALLY ADDED AN EIGHTH
WEBINAR.
SO THE PROCESS HERE IS THAT WE
IDENTIFIED INDIVIDUALS TO SERVE
ON THE ME/CFS WORKING GROUP OF
COUNCIL, AND I'LL SHOW YOU
THAT -- HOW HA COMMITTEE IS
COMPOSED IN A MOMENT.
WE THEN DECIDED WE WOULD LIKE TO
INCLUDE ADDITIONAL INDIVIDUALS
WITH LIVED EXPERIENCE, SO WE PUT
OUT A CALL FOR NOMINATIONS AND
RECEIVED ALMOST A HUNDRED
NOMINATIONS, SELF-NOMINATIONS
FROM INDIVIDUALS WHO WANTED TO
PARTICIPATE IN THIS PROCESS.
WE SELECTED 21 INDIVIDUALS WITH
LIVED EXPERIENCE, WHO ARE NOW
PARTICIPATING, WE SPREAD THEM
OUT ACROSS ALL OF THE WEBINAR
PLANNING GROUPS AND HAVE BEEN
PARTICIPATING IN THIS PROCESS
WITH US, AND OF COURSE NIH STAFF
TO SUPPORT THE ERT.
THE EFFORT.
SO WE'VE ALREADY HAD SIX OF THE
WEBINARS ON THE SYSTEMS YOU CAN
SEE HERE.
WE HAVE TWO LEFT, AND THANKS,
DAVID, FOR THE ADVERTISEMENT FOR
THE CIRCULATION ONE, AND THEN
THERE'S ONE LESSER STUDY
PATHOLOGY THAT WILL TAKE PLACE
ON JANUARY 5TH.
SO THE END RESULT OF THIS IS
THAT THE RESEARCH PRIORITIES
THAT COME FROM ALL OF THESE
WEBINAR GROUPS, WHAT WE HEAR AT
THE WEBINARS AND WEBINAR
PLANNING GROUPS ARE RESEARCH
PRIORITIES THAT WILL COME
TOGETHER AGAIN INTO A REPORT
WHICH WE'LL PUT OUT FOR PUBLIC
FEEDBACK AND THEN EVENTUALLY
THAT REPORT WILL GO TO THE NINDS
ADVISORY COUNCIL AND NINDS
LEADERSHIP AND NIH LEADERSHIP
OVERALL.
SO THE WORKING GROUP CONSISTS OF
INDIVIDUALS THAT CROSS THE
PATIENT ADVOCACY GROUPS, AS I
SAID SOME INDIVIDUAL WITH LIVED
EXPERIENCE, SOME OF OUR FEDERAL
PARTNERS, CLINICIANS, AND
INVESTIGATORS, AND THE CO-CHAIRS
OF THIS WORKING GROUP ARE CINDY
BATEMAN FROM BATEMAN HORNE
CENTER, AND MAUREEN HANSON, WHO
YOU'LL HEAR -- FROM CORNELL WHO
YOU'LL HEAR FROM IN A MOMENT.
I'D LIKE TO ACKNOWLEDGE ALL OF
THE INDIVIDUALS WITH LIVED
EXPERIENCE WHO HAVE REALLY
PROVIDED REALLY SIGNIFICANT AND
IMPORTANT INPUT INTO THE
PERSPECTIVE OF RESEARCH AND INTO
THE -- AND THEIR PERSPECTIVE ON
LIVING WITH THE DISEASE OR
CARING, SOME OF THEM ARE
CAREGIVERS, FOR ONE OR MORE
INDIVIDUALS WITH ME/CFS.
SO WITH THAT, I'M GOING TO TURN
IT OVER TO CINDY, BUT JUST
BEFORE I DO THAT, WHAT YOU SEE
NEXT ARE SLIDES THAT REPRESENT
THE RESEARCH PRIORITIES FOR THE
FIRST FOUR WEBINARS.
THE FIRST IS THE NERVOUS SYSTEM.
WEBINAR.
THERE WAS A VERY LONG AND
EX-TENSE SEXTENSIVE LIST OF PRIS
THAT THIS PLANNING GROUP HAS
CONDENSED INTO THE RESEARCH
PRIORITIES THAT YOU'LL SEE HERE.
THE OTHER THREE THAT YOU WILL
SEE ARE SORT OF LONGER LISTS
THAT HAVEN'T YET KIND OF COME TO
CONSENSUS, AND WE WILL BE,
AGAIN, ESTABLISHING THESE
SIMILAR TYPE RESEARCH PRIORITIES
FOR THE ADDITIONAL FOUR
WEBINARS.
THE TWO THAT HAVE BEEN HELD
ALREADY, THOSE ARE IN THE WORKS,
AND THEN THE TWO WILL BE HELD IN
JANUARY, WE'LL COME UP WITH
SIMILAR RESEARCH PRIORITIES.
AND THERE ARE SOME SIMILARITIES,
CROSS AND OVERLAPPING PRIORITIES
THAT AGAIN WILL ALL COME
TOGETHER IN THE REPORT THAT WILL
GO TO THE NINDS COUNCIL.
SO WITH THAT, I'LL INTRODUCE
CINDY BATEMAN FROM BATEMAN HORNE
CENTER WHO WILL TAKE OVER HERE.
[APPLAUSE]
>> THANK YOU.
THIS HAS BEEN A REALLY
INCREDIBLE EFFORT, AND IT'S BEEN
AN HONOR TO PARTICIPATE IN THIS
EFFORT AS A CLINICIAN.
SO MAUREEN AND I ARE CHAIRING
THIS, AND PARTNERING WITH VICKY,
BUT WE'VE HAD THE OPPORTUNITY TO
BE WITH MANY, MANY PEOPLE AND
LEARN FROM THEM.
SO I'M GOING TO PRESENT TO YOU
SOME OF WHAT THE NERVOUS SYSTEM
PRIORITIES ARE AT THIS POINT AND
THE IMMUNE SYSTEM PRIORITIES,
AND THEN MAUREEN WILL TAKE IT
OVER FROM THERE.
SO AS YOU CAN IMAGINE, THESE
WEBINARS WERE ABOUT FOUR HOURS
LONG WITH EXCELLENT
PRESENTATIONS, AND THEN THE
COMMITTEES MET AFTERWARDS TO
SORT OF REVIEW EACH OF THE
SPEAKERS' RESEARCH PRIORITIES
AND GIVE INPUT AND THEN AS VICKY
SAID, SOME OF THEM ARE MORE
ORGANIZED AND HONED DOWN AND
LESS REPETITIVE THAN OTHERS
BECAUSE THEY'RE ALL IN STAGES OF
DEVELOP M.
MENT.
SO THESE ARE THE SUBCATEGORIES
IN THE NERVOUS SYSTEM RESEARCH
PRIORITIES.
NOT NECESSARILY IN ANY ORDER.
AND WE PUT RED PRINT IN THERE TO
MAYBE PICK OUT SOME TO
EMPHASIZE, BUT THERE ISN'T
ANYTHING MORE REAL SIGNIFICANT
ABOUT THAT PRINT.
SO COGNITION WAS A VERY
IMPORTANT AREA.
AND WE ALL SENSE THAT IT'S
IMPORTANT TO DEVELOP AND
VALIDATE TOOLS, OBJECTIVE TOOLS
FOR COGNITIVE ASSESSMENT AND
SPECIFICALLY FOR REMOTE
ASSESSMENT.
AND COGNITIVE BATTERIES THAT ARE
SPECIFICALLY FOR USE IN ME/CFS
STUDIES EASILY ADMINISTERED, ET
CETERA.
THE NEXT CATEGORY IS THAT OF
DYSAUTONOMIA.
AND SOME OF THE TOP PRIORITIES
WERE TO REALLY TRY TO UNDERSTAND
THE IMPACT OF OR T ORTHOSTATIC S
AND HOW IT HELPS OR REVEALS
ME/CFS PATHOLOGY SYMPTOM AND
DISEASE SEVERITY, AND REALLY
INVESTIGATE CIRCULATORY
DYSFUNCTION IN ME/CFS NEURAL,
IMMUNE AND AUTO NO MIBG
SYMPTOMS.
KNOW MIBG
SYMPTOMS.
ALSO I'M GOING TO ADD THERE THAT
IT WOULD BE GOOD TO UNDERSTAND
THE IMPACT, THE RELATIONSHIP OF
MAST CELL ACTIVATION ON
ORTHOSTATIC INTOLERANCE AS WELL.
THE SUBCATEGORY OF
NEUROINFLAMMATION EMPHASIZED
THAT WE NEED TO STUDY MORE
CEREBROSPINAL FLUID TO REVEAL
IMMUNOLOGICAL AND
NEUROINFLAMMATORY ABNORMALITIES,
AND MAYBE TO USE MEDICATIONS
THAT CROSS THE BLOOD BRAIN
BARRIER TO UNDERSTAND SOME OF
THESE MECHANISMS OF
NEUROINFLAMMATION.
SO ANOTHER SUBCATEGORY WAS
NEUROIMAGING, AND WE REALLY NEED
TO UNDERSTAND MORE ABOUT
NEUROIMAGING USING MRI, PET
SCANS AND EEG.
AND COMPARE ACROSS STUDIES AND
AMONG PATIENTS TO UNCOVER BRAIN
ABNORMALITIES, BUT ALSO TO
UNDERSTAND THE EFFECTS OF
PATIENT TRAVEL AND UNDERSTAND
ALL THE DIFFERENT THINGS THAT
COULD IMPACT THESE OUTCOMES OF
THESE SCANS.
AND TO TRY TO GET AS MANY
NEUROIMAGING SCANS IN CLINICAL
TRIALS AS POSSIBLE.
THE NEXT SUBCATEGORY IN NERVOUS
SYSTEM RESEARCH PRIORITIES WAS
DISORDERED SLEEP, AND WE
REALLY -- WE HAVE A LOT TO DO ON
WHY SLEEP IS DISORDERED AND
UNREFRESHING AND NEED TO DEVELOP
AND VALIDATE BIOMARKERS TO
UNDERSTAND MORE ABOUT THIS
NON-RESTORATIVE SLEEP, MAYBE
LEARNING MORE ABOUT EEG
CORRELATES, SUBGROUPS,
INDIVIDUAL SLEEP PATTERNS, AND
UNDERSTANDING WHY SLEEP PHASE
REVERSAL HAPPENS IN ME/CFS.
SMALL FIBER NEUROPATHY AND HOW
IT DRIVES ME/CFS, ORTHOSTATIC
INTOLERANCE, CEREBROPIE CEREBRON
AND POTS, WHAT ARE THE
CHARACTERISTICS OF ORTHOSTATIC
INTOLERANCE WITH AND WITHOUT
ME/CFS, AND I WOULD SAY WE NEED
TO UNDERSTAND POTs THAT OCCURS
WITHOUT ME/CFS, AND ME/CFS THAT
DOESN'T HAVE POTs, AND TRY TO
UNDERSTAND THESE OVERLAPS.
THERE WERE SOME OVERARCHING
COMMENTS THAT MAYBE A LITTLE BIT
LESS DISTINCT BUT REALLY TO
UNDERSTAND HOW -- AND THIS IS
RELATED ALSO TO THE COMMENT
ABOUT IMAGING, HOW -- WHAT IS
THE IMPACT OF GOING TO THE
CLINIC, GOING TO THE LABORATORY
TO GET VARIABLES OR GOING TO THE
RESEARCH LAB AND REALLY TRY TO
UNDERSTAND HOW SOME OF THESE
MEASURES CAN BE DONE AT HOME IF
POSSIBLE AND ALSO PRIORITIZING
SEX DIFFERENCES, AND UNCOVER
PROVOCATION STRESS TASKS OR
CREATE THEM, THAT CAN UNCOVER
PATHOLOGY WHILE MINIMIZING
BURDENS ON PARTICIPANTS TO THE
EXTENT THAT ARE POSSIBLE.
I THINK THAT'S IN PART A
REFERENCE TO CARDIOPULMONARY
EXERCISE TESTING, FOR EXAMPLE,
AND HOW HARD THAT CAN BE ON
PATIENTS AND THE SACRIFICE THEY
MAKE TO HELP GET THAT IMPORTANT
DATA.
WE NEED TO COMPARE AND CONTRAST
ME/CFS FOLLOWING COVID-19
INFECTION, TO ME/CFS OCCURRING
INDEPENDENTLY OF COVID, AND
REALLY TRY TO UNDERSTAND
SUBGROUPS BASED ON AGE, DURATION
OF ILLNESS, NON-RESTORATIVE
SLEEP AND OTHERS.
OKAY, ON TO THE IMMUNE SYSTEM
RESEARCH PRIORITIES.
REMEMBER, THESE ARE STILL SOME
OVERLAPPING CATEGORIES THAT NEED
TO BE DEVELOPED AND NEED INPUT.
UNDER THE CLINICAL IMMUNOLOGY
SUBGROUP, I PRIORITIZE, IDENTIFY
AND CHARACTERIZE DYINGS NO TICK
IMMUNOLOGIC INDICATORS AND
MEDIATORS OF ME/CFS.
A LOT OF SIGH NENS THERE, BUT WE
NEED TO PULL IT TOGETHER AND
UNDERSTAND MORE ABOUT HOW THESE
THINGS CAN BE USED IN THE CLI
CLINIC.
PULL TOGETHER PUBLISHED REPORTS
AND DEVELOP MORE ROBUST SAMPLE
REPOSITORIES AND DATA SHARING
PLATFORMS AND MAYBE BRING IN
INPUT FROM CLINICAL PROVIDERS
BECAUSE THEY ORDER A LOT OF
THESE DIFFERENT LABS, AND SEE IF
WE CAN LEARN MORE FROM THAT.
AND THEN AGAIN PRIORITIZE
STUDIES THAT FOCUS ON
DIFFERENCES IN GENDER, AGE,
STAGE OF ILLNESS, CO-MORBID
CONDITIONS.
AND ENSURE RESEARCH HAS
REPRESENTATIVE DEMOGRAPHICS AS
WELL.
THE SUBCATEGORY OF AUTOIMMUNITY,
ONE OF THE BIG FOCUSES OF
DISCUSSION WAS ON D PROTEIN
RECEPTOR COUPLED ANTIBODIES AND
WHETHER THESE TESTS CAN BE
REPLICATED AND WHETHER OTHER
AUTOANTIBODIES CAN BE ASSOCIATED
WITH ME/CFS.
INVESTIGATE THE ROLE OF B CELL
AND B CELL RECEPTOR SIGNALING
CONTRIBUTING, AND EVERYBODY
WOULD LOVE TO HAVE A RELIABLE
CONSISTENT ANIMAL MODEL FOR MANY
OF THE THINGS WE DO INCLUDING
SERUM TRANSFER ASSAYS.
IMMUNE CELL TYPES WAS A
SUBCATEGORY.
WE NEED TO INVESTIGATE THE
SIGNALING PATHWAYS RESPONSIBLE
FOR DRIVING DYSREGULATION.
AND DETERMINE MORE ABOUT THESE
EXHAUSTED T CELLS AND WHETHER
THEY'RE CHARACTERISTIC OF
ME/CFS.
BUT WE NEED TO LOOK AT OTHER
CELL TYPES.
AND REALLY CLARIFY WHETHER
IMMUNE CELLS ARE FUNCTIONING
NORMAL IN TISSUES AND IN ORGANS
AS OPPOSED TO JUST IN THE
BLOODSTREAM.
IMMUNE PERTURBATION SUBCATEGORY
AGAIN HAS SOME OVERLAP, BUT TO
IDENTIFY ACTIONABLE METABOLIC OR
MICROBIOTA TARGETS THAT ARE
DISRUPTED, TO DEVELOP SENSITIVE
AND SPECIFIC BIOMARKERS BASE ON
IMMUNE AND METABALOME DATA FOR
ACCURATE ME/CFS DIAGNOSIS.
AND REALLY MAYBE CONDUCT SMALL
INTERVENTION TRIALS BASED ON
AVAILABLE TARGETS THAT WE KNOW
NOW TO EVALUATE CHANGES IN
IMMUNE RESPONSE METABOLIC
PATHWAYS IN MICROBIOME IN WAYS
THAT MIGHT LEAD US FORWARD TO
UNDERSTAND THE SIGNIFICANCE
BETTER.
THE GUT IMMUNE METABOLIC
INTERPLAY HAS BEEN REFERRED TO,
BUT WE FEEL LIKE IT'S REALLY
IMPORTANT TO ELUCIDATE THE
DISTINCT MECHANISMS UNDERLYING
THE GUT IMMUNE METABOLIC
INTERPLAY AS WELL AS BIOMARKER
PROFILES OF INDIVIDUALS WITH
ME/CFS TO REALLY UNDERSTAND THE
CONNECTIONS BETWEEN THEM AND
DEVELOP BIOMARKERS TO STRATIFY
THEM BASED ON DISEASE ETIOLOGY
AND UNDERLYING MECHANISMS.
THERE IS THE POTENTIAL TO DESIGN
POSITION THERAPIES TAILORED TO
SPECIFIC SUBSETS OF INDIVIDUALS
WITH ME/CFS IF WE CAN DO SOME OF
THESE THINGS.
SO THIS GROUP MADE SPECIFIC
RECOMMENDATIONS FOR ME/CFS
CLINICAL TRIALS.
THIS CAME A LOT FROM THE LIVED
EXPERIENCE PEOPLE TO INVOLVE
MORE INDIVIDUALS WITH LIVED
EXPERIENCE IN CLINICAL TRIALS,
WHILE BALANCING THE POTENTIAL
ASSOCIATED HEALTH RISKS.
IN OTHER WORDS, CONSIDER TAKING
MORE RISKY ACTIONS IN CLINICAL
TRIALS TO ASSERTIVELY TACKLE
ME/CFS.
THE WAY WE DO WITH LETHAL
DISEASES AND LETHAL CANCER IN
ORDER TO MOVE MORE QUICKLY.
IT IS IMPORTANT TO IDENTIFY AND
ESTABLISH A CLINICAL TRIALS
CONSORTIUM MAYBE USING THE
EXISTING NINDS NEURONEX NETWORK
TO SUPPORT AN INFRASTRUCTURE TO
ROLL OUT CLINICAL TRIALS WITH
THE INCLUSION OF SITES WITH
EXPERTISE IN ME/CFS TO ASSIST
THIS GRANT FUNDING MECHANISM.
WE NEED TO PROVIDE SUPPORT AND
GUIDANCE FOR THE USE OF IMMUNE
MEASURES IN CLINICAL PRACTICE,
AND EDUCATE CLINICIAN -- REALLY
ENHANCE THE EDUCATION OF
CLINICIANS AND PHYSICIANS ABOUT
ME/CFS IN ORDER TO DIAGNOSE AND
CHARACTERIZE CASES MORE
ACTIVELY, WHICH IS A REALLY
OVERARCHING PROBLEM IN OUR
FIELD.
I'LL ALSO BACK UP AND SAY WE
REALLY NEED TO HAVE GUIDELINES
FOR CLINICIANS ABOUT HOW TO
TREATY MTREAT IMMUNE DYSFUNCTIOE
WE'RE WAITING FOR INSIGHTS FROM
LATE STAGE TRIALS.
AND I THINK I'M GOING TO TURN IT
OVER TO MAUREEN TO CONTINUE WITH
THE NEXT WEBINAR.
PRIORITIES.
MAUREEN HANSON.
THINK WE ALL KNOW HER.
[APPLAUSE]
>> THANKS.
SO THE NEXT TWO WEBINARS HAVE
UNDERGONE LESS DISCUSSION AND
POLISHING, SO ACTUALLY I PUT THE
RED THERE TO REMIND MYSELF WHAT
I CAN TALK ABOUT IN THE SHORT
TIME THAT WE HAVE.
SO I SELECTED THINGS THAT I KNOW
SOMETHING ABOUT, OR THAT I AGREE
WITH.
[LAUGHTER]
SO THE FIRST ONE IS RESEARCH
INTO TRANSCRIPTOMIC DATA BULK
AND SINGLE CELL RNA SEQ.
TOMORROW YOU'RE GOING TO HEAR AN
EXAMPLE OF A STUDY LIKE THAT,
BUT I THINK WE NEED MORE
STUDIES.
YOU'LL HEAR IT FROM ANDREW
GRIMSON.
MORE NEEDS TO BE DONE IN THAT
AREA TOO.
I ALSO AGREE THAT WE NEED TO
EXPAND THE ME/CFS BIOREPOSITORY,
BECAUSE WHEN I STARTED GETTING
IN THE FIELD, THE THING THAT WAS
MOST DAUNTING TO ME WAS WHERE
ARE THE SAMPLES, WHERE AM I
GOING TO GET THEM.
BUT ALSO IT'S IMPORTANT TO THINK
ABOUT HAVING A BIOREPOSITORY
FROM CLINICAL TRIALS IN WHICH
PEOPLE EITHER GET BETTER OR
WORSE AS A RESULT OF THE
CLINICAL TRIAL.
WE KNOW HOW TO MAKE PEOPLE WORSE
IF THEY HAVE ME/CFS.
WE DON'T KNOW HOW TO MAKE THEM
BETTER.
SO IF A CLINICAL TRIAL MAKES
SOMEONE BETTER, HAVING SAMPLES
OF SOMEONE WHEN THEY WERE WORSE
AND SOMEONE WHEN THEY'RE BETTER
WOULD BE EXTREMELY VALUABLE.
SO YOU HEARD -- THIS IS AN
EXAMPLE OF -- ANOTHER EXAMPLE OF
THE OVERLAP BETWEEN METABOLISM
AND IMMUNOLOGY IN THAT YOU HEARD
A TALK FROM JESSICA MAYA ABOUT
IT. ABOUTIT. CELL EXHAUSTION.
THIS NEEDS TO BE EXPLORED TO
FIND OUT IF IT IS REALLY T-CELL
EXHAUSTION GOING ON AND IF IT IS
GOING ON, WHY IS IT HAPPENING.
I WAS ALSO VERY IMPRESSED BY THE
WEBINAR ON -- THE TALK AT THE
WEBINAR ON RAMON SPECTROSCOPY.
THIS SEEMS LIKE A VERY PROMISING
METHOD THAT WE MIGHT BE ABLE TO
USE IN CLINICAL TRIALS AND ALSO
TO USE MORE TO FIND OUT WHAT'S
HAPPENING IN ME/CFS.
SO THEN WITH REGARD TO
COMPUTATION, A LOT OF THE
STUDIES ON METABOLISM ARE ON THE
EASIEST TO ACQUIRE CELL, WHICH
ARE IMMUNE CELLS, BUT IT WOULD
BE IMPORTANT TO LOOK AT TISSUE
METABOLISM IN MUSCLES AND IN THE
CENTRAL NERVOUS SYSTEM AS WELL,
ACCORDING TO THE RESEARCH
PRIORITIES PRESENTED IN THIS
METABOLISM WEBINAR.
I ALSO WANTED TO HIGHLIGHT THAT
WE SHOULD BE LOOKING OBJECTIVELY
AT METABOLITE MARKERS DOING
UNBIASED ANALYSIS.
WE STILL NEED TO DO UNBIASED
ANALYSES TO FIND METABOLIC
MARKERS.
ONE THING THIS GROUP SUGGESTED
WAS TO ESTABLISH CONNECTIONS
BETWEEN THE METABALOME WITH
PHYSICAL -- PHYSIOLOGICAL
MEASURES AND FUNCTION, AND I
WOULD ADD TO THAT, WITH CLINICAL
DATA, BECAUSE IT'S EXTREMELY
POWERFUL TO CORRELATE YOUR ASSAY
WITH CLINICAL DATA IF IT
CORRELATES WITH SEVERITY, FOR
EXAMPLE, THEN IT REALLY
REASSURES YOU THAT WHAT YOU'RE
MEASURING MIGHT HAVE SOME
RELEVANCE TO THE DISEASE.
THERE ARE A LOT OF
RECOMMENDATIONS FOR CLINICAL
TRIALS HERE, NOT FOR WHICH DRUGS
TO TRY BUT HOW TO PERFORM THEM.
AND ONE THING THAT I DECIDED TO
HIHIGHLIGHT HERE WAS, WE DO HAVE
THIS PROBLEM OF METABOLOMICS
HETEROGENEITY AMONG INDIVIDUALS,
AND ONE OF THE PROBLEMS IS IT'S
SO DIFFICULT TO CONTROL PEOPLE'S
DIETS AND WHAT DRUGS THEY MIGHT
BE TAKING AND EVERYTHING ELSE,
SO THAT'S ALWAYS A CONFOUNDING
ASPECT OF ANY SORT OF
METABOLOMICS STUDY.
SO THE LAST ONE I'M GOING TO
MENTION IS THE GENOMICS WEBINAR,
WHICH WAS QUITE FASCINATING, I
THOUGHT, BECAUSE IT HAD A HIGH
PERCENTAGE OF UNPUSH LISHED
DATA.
OF I THINK THERE'S GOING TO BE A
LOT OF INTERESTING INFORMATION
COMING OUT OF THE LARGE GWAS
STUDY IN THE U.K., AND WE HEARD
THIS MORNING FROM IAN LIPKIN
THAT HE'S INTERESTED IN
COLLABORATING WITH THE UK AND
WORKING WITH THE COHORT TO DO
GENETIC STUDIES.
I THINK IT WILL BE IMPORTANT TO
FIND COMMON DNA VARIANTS THAT
MIGHT BE CORRELATED WITH ME/CFS
IN ORDER TO UNDERSTAND THEIR
ROLE IN DISEASES, NOT JUST RARE
VARIANTS.
IT IS IMPORTANT TO KNOW HOW
THESE GENETIC VARIATIONS CAN BE
CONTRIBUTING AND WE ALWAYS THINK
ABOUT WHAT'S CAUSING THEM TO GET
ME/CFS BUT I THOUGHT IT WAS
INTERESTING THAT THIS GROUP CAME
UP WITH THIS POINT THAT WE
SHOULD FIND OUT WHAT MIGHT BE
PROTECTIVE OF WHAT VARIANTS
MIGHT PROTECT YOU FROM GETTING
ME/CFS.
SO THEN WITH REGARD TO MORE ON
THE GENETIC SUSCEPTIBILITY, I
THINK USING POPULATION-LEVEL
DATA FOR, AGAIN, UNBIASED
SCREENS FOR GENETIC VARIANTS,
ASSOCIATED WITH ME/CFS IS GOING
TO BE QUITE IMPORTANT, AND
LOOKING AT WHAT FUNCTION THESE
VARIANTS MIGHT HAVE IN THE
DISEASE IS ALSO REALLY
ESSENTIAL.
AS YOU CAN SEE, THIS IS QUITE A
LONG LIST.
WITH REGARD TO CASE CONTROL AND
FAMILY STUDIES, THE SUGGESTION
IS TO COMBINE FAMILY AND
POPULATION-BASED STUDIES,
BECAUSE FAMILY STUDIES CAN BE
QUITE INFORMATIVE.
AND THEN AGAIN, EPIGENETICS, SO
WE HEARD IN THE YOUNG
INVESTIGATOR TALKS ABOUT AN
EPIGENETIC ASPECT OF MEFERS AND
ME/CFS ANWE REALLY NEED TO UNDEE
GENETIC FACTORS INVOLVED IN THE
CONDITION.
SO WITH REGARD TO ME/CFS
CLINICAL TRIALS, THE SUGGESTION
IS TO PRIORITIZE INTEGRATION OF
GENETIC INFORMATION WITH OTHER
RESEARCH FINDINGS, AND WE HEARD
ABOUT MULTI-OMICS TODAY ALSO,
AND I THINK MULTI-OMICS IS ALSO
VERY CRITICAL.
GETTING A LOT OF DATA ON THE
SAME POPULATION, IT WILL BE VERY
INFORMATIVE.
SO DO YOU WANT TO TAKE OVER?
[APPLAUSE]
>> SO THANK YOU, MAUREEN AND
CINDY.
SO AGAIN, WE HAVE TWO WEBINARS
COMING UP ON JANUARY 5TH AND THE
11TH, SO YOU CAN GO TO THE NINDS
WEBSITE, IF YOU GO TO THAT
WEBSITE, RATHER THAN TAKING DOWN
THIS URL, IF YOU GO TO THE
WEBSITE AND JUST TYPE IN ME/CFS
RESEARCH ROAD MAP, IT WILL TAKE
YOU TO THE PAGE.
AND THAT WILL ALSO TAKE YOU TO
THE PAGE FROM OUR CONTRACTOR,
ROSAROSELI ASSOCIATES, RECORDINS
FROM MOST OF THE WEBINARS AND
TRANSCRIPTS ARE POSTED AND THEY
WILL ALL EVENTUALLY BE POSTED AT
THIS SITE.
IF YOU WANT TO PROVIDE FEEDBACK,
YOU CAN GO TO THIS -- OR SEND AN
EMAIL TO ME/CFS RESEARCH ROAD
MAP AT NINDS.NIH.GOV.
THE BEST WAY TO GET UPDATES
ABOUT WHAT'S HAPPENING WITH THIS
INITIATIVE AND OTHER ACTIVITIES
AT NIH IS TO SIGN UP FOR THE NIH
ME/CFS LISTSERV AT THIS WEBSITE
IF YOU GO TO NIH.GO.GOV/ME/CFS,
THAT'S THE WEBSITE FOR ME/CFS
AND THE TRANS ME/CFS WORKING
GROUP AND WHERE CAN YOU FIND
ADDITIONAL INFORMATION.
AND AS I SAID, WE'LL SOLICIT
INFORMATION AND FEEDBACK FROM
THE COMMUNITY ON THE RESEARCH
PRIORITIES IDENTIFIED, AND THIS
IS COMING SOON, SO WE'RE GOING
TO ROLL OUT PART OF IT AS WE'RE
COMPLETING THE OTHER FOUR
WEBINARS.
AND JUST ONE LAST PLUG BEFORE I
CALL CINDY AND MAUREEN BACK UP,
WE DO HAVE AN EXISTING BIO
REPOSITORY.
SO NINDS HAS BEEN -- NIH HAS
BEEN SUPPORTING A DATA
MANAGEMENT COORDINATING CENTER
AT RTI FOR FIVE YEARS, WHICH WAS
JUST RENEWED FOR ANOTHER FIVE
YEARS, AND THEY HAVE DEVELOPED,
TOGETHER WITH THE NINDS
CONTRACTED BIOREPOSITORY AT
INDIANA UNIVERSITY CALLED
BIOSEND, THE DATA COORDINATING
CENTER DEVELOPED A TOOL CALLED
SEARCH ME/CFS, WHERE YOU CAN GO
ONLINE AND SEARCH FOR WHAT
BIOSPECIMENS ARE AVAILABLE, AND
THERE'S CLINICAL DATA THAT
CORRELATES AND GOES ALONG WITH
THOSE BIOSPECIMENS.
WHAT'S THERE CURRENTLY IS FROM
THE CFI STUDY THAT WAS DONE
SEVERAL YEARS AGO, WHICH WAS A
MULTISITE STUDY, AND WE'VE JUST
GOTTEN PERMISSION TO AND WE'RE
WORKING WITH THE CDC TO INCLUDE
LOTS MORE BIOSPECIMENS FROM THE
MCAM STUDY THAT WAS DONE, AGAIN,
ANOTHER MULTISITE STUDY WITH
EXTENSIVE CLINICAL DATA, SO
WE'RE WORKING WITH THE CDC
TOGETHER WITH OUR DATA
COORDINATING CENTER.
SO QUINN BARNETT AND MEGAN
CARNES ARE HERE FROM RTI, THEY
HAD A TABLE UP WHERE WE WERE ON
THE TERRACE, SO STOP BY AND SEE
THEM IF YOU HAVE ANY QUESTIONS
OR NEED INFORMATION ABOUT EITHER
SEARCH ME/CFS OR MAP ME/CFS.
SO WITH THAT, IT'S ALMOST 5:00.
SO A COUPLE OF QUICK QUESTIONS?
JEFF.
NO, HE DOESN'T HAVE A QUESTION.
ANY QUICK QUESTIONS?
BECAUSE WE'RE TWO SECONDS AWAY
FROM 5:00.
OKAY.
IF NOT, THANK YOU.
AND WE'LL BE AROUND, SO IF YOU
HAVE QUESTIONS ABOUT THE ROAD
MAP PROCESS, JUST CHECK US OUT.
THANK YOU.
SO WE'LL START AT 9:00 TOMORROW,
SO HAVE A GOOD EVENING AND WE
LOOK FORWARD TO SEEING YOU 10392 06:26:07,911 TOMORROW.