>> GOOD MORNING, EVERYONE.
WELCOME TO THE SECOND TALK IN
THE BIOWULF SEMINAR SERIES.
THIS YEAR WE, THE HIGH
PERFORMANCE COMPUTING GROUP ARE
CELEBRATING 25 YEARS OF
PROVIDING SCIENTIFIC, SUPER
COMPUTING SERVICES TO THE NIH
INTRAMURAL RESEARCHERS.
STARTING 1999 WITH 40 BOXES AND
SHELVES AND ONLY 14 USERS, 1-4,
BIOWULF HAS GROWN NOW TO 4000
USERS AND MORE THAN 2400 --
SORRY, COMPUTE NODES AND 2400
ACTIVE USERS.
TODAY WE ARE HONORED TO HAVE
DR. RUTH NUSSINOV AS OUR
SPEAKER.
DR. NUSSINOV OBTAINED DEGREE
FROM UNIVERSITY OF WASHINGTON
AND RUTGERS, DISSERTATION
DEVELOPED FIRST ALGORITHM FOR
FOLDING OF RNA.
THIS IS STILL TAUGHT IN
BIOINFORM ATTICS CLASSES IN THE
U.S. AND IN EUROPE.
SHE WAS A POST-DOC RESEARCH
ASSOCIATE IN THE WEISMAN
INSTITUTE, BERKELEY, HARVARD AND
TEL AVIV UNIVERSITY.
SHE JOINED THE SCHOOL OF
MEDICINE IN TEL AVIV UNIVERSITY
WHERE SHE BECAME A FULL
PROFESSOR AND LATER BECAME
ASSOCIATED WITH NATIONAL CANCER
INSTITUTE IN FREDERICK NATIONAL
LABORATORY FOR CANCER RESEARCH.
ELECTED FELLOW IN SEVERAL
SOCIETIES, WON MULTIPLE NATIONAL
AND INTERNATIONAL AWARDS AND HAS
SERVED IN SEVERAL ROLES IN THE
SCIENTIFIC COMMUNITY.
DR. NUSSINOV'S LAB HAS MADE VERY
EFFECTIVE USE OF BIOWULF.
YEAR AFTER YEAR, GROUP
CONSISTENTLY USING 10 TO 20% OF
ALL PSYCH EMS IN THE HPC
CLUSTER.
JUST THIS YEAR, HER GROUP HAS
USED 123 MILLION CPU HOURS.
SO FAR IN 2024.
THE YEAR HAS NOT ENDED YET,
HOPEFULLY MORE.
THIS NUMBER CORRESPONDS TO 40%
OF USAGE OF NCIAS A WHOLE.
USED GPU HOURS THIS YEAR AND
JUST TO MENTION A FEW OF THE
APPLICATIONS THAT THE GROUP USES
ARE AMONG OTHERS MD, AMBER,
BROMAX, CHARM, ROSETA, AMONG
OTHER APPLICATIONS.
DR. RUTH NUSSINOV TALK TODAY
TITLED SCIENCE IS ABOUT
CURIOSITY AND ASKING SIGNIFICANT
QUESTIONS.
WELCOME.
[APPLAUSE]
>> SO TO BEGIN WITH, OF COURSE,
I WOULD LIKE TO THANK FIRST THE
HELIX, WHICH IS WHERE WE STARTED
AND THEN THE BIOWULF AND TO SAY
THAT WITH ALL OF THIS TIME
OBVIOUSLY, LIKE ANTONIO QUOTED,
WITHOUT FIRST HELIX AND THEN THE
BIOWULF, WE WOULDN'T BE WHERE WE
ARE.
I'M SPEAKING FOR EVERYBODY WHEN
I SAY HOW GRATEFUL WE ALL ARE
FOR THESE WONDERFUL FACILITIES,
MAINTAINING THEM, GO IING FORWA
WITH THEM, IMPLEMENTING NEW
ADVANCES ALWAYS, NOT JUST
SITTING, YOU KNOW, WHERE YOU
ARE, BUT ALWAYS THE VERY LATEST
AND FOR US, IT HAS BEEN A GOD
SEND AND WE ARE VERY, VERY
GRATEFUL.
AND TODAY, I'LL DISCUSS SOME OF
IT, OF COURSE, IT IS NOT
POSSIBLE TO DISCUSS ALL.
SO THE TITLE OF MY TALK IS A
LITTLE UNUSUAL.
AND IT CAME ABOUT -- LET ME SEE,
IT CAME ABOUT FROM -- IT CAME
ABO
ABOUT, FROM THIS ISSUE, PHYSICS
TODAY, I DON'T KNOW IF ANY OF
YOU ARE FAMILIAR WITH THIS, IT
IS ACTUALLY A VERY GOOD
PUBLICATION, WHICH IS WE SHOULD
PREPARE AND PUBLISHED BY
AMERICAN INSTITUTE OF PHYSICS
AND I GET IT BECAUSE I AM ON THE
EDITORIAL BOARD OF PHYSICAL
BIOLOGY FOR MANY YEARS.
SO A FEW MONTHS AGO, YOU CAN
SEE, JANUARY 2024, I RECEIVED
THIS SPECIAL ISSUE AND I SEE
GO
GOODNESS, THEY SHOWED A
WOODPECKER, SOMETHING FROM
PHYSICS TODAY I DID NOT EXPECT.
THEN I LOOK AND I SEE, OH,
PECKING WITHOUT HEADACHES AND I
THINK TO MYSELF, INDEED HOW COME
I NEVER THOUGHT OF IT.
HOW COME THE BIRD HITS THE TREE
SO MUCH AND STILL DOES NOT GET
HEADACHE?
SURELY WE WOULD HAVE.
AND YES, SO WHY WOODPECKERS
DON'T GET CONCUSSIONS?
I OPENED THE ISSUE AND I SEE
THIS PIECE WRITTEN BY -- OH, OR
DISCUSSING THE WORK OF OBVIOUSLY
BY THE PAPER WRITTEN, BUT
DISCUSS
DISCUSSING THE WORK OF TWO
SCIENTIFICS FROM BELGIUM, FROM
UPENN UNIVERSITY, PROFESSOR AND
HIS PhD STUDENT AND FROM WHAT I
UNDERSTAND, THIS PARTICULAR
QUESTION IS THE TOPIC OF THE PhD
OF THE STUDENT.
SO I LOOK AT IT AND THE STORY IS
AS FOLLOWS.
IN THE 1970S, PSYCHIATRIC MAY
AND CO-WORKERS SAW POTENTIAL
LEARNING FROM AN TOM CAL
ADAPTION IN WOODPECKER TO
WITHSTAND REPEATED BLOWS.
BUT, OBVIOUSLY, THEY WERE A
LITTLE SKEPTICAL.
IN THE LANSET ARTICLE IN 1976,
THEY QUESTIONED ONGOING
HYPOTHESIS AT THE TIME AS TO THE
CRANEIEL ABSORPTION OF SHOCK
WHICH IS PART OF ADAPTION AND
THEY WERE ASKING, IF THE BEAK
ABSORBED MUCH OF ITS OWN IMPACT,
THAT IS TO SAY COMING BACK FROM
THE TREE TO THE BRAIN, THE
UNFORT
UNFORTUNATE BIRD WOULD HAVE TO
POUND EVEN HARDER.
SO HOW TO UNDERSTAND THIS?
SO HOW DOES THE WOODPECKER DO
IT?
SOME THINK WOODPECKERS STRIKE
TREES WITH THEIR BEAKS AT SPEEDS
OF 20 KILOMETERS PER HOUR AND
CAN REACH RATES OF 30 TIMES PER
SECOND DURING DRUMMING.
A SUDDEN DECELERATION WHEN THEY
HIT A TREE, RIGHT? WOULD EXCEED
THE THRESHOLD THAT WOULD RENDER
A CONCUSSIVE BLOW TO THE HUMAN
BRAIN.
BUT, THE BIRD'S BRAINS ARE
UNHARMED, LEADING THE COMMUNITY
TO BELIEVE IN THIS SPONGY BONE
HYPOTHESIS.
SO HERE IS OUR BIRD AND THAT
SPONGY BONE OF CRANIAL ABS
ABSORPTION OF THE SHOCK, SHOCK
ABSORBERS AND HELMETS.
BUT, YES, A SHOCKWAVE TROUBLING
FROM THE BEAK WOULD BECOME
CUSHION CUSSIONED EXCEPT BIRD
WOULD LOSE PART 'VE BUILT-IN
ENERGY BY BEAK SHOCK ABSORBER.
SO THAT THEN READ 30 YEARS
LATER, IN 2006, LAUREN GIBESON
FROM THE PHYSICS DEPARTMENT AT
MIT TO CARRY OUT SOME
CALCULATIONS, LEADING HER TO
SUGGEST THAT THE ANSWER LIES IN
THE MASS DIFFERENCE BETWEEN THE
HUMAN AND THE BRAIN AND THE
BIRDS BRAINS.
BIRDS CAN WITHSTAND THE
DECELERATION BECAUSE OF THE
SMALL SIZES OF THEIR BRAIN.
WHICH DISTRESS THAT SHOWED
DURINGATION OF THE IMPACT AND
THE ORIENTATION OF THE SKULL.
THE PRESSURE ON THE BRAIN IS
PROPORTIONATE TO DECELERATION
AND THE CT, BRAIN LENGTH IN
DIRECTION OF IMPACT ALL TOGETHER
IS ONE-SEVENTH OF THE HUMAN AND
THIS IS THE EQUATION THAT SHE
USED.
SO STILL CONTINUING THE SAGA OF
THE WOODPECK ERS AND THE TREES
AND THE BRAIN CONCUSSIONS, TWO
YEARS AGO, AN INTERNATIONAL TEAM
FROM EUROPE AND CANADA TOOK IT
UP AGAIN, ASKING SO HOW DOES THE
BIRD AVOID INJURY?
SO THEY LOOKED AT THREE SPECIES
AND RECORDED HIGH-SPEED VIDEOS
IN EUROPE AND CANADA, BUT NO
CONSISTENT DECELERATION OF THE
BRAIN VERSUS THE BEAK, THUS NO
CUSS
CUSSIONING AND THE MECH AN
CALAMITY
CALAMITY CALCULATION SHOWED IF
THERE WAS THE ENERGY WOULD BE
REDUCED, THUS THE TREE
PENETRATION DIPPED.
AND HERE THEY TOOK THE X-RAY
COMPUTER TOMOGRAPHY,
RECONSTRUCTIVE OF THE LEFT PART
OF THE SKULL AND ENLARGED CIRCLE
SHOWS THE SPONGY AND THE
ENLARGED CIRCLE SHOWS THE SPONGY
BRAIN LOCATED AT THE INTERFACE
BETWEEN THE BEAK AND THE CRANIUM
AS SUGGESTED THAT WHICH RELATES
TO HYPOTHESIS FOR EACH SERVING
AS SHOCK ABSORBERS.
EXCEPT WHAT THE GROUP OBSERVED
IS THE HEAD FUNCTIONS AS STIFF
HAMMER.
SO YES, THE SIZE OF THE BRAIN OF
THE WOODPECKER IS MUCH SMALLER
THAN THAT OF THE HUMAN AND THE
ISSUE IS NEWTON SECOND LAW OF
MOTION.
WE KNOW THE NET FORCE EQUALS NOW
TIMES ACCELERATION, A LARGE NET
FORCE ACTING ON AN OBJECT HERE,
THE BRAIN, CAUSES A LARGER
ACCELERATION AND OBJECT WITH
LARGER MASS REQUIRE MORE FORCE
TO ACCELERATE.
SO BIRDS CAN WITHSTRAND
ACCELERATION BECAUSE OF SIZE OF
BRAIN AND REDUCES STRES AND
SHOWS DURATION OF THE IMPACT AND
ORIENTATION OF THE SKULL.
SO HERE IS OUR LITTLE
WOODPECKER.
THIS OF COURSE WE DON'T DO WITH
THE BIOWULF.
[LAUGHTER]
>> BUT I THOUGHT I WOULD JUST
BRING THE QUESTIONS HERE, THIS
IS PHYSICS, THE QUESTIONS THAT
PEOPLE ASK AND OVER SO MANY
YEARS PRACTICALLY 50 YEARS, IN
CANADA, AT MIT, STILL WANTING TO
UNDERSTAND BASIC PROCESSES
TAKING PLACE IN ANIMAL LIFE,
RIGHT? OUR QUESTIONS ARE ON THE
MOLECULAR AND CELLULAR LEVELS.
SOME EXAMPLES, QUESTIONS THAT WE
ASK USING ALSO THE BIOWULF IS
EPIDEMIOLOGICAL SURVEYS OBSERVE
THAT PEOPLE WITH AUTISM IS
HIGHER RISK OF CANCER.
THOSE WITH SCHIZOPHRENIA BY AS
MUCH AS 50%.
WE WERE WONDERING WHY THE HIGHER
RISK.
MUTATIONS CAN INVOLVE
SUBSTITUTIONS OF SINGLE AMINO
ACID IN PROTEIN SEQUENCE, THAT
CHANGE CAN CAUSE CANCER.
EXACTLY HOW?
SOME OF THE MUTATIONS ARE MORE
AGGRESSIVE THAN OTHERS.
WHY?
WHAT IS DIFFERENT ABOUT SUCH
MUTATIONS?
OUR AIM OVER THE YEARS HAS BEEN
UNDERSTANDING THE MECHANISMS ON
THE BASIC STRUCTURAL AND
CELLULAR LEVEL AND WE DID THIS
FRAMEWORK WE HAVE BEEN FOCUSING
LARGELY ON THE ONCOGENIC
CROSS-SECTIONING, WE STARTED ON
SIGNALLING IN 2013, JUST A FEW
MONTHS BEFORE VARMOS, THEN
DIRECTOR OF NCI ANNOUNCED
PROJECT OF NATIONAL INTEREST.
WE SENSED THIS IS DIRECTION TO
GO, RUSS IS SO CENTRAL, SO
CRUCIAL IN CANCER AND THE SECOND
THING WE REALIZE BECAUSE IT IS
SO IMPORTANT, CHANCES ARE MANY
EXPERI
EXPERIMENTALISTS WOULD FOCUS ON
IT AND EXPERIMENTAL DATA WOULD
COME OUT, WHICH IS ESSENTIAL FOR
COMPUTATIONAL BIOLOGY BECAUSE
YOU BASE YOUR SIMULATIONS ON
EXPERI
EXPERIMENTAL DATA AND THEN YOU
WANT TO TEST WHAT YOU GET AGAIN
WITH EMERGING EXPERIMENTAL DATA.
SO THIS IS CRUCIAL.
ALL THE PROTEINS THAT YOU WILL
SEE HERE ARE THOSE CIRCLED ONES
ARE THOSE THAT WE HAVE EITHER
WORKED ON DURING 10 OR 11 YEARS
OR ARE WORKING ON.
SO FIRST, ACT VAGSZ ACTIVATION
OF RAS FROM GPT AND GPT
ACTIVATION.
WHEN I SAY MECHANISMS, THE TOP,
THE TITLE, WHAT I MEAN IS AUTO
INHIBITION OF THE PROTEIN AND
ACTIVATION MECHANISM.
ACTIVATION PHYSIOLOGICAL
CONDITIONS AND IN CANCER
MUTATIONS.
SO YES, PROTEIN ARE INVOLVED IN
RAS ACTIVATION WE HAVE LOOKED
AT.
RAS MAKE THE VASTLY IMPORTANT
PATHWAY, MAPK LEADING TO CELL
PROLIFERATION.
HERE ALSO CASE ARE AND ERC, WE
LOOKED AT THESE AND LEUKEMIA.
BCRA ABL, A KINASE INVOLVED IN
LEUKEMIA AND RELATES TO RAS.
THE SECOND MAJOR PATHWAY,
PI3KAKT, WE LOOKED AT LIPID
KYNASE, TUMOR REPRESSAL.
THIS PATHWAY LEADS TO
CONTRIBUTES TO CELL GROWTH AND
BOTH OF THESE, TWO PATHWAYS,
MAPK AND PI3KAKT, LEAD TO THE
CELL CYCLE, WHICH SEVERAL
STAGES, AS YOU CAN SEE.
AND IN EACH STAGE, THERE IS A
KEY KINASE, CDK46 AND CDK2 WITH
PARTNER CYCLINE.
WE ARE FOCUSING ON ALSO THE CELL
CYCLE.
CELL CYCLE, ENTER ERK, AKT, PDK1
AND NF1, ALSO, WHICH IS A GAP IN
RAS.
TO GIVE YOU A FLAVOR OF THE
QUESTIONS THAT WE ASK, AND THAT
THE BIOWULF NOW IS SORT OF
CRUNCHING FOR THE CELL CYCLE,
YOU CAN SEE THE LENGTH OF TIME
SPENT IN THE CELL CYCLE ON THE
DIFFERENT STAGES IS NOT THE SAME
G1 IS MUCH LONGER THAN S.
AND THEN THERE IS THE TRANSITION
FROM G1 TO S.
G1 ON AVERAGE IS ABOUT 12 HOURS
IN HUMAN, THE TRANSITION IS
ABOUT TWO ON AVERAGE.
SO ONE OF THE QUESTIONS WE ASK,
WHY IS THE MOTHER NATURE CHOOSE,
HOW IS IT OPTIMIZE THE CDK4 AND
CDK6, TO WORK OVER SUCH MUCH
LONGER TIME SCALE AND THE CDK2,
WITH CYCLINE A SPENDS HERE ABOUT
TWO HOURS ON TRANSITION.
WHAT IS DIFFERENT BETWEEN CDK4
AND CDK2?
I SHOULD SAY THESE QUESTIONS ARE
VERY IMPORTANT.
FIRST OF ALL, WE WANT TO
UNDERSTAND, IT IS THE BASIC
BIOLOGY OF THE CELL.
SECOND, THESE CDK'S IS OTHER
PROTEINS IN THE RAS SIGNALLING
NETWORK, A MAJOR TARGETS IN DRUG
DISCOVERY.
SO AS I'LL SHOW IN A MINUTE, IF
YOU HAVE CONFIRMATIONS THAT ARE
GENERATED DURING ACTIVATION, IT
CAN HELP YOU IN DESIGNING BETTER
OR MORE OPTIMIZED DRUGS TO
TARGET THESE CONFORMATIONS.
SO HERE COMING BACK TO THE
QUESTION ABOUT MUTATION, SO HERE
FOR EXAMPLE, WE SEE K-RAS, THE
MOST ONCOGENIC FORMATION OF THE
RAS FAMILY AND HERE WE LOOK AT
ITS MOST AGGRESSIVE MUTATIONS,
RAS HAS MANY MUTATIONS, THE MOST
AGGRESS ITCH IS G12V.
G12V MEANS RESIDUE NUMBER 12 IS
G
GLYCINE, WHY THIS MUTATION IS
MOST AGGRESSIVE IN CANCER?
WE CARRIED OUT SIMULATIONS,
USING THE BIOWULF AND THE
SIMULATION SHOWED THAT THE
INACTIVE GDP K-RAS SPENDS MORE
TIME IN THE ACTIVE-LIKE STATE
THAN ANY OTHER MUTATIONS.
OUR COLLEAGUES CARRIED OUT NMR
EXPERIMENTS AND CONFIRMED OUR
PREDICTIONS.
THE LONGER TIME, THE LONGER THE
TIME THE PROTEIN AND THIS IS --
THIS HOLDS FOR ALL PROTEINS, OF
COURSE, ONCOGENES REPRESSOR ARE
OPPOSITE.
LONGER TIME THEY SPEND IN THE
ACTIVE STATE, THE LONGER THE
TIME THEY CAN ACTIVATE THE
ONCOGENIC PATHWAY, FOR EXAMPLE,
MAP-K, WHICH IS THE NUMBER ONE
PROLIFERATION PATHWAY IN CANCER.
WHY DOESN'T IT MOVE?
OH.
DID I SKIP ONE?
I DON'T THINK SO.
OKAY.
HERE IS AN EXAMPLE.
WHY WHAT WE CAN LEARN FROM
KINASE ACTIVATION AND HERE WE
CAN SEE THIS IS VERY IMPORTANT
KINASE, IN PI3KAKT, PDK1 AND
CELL GROWTH PATHWAY AND IS MAJOR
TARGET IN DRUG DISCOVERY
CONSEKWENTLY AND WHAT WE OBSERVE
HERE, WHAT YOUR BE GLAND
OBSERVED HERE IS THAT IN THE
ACTIVATION, WHAT YOU OBSERVE, SO
THE DRUG DESIGNERS USE CRYSTAL
STRUCTURE TO DESIGN THE DRUGS,
BUT IN THE SIMULATIONS, WE
ACTUALLY SEE HERE OF THE MUTANT,
WE ACTUALLY SEE THAT THE SPACE
IS LARGER.
HERE IT IS LONGER, THE ACCESS,
SUGGESTING THAT THE DRUG COULD
BE OPTIMIZED FURTH ER OPTIMIZED.
SO HERE -- I DON'T KNOW IF I --
YES, I MISED THIS ONE.
ACTIVATION, AFTER THE MUTATIONS.
SO HERE IS I WONDER, YEAH, OKAY.
HERE WE SEE ACTIVATION OF RAF,
TOP OF MAP-K PATHWAY, SO WHAT WE
SEE IS THE RAF, HERE, ACTIVATED
BY RAS HERE TO RAS TO RAF
MOLECULES, RAF HERE IS IN THE
ACTIVE STATE BECAUSE IT IS BOUND
TO RAS, AND THIS IS THE
MEMBRANE, WHICH THIS BINDING
PROMOTES OPENING OF RAF,
TRANSITIONING IT FROM INACTIVE
STATE TO THE ACTIVE STATE.
SO WHAT WE SEE HERE, THIS IS AN
EXAMPLE OF WHAT HAPPENS IN
KINASE, AND OTHER PROTEIN
ACTIVATION.
NORMALLY AND PHYSIOLOGICAL
CONDITIONS, MOST OF THE C
CONFORMATIONS OF THE PROTEINS
ARE IN THE INACTIVE STATE.
THIS IS BECAUSE THE ENERGY IS
LOWER.
SO MOST OF THE CONFORMATIONS
PREFER TO BE THIS HERE, IN
ACTIVATION, IT SWITCHES, NOW
MOST OF CONFORMATIONS ARE IN THE
ACTIVE STATE.
WHAT CAUSES THE SWITCH?
THIS BY STABLE SWITCH IS BINDING
TO THE MEM BRACE AND TO RAS
BECAUSE IT STABILIZES THIS OPEN
CONFORMATION, WHICH OTHERWISE IS
VERY UNSTABLE, VERY UNSTABLE
MEANS LOWER POPULATION TIME BUT
STABILIZATION LEADS TO THE SHIFT
BECAUSE IT IS MORE STABLE,
HIGHER POPULATION TIME AND
MUTATIONS MEAN PHYSIOLOGICAL
ACTIVATION.
THEY ALTER THE RELATIVE
STABILITY OF THE ACTIVE VERSUS
THE INACTIVE STATE.
AND HERE, DISCUSS THIS MUTATION
AND HERE THIS PARTICULAR
MUTATION IS PRIMARY IN MELANOMA.
YEAH.
WE ALREADY SAW THIS ONE.
SO WE ARE INTERESTED IN
MECHANISMS OF ACTIVATION AND
SIGNAL
SIGNALLING, FIRST TO UNDERSTAND
AND SECOND, THEY CAN HELP DRUG
DISCO
DISCOVERY AND REGIMEN OF THE
DRUG DISCOVERY.
MECHANISMS OF ACTIVATION CAN
HELP DISCOVERY OF SINGLE DRUGS,
HOWEVER, WE KNOW RESISTANCE IS
EXPECTED.
MECHANISMS ARE CELL SIGNALLING
CAN HELP DECIDE DRUG
COMBINATIONS, COMBINATIONS CAN
LESSEN RESISTANCE FOR MOBILITY.
SO HERE WE CAN SEE THE DRUG
RESISTSANCE PROBLEM.
ON THE LEFT-HAND SIDE HERE, THIS
IS WHAT CAN HAPPEN IN A TUMOR IN
CANCER.
ALL CELLS, WHICH HAVE THIS RED
DOT, HAVE A COMMON DRIVER
MUTAT
MUTATION.
AND HERE ONE THAT HAS A
DIFFERENT, RARE MUTATION,
CHANCES ARE THAT WHEN THE TUMOR
IS SEQUENCED TO FIND OUT WHICH
MUTATION DOES THE INDIVIDUAL
HAVE BECAUSE SO MANY ARE -- HAVE
FREQUENT MUTATION, THEY WILL BE
SEQUENCED.
ONCE THEY -- THE DRUG IS
ACCORDINGLY TARGETS THEM, THEN
DRUG TREATMENT TARGETS THIS
COMMON DRIVER MUTATION
DECIMATING ALL OF THESE CELLS.
WHAT HAPPENS NOW?
NOW ONLY THESE CELL REMAINS
BECAUSE EACH REAL MUTATION IS
RESISTANT TO THAT SPECIFIC DRUG.
SO NOW THAT THESE CELLS ARE
DECIMATED, THESE PARTICULAR
PROTEIN, A PARTICULAR CELL KEEPS
DIVIDING AND NOW THE TUMOR IS
RESISTANT TO THIS PARTICULAR
DRUG.
AND SO IT GROWS.
NOW THIS, THESE PARTICULAR
MUTATION WOULD BE TARGETED AND
AGAIN, I -- WE DON'T SHOW HERE
REPEATEDLY THIS, AND AGAIN, IT
COULD HAPPEN THAT IT COULD, ONE
WOULD EXPECT THAT THE TARGETED
CELLS WITH TARGETED MUTATION
WOULD BE DECIMATED AND ANOTHER
CELL WITH RARE RESISTANT
MUTATION WOULD REMAIN.
UNTIL YOU CAN DO IT MULTIPLE
TIMES AND HOPEFULLY EVENTUALLY
YOU HAVE THE SET, THE TUMOR
WITH, WITHOUT CANCER, WITHOUT
ONCOGENIC MUTATIONS.
SO THIS IS WHAT CAN HAPPEN IF
YOU GIVE A DRUG TO A CANCER
PATIENT AND WHY EVERY TIME
RESISTANCE COMES UP AND THE
CANCER RETURNS.
INSTEAD YOU CAN DO SIMULTANEOUS
TREATMENT, NOT JUST A DRUG THAT
WOULD HIT THIS ONE, BUT A
PRIORITY THIS ONE.
SO THE POINT IS THE DRUG
COMBINATION HAS A BETTER CHANCE.
OF COURSE, THERE IS A PROBLEM
HERE.
HOW TO SELECT THE COMBINATION.
HOW DOES THE ONCOLOGIST KNOW
WHICH IS OPTIMAL COMBINATION,
WHAT TO EXPECT?
OKAY, ONCOLOGIST KNOWS WHICH IS
THE FREQUENT MUTATION, BUT WHICH
OTHERS?
SO SMALL MOLECULES ARE AT THE
FO
FOREFRONT OF ANTI-CANCER
THERAPIES, SUCCESSIVE TREATMENTS
HAVE PROBLEMS WITH SINGLE
MOLECULES IN CARRYING DRUG
RESISTANCE.
ONCOLOGISTS THEN FACE TOUGH
CHOICES, NOT JUST WHICH DRUGS TO
USE, BUT THE BEST TREATMENT
PLANS BASED ON FACTORS LIKE
TARGET PROTEINS, TARGET PATHWAY
AND GENE EXPRESSION.
SO WHAT THE ONCOLOGIST HAS
ESSENTIALLY ALL OF THESE DRUGS,
WHICH ONES TO CHOOSE.
THE QUESTION THEN IS HOW TO
SELECT SMALL MOLECULE
COMBINATIONS.
CONSIDERING THE REALITY OF
CANCER'S DISRUPTION OF NORMAL
CELLULAR PROCESSES, CLARIFIES
WHY IT IS CRUCIAL TO UNDERSTAND
THE INS AND OUTS OF CARE AND
TREATMENT METHODS.
FOR EXAMPLE, SMALL MOLECULE
COMBINATIONS THAT TARGET
MULTIPLE PATHWAYS APPEAR A
PROMISING APPROACH, BUT HURDLES
COME WITH IT, LIKE DEALING WITH
PATHWAY CROSS TALK.
IN OVER EXPRESSION, WHICH
HAPPENS ALL THE TIME IN
AGGRESSIVE CANCERS, SAME PATHWAY
COMBINATION CAN ENCOUNTER
ACTIVATION OF MULTIPLE ONCOGENIC
PATHWAYS THROUGH CROSSTALKS, FOR
EXAMPLE.
SIMILARLY, STRONG ACTIVATING
MUTATION, HAVE MANY ACTIVE
CONFORMATIONS, SO HOW TO SELECT
SMALL MOLECULE COMBINATIONS?
DRUG COMBINATIONS CAN TARGET
SAME PROTEIN, AUTOSTERIC ARE
DRUGS THAT BIND AT THE ACTIVE
SITE, THEY ARE COMPETITIVE WITH
THE SUBSTRATE.
SAME PATHWAY, UPSTREAM AND
DOWNSTREAM PROTEIN, PROEN TOOS,
REDUNDANT PATHWAY SIGNAL THROUGH
SAME FAMILY PROTEINS, PARALLEL
PATHWAYS, SIGNAL TO DIFFERENT
FAMILY PROTEINS.
C
COMPENSATORY PATHWAYS AND THE
COMBINATIONS OF TARGET PROTEINS
IN REDUNDANT AND COMPENSATORY
PATHWAYS CONSIDER MUTATIONS AND
CROSS LINKAGES BETWEEN THEM.
OVER EXPRESSION CONTRIBUTES
DOMINANTLY TO THE NUMBER OF
ACTIVE MOLECULES, COMBINATION
SHOULD INCLUDE TRANS SCRIPTION
FACTOR AND EPIGENETIC MODALATORS
TO HELP IN OVER EXPRESSION.
HERE IS AN EXAMPLE TO EXPLAIN
THE ISSUE OF THE PATHWAYS
BECAUSE DRUG RESISTANCE CAN
BYPASS, CAN BYPASS DRUGS.
SO HOW TO SELECT SMALL MOLECULE
COMBINATIONS.
SO HERE IS FOR EXAMPLE, MAPK
EFGR KIND IS MAJOR RECEPTOR.
HERE IS OUR MAPK, WHICH LEADS TO
CELL SEPARATION AND THIS CELL
GROWTH.
WHAT THEN HAPPENS IS, WHAT CAN
HAPPEN I SHOULD SAY, IS HERE,
OKAY, EGFR.
NOW EGFR HAS A MUTATION HERE
NEXT TO IT.
SO IT IS GOING TO KEEP WORKING
ALL THE TIME, NOT ACTIVATED BY
BINDS AT THE TOP.
THEN THE ONCOLOGIST MAY TARGET
IT HERE WITH ANTIBODY DRUG AND
WITH DRUG, TARGET PROTEINS ONCE
YOU TARGET PROTEIN, YOU ALSO
BLOCK THE PATHWAY.
THEN, HOWEVER, WHAT CAN HAPPEN,
THERE ARE OTHER SAME FAMILY EGF
KINASES, WHICH CAN BE ACTIVATED,
TOO, NOT NECESSARILY NOW WITH
LIGUNS, THEY CAN HAVE MUTATIONS.
THIS IS WHAT HAPPENS.
THEN THEY SUBSTITUTE FOR EGFR
AND ACTIVATORS AND THESE
PATHWAYS.
IN ANOTHER CASE HERE WE SEE RAF
HAS THIS MUTATION, NOW IT IS
INHIBITED, THEN MAKE THIS HERE,
SO THIS MAPK PATHWAY CAN MAP IS
BLOCKED, BUT SIGNALLING CAN GO
VIA MAKE FIVE SAME FAMILY.
SO PATHWAYS.
HOW TO SELECT SMALL MOLECULE
COMBINATIONS, SO THESE ARE THE
MAJOR POSSIBILITIES THAT I SAID
BEFORE HERE.
CAN STOP HERE, FOR EXAMPLE.
SAME PROTEIN COMBINATION, TWO
DRUGS.
HERE, COMBINATION.
STOPPING OR BLOCKING, SAME
PATHWAY HERE AND HERE.
HERE COMBINATION DIFFERENT
PROTEINS ALSO BLOCKING.
HE
HERE, PARALLEL PATHWAYS OR I
THINK HERE -- NO REDUNDANT
PATHWAY, I'M SORRY AND HERE
COMPENSATORY PATHWAY CAN HAPPEN.
SO ALL OF THIS NEEDS WORKING
OUT, WHICH IS BEST COMBINATION
AND ULTIMATELY THE BEST WAY IS
TO KEEP PROTATING SO NEW
MUTATIONS DO NOT COME UP.
OUR QUESTIONS ARE INDEED ON THE
BIOPHYSICAL LEVEL.
I DON'T KNOW IF I'M RUNNING OVER
TIME.
HUH?
I'M FINE.
THEN I WILL MENTION ALSO THAT
OTHER QUESTION THAT I MENTIONED
BEFORE ABOUT THE EPIDEMIOLOGICAL
SURVEYS THAT OBSERVE THAT PEOPLE
WILL AUTISM IS HIGHER RISK OF
CANCER AND THOSE WITH
SCHIZOPHRENIA BY AS MUCH AS 50%.
WHEN WE SAW THIS, WE WERE JUST,
WE DIDN'T KNOW THIS.
THIS IS MEANT PEOPLE WORK ON IT
AT THE NCI.
HOW TO UNDERSTAND THIS.
SO THIS IS WHAT WE HAVE.
AUTISM IS NOT UNIQUE, AUTISM HAS
BEEN ASSOCIATED
EPIDEMIOLOGICALLY WITH THYROID
CANCER, BREAST CANCER, BIPOLAR,
BREAST AND LUNG, SCHIZOPHRENIA,
COLON, LUNG, BREAST AND -- HOW
TO UNDERSTAND THIS.
THE POINT IS THAT THE SAME
PATHWAYS ARE USED.
AND THIS OF COURSE ARE
NEURODEVELOPMENTAL DISORDERS AND
CANCERS.
WE ASK WHY THE INCREASED CANCER
RISK.
SO WE PUZZLED OVER THE
TANTALIZING CROSSTALK BETWEEN
CANCER AND NEURODEVELOPMENTAL
DISORDERS.
WE PUZZLED HOW MUTATIONS IN THE
SAME GENE AND EVEN THE SAME
MUTATIONS CAN LEAD TO SUCH
DIFFERENT FETAL TYPE.
CANCER VERSUS NEURODEVELOPMENTAL
DISORDERS AND WHY PEOPLE WITH
NEURODEVELOPMENTAL DISORDERS
HAVE HIGHER RISK OF CANCER AND
SCHIZOPHRENIA BY AS MUCH AS 50%.
AND THE POINT FOR US, FOR MY
GROUP PERSONALLY, WAS THAT
PROTEINS THAT WE WERE ALREADY
STUDYING, FOR EXAMPLE, RAS, RAF,
ERK, AND P10 ARE AMONG THE
ONCOGENIC PROTEINS THAT CAN
HARBOR MUTATION THAT INCLUDE
NEURODEVELOPMENTAL DISORDERS,
SUCH AS AUTISM, SERB SER BRAL
/* /* CEREBRAL PALSY.
SO MANY WORK ON THIS BUT NOT AT
THE DETAILED LEVEL.
SO HERE WHAT HAPPENED AT THE
TIME, WE WERE LOOKING AT THIS,
WE WERE INVITED TO CONTRIBUTE TO
ISSUE ON BIOPHYSICS OF IMMUNITY
AND CANCER LEADING US TO LOOK
INTO THE ORIGIN OF THE
CONNECTION BETWEEN CANCER AND
NEURODEVELOPMENTAL DISORDERS.
WE SUGGESTED THAT IMMUNITY COULD
BE VIEWED AS A KEY COMMON FACTOR
AND IT IS NEURODEVELOPMENTAL
DISORDERS AND CANCER WITH IMMUNE
AND NERVOUS SYSTEMS EVOLVING AS
EMBRYO DEVELOPS.
SO HERE WE LOOKED, FOR EXAMPLE,
RAS, SAME PROTEIN, SAME MOLECULE
RAS, RAS CAN HAVE MUTATIONS
ASSOCIATED WITH CANCER, FOR
EXAMPLE, HERE ARE CANCER,
MELANOMA, PANCREATIC CANCER,
LUNG CANCER, ETCETERA.
AND ALSO IN RASOOPATHY, ALSO
ASSOCIATED WITH CANCER.
SO HOW TO UNDERSTAND THIS.
HERE WE LOOKED AT P10, THE
PROTEIN IN THE GROUP WAS
SIMULATING, WHERE WE SEE THAT
SAME HERE EVEN SAME MUTATIONS
CAN ENCODE NEURODEVELOPMENTAL
DISORDERS AND CANCER.
SO HERE FOR EXAMPLE, COWDEN
SYNDROME, A NEURODEVELOPMENTAL
DISORDER, WE SEE FOR EXAMPLE,
HY68 IS BOTH HERE AND IN ANOTHER
ONE AND IN GLYOBLASTOMA, VERY
SERIOUS BRAIN CANCER, BRAIN
TUMORS, HERE THIS ONE, H93,
AGAIN, IN COWDEN SYNDROME, IS
ALSO IN ENDOMETRIAL CARCINOMA.
HOW TO UNDERSTAND THIS.
SO DECIPHERING THE CONNECTION
BETWEEN CANCER AND
NEURODEVELOPMENTAL DISORDERS.
OUR GOALS ARE TO FIGURE OUT HOW
SHOULD MUTATIONS LEAD TO THE
TRANSITION OF CELL FROM
NEURODEVELOPMENTAL DISORDERS TO
CANCERS AND TO DEVELOP A
STRATEGY TO PREDICT
NEURODEVELOPMENTAL DISORDER
RELATED MUTATIONS THUS THE RISK
FOR CARRIERS, EVEN IN THE
ABSENCE OF CLINICAL
PRESENTATION, IF WE'RE ABLE TO
DO THIS, IT WOULD HELP IN EARLY
DETECTION AND CARE.
TOWARD THIS AIM WE TEST, HAVE
BEEN TESTING OUR CONCEPT THAT
NEURODEVELOPMENTAL DISORDER
PROMOTING MUTATIONS TEND TO BE
WEAKER THAN THOSE OF CANCERS.
MUSIC ALSO THE BIOWULF.
YEAH.
SIMULATIONS, WE EXPECT CANCER
RELATED BUT NOT INDEED
NEURODEVELOPMENTAL DISORDER
RELATED MUTATIONS WOULD TEND TO
FAVOR CONFORMATIONS SO WE LOOKED
AT ENSEMBLES, THE PROPENSITY OF
THE ENSEMBLE GENOMIC ANALYSIS,
DONE THAT, AS WELL, THIS IS
BIOINFORM ATTICS AND EXPECT
HIGHER LEVELS FOR CERTAIN
ISOFORMS IN EMBRYONIC BRAIN,
CARRIER OF ISOFORM HARBORING
MUTATIONS MAY FACE HIGHER RISK
LATER IN LIFE.
AND THE FREQUENCIES, STRONGER
MUTATIONS TEND TO HAVE HIGHER
FREQUENCIES.
SO I DON'T KNOW IF I SHOULD, LET
ME KNOW WHEN I SHOULD STOP.
SO WHY ARE CANCERS AND
NEURODEVELOPMENTAL DISORDERS
CONNECTED AND WHY IS SIGNALLING
STRONGER IN CANCER AND WEAKER IN
NEURODEVELOPMENTAL DISORDERS?
SO WHY ARE CANCER AND
NEURODEVELOPMENTAL DISORDERS
RELATED?
BOTH ARE DEVELOPMENTAL
DISEASES,ING PROLIFERATION AND
DIFFERENTIATION, DIFFERENTIATION
IS KEY IN NEURODEVELOPMENTAL
DISORDERS.
PROLIFERATION IS THE KEY IN
CANCER.
OF COURSE, BOTH PATHWAYS ARE
NEEDED IN BOTH.
WHY STRONGER SIGNALLING IN
CANCER?
PROLIFERATION IS A HALLMARK OF
CANCER WITH MAP K AND MAJOR
PATHWAY DIFFERENTIATION IS
HALLMARK OF NEURODEVELOPMENTAL
DISORDERS, WITH PIK3, AND MAJOR
PROLIFERATION AND PATHWAY IN
CELL GROWTH, WE HAVE SEEN THIS.
BOTH ASSOCIATED WITH CELL CYCLE
POPULATION, SIGNALLING IN
PROSECUTE LIFERATION IS EXPECTED
TO BE STRONGER, WE HAVE TO LOOK
ALSO AT CHROMA TIN ACCESSIBILITY
AND BECAUSE IT RELATES TO
DIFFERENTIATION CHROMETIN MAKING
MUTATION MORE HIGHLY LIKELY IN
THE AGENT.
AND I'M SORRY, I -- I PRESSED
END SIGNAL STRENGTH DETERMINES
THE DURATION DETERMINES CELL,
THAT WAS OUR CONCLUSION OR
SUGGESTION.
AND FINALLY, JUST TO SAY AGAIN
HERE WHAT I MENTIONED BEFORE,
UNDERSTANDING MECHANISMS ON THE
BASIC STRUCTURAL AND CELLULAR
LEVELS.
I WILL KEEP THE NEXT TWO SLIDES
OF THE PI3K MECHANISM SO THAT I
AM NOT OVER TIME AND JUST
ACKNOWLEDGE MY COLLEAGUES.
THANK YOU VERY MUCH.
[APPLAUSE]
>> ALL RIGHT, SO WE HAVE SOME
TIME FOR QUESTIONS.
THOSE PEOPLE IN THE VIDEOCAST
CAN PRESS THE FEEDBACK BUTTON TO
SEND US QUESTIONS AND YES, WE
HAVE A MICROPHONE IN THE CENTER,
IF YOU WANT TO LINEUP FOR THE
QUESTIONS, PLEASE.
>> I HAVE A QUESTION.
SO WE KNOW THAT AND I HAVE
EXPERIENCED THIS THAT CERTAIN
DRUGS THAT TARGET CANCER CAUSE
LIKE PROBLEMS LIKE CENTRAL
NERVOUS SYSTEM, RIGHT?
LIKE PROBLEMS AND LIKE MOVEMENT
AND MANY, MANY DIFFERENT
PROBLEMS.
I WONDER IF YOU INVESTIGATED
THAT LIKE RESEPTIN, WHAT TYPE OF
INTERACTION HAPPENING THERE?
>> NOT GOING TO -- SO MANY, MANY
QUESTI
QUESTIONS, THERE ARE NO
SIMULATIONS OF SIMULATIONS OF
(AWAY FROM MIC) -- SIMULATION OF
RECEPTORS INVOLVE VERY LARGE,
THERE IS THE MEMBRANE, RIGHT, SO
WE SIMULATE SO MUCH SO WE FOCUS,
WE LOOK AT THEM, WE CONSIDER
THEM, WE ACCOUNT FOR THE ROLES
AND WE LOOK AT CLINICAL AND
EXPERI
EXPERIMENTAL DATA RELATING TO
THEM AND ALWAYS THERE IN OUR
MINDS, LIKE FOR EXAMPLE,
FREQUENTLY MUTATED IN CANCER, WE
DO NOT SIMULATE IT.
I CANNOT FROM OUR WORK, CANNOT
SAY.
>> NO WORRIES.
>> HELLO.
SO WHEN YOU WERE DISCUSSING THE
RISKS OF NEURODEVELOPMENTAL
DISORDERS AND NEUROLOGICAL
MENTAL DISORDERS VERSUS CANCER.
YOU MENTIONED LINK BETWEEN
NEURODEVELOPMENTAL DISORDERS AND
CANCER RISK.
YOU SHOWED I SAW FOR
SCHIZOPHRENIA LINK BETWEEN THAT
AND LUNG CANCER AND COLON
CANCER.
I READ THAT SCHIZOPHRENICS HAVE
HIGHER RISKS OF SMOKING AND
POORER DIETS, HOW DO YOU CONTROL
FOR LIFESTYLE RISK VERSUS
MUTATIONAL RISK?
>> I CANNOT SAY (AWAY FROM
MIC) -- WHAT WE ARE SHOWING AND
HAS DIRECT -- (INAUDIBLE) --
HYPOTHESIS AND THEN AFTER WE
FORMULATE THE HYPOTHESIS, WE GO
BACK AND WE CHECK AGAINST THE
LITERATURE, ALWAYS, ALWAYS,
ALWAYS WE CHECK.
YOU KNOW, THERE IS BARELY A DAY
THAT I DON'T CHECK LITERATURE,
ALWAYS WE'RE VERY AND
LITERATURE, I MEAN, YES, OTHER
COMPUTATIONS FOR SURE, WE WANT
TO KNOW WHAT OTHER PEOPLE ARE
DOING.
EXPERIMENTAL WORK VERY CRITICAL
SO SIMULATIONS ARE EXTREMELY
IMPORT
IMPORTANT.
I MEAN, THIS IS WHAT WE'RE DOING
OTHERWISE WE WOULDN'T BE
SPENDING SO MUCH OF THE BIOWULF
MONEY BUDGET, SAME TIME ONE HAS
TO BEAR IN MIND, THESE ARE
SIMULATIONS AND THEY NEED ALSO
EXPERIMENTAL VALIDATION,
EXPERIMENTAL AND CLINICAL IN
THIS CASE.
>> GOT YOU.
THANK YOU.
>> SO TO GO ALONG WITH THE TITLE
OF YOUR TALK, I'M JUST CURIOUS,
WHY DO YOU THINK THERE IS NOT
MORE CONTROL MECHANISMS SINCE
RAS MUTATION HAVE DELIRUOUS
EFFECT.
>> I DID NOT UNDERSTAND
QUESTION.
>> I DID NOT FINISH YET, SO WHY
IS IT THAT THE CIRCUITRY IS NOT
TRYING TO ACCOUNT FOR THE FACT
THAT RAS IS SO MUTOGENIC OR WHY
HAS RAS NOT BECOME EVOLUTIONARY
WISE LESS MUTOGENIC OR LESS
MUTATABLE.
>> THE ISSUE IS AS FOLLOWS,
CANCER IS VERY, IS BYPASS,
RIGHT, OF EVOLUTION.
SAME PATHWAYS, SAME PROTEINS.
WE ALSO KNOW AND MANY PAPERS
ABOUT THIS, WE ALSO WITH DEBATE,
WHAT IS THE MINIMUM NUMBER OF
MUTATIONS NEEDED FOR CANCER?
SOME PEOPLE SAY EVERYBODY AGREES
ONE IS NOT ENOUGH.
IF ONE WERE ENOUGH, I THINK SO
VERY MANY PEOPLE WOULD HAVE
CANCER.
THINK OF THE PROBABILITY, YOU
HAVE ALL OF THESE GENES, WHICH
HAVE SO MANY RESIDUES OR
NUCLEOTIDES, SO THE CHANCE THAT
A MUTATION WOULD COME UP IS VERY
HIGH.
SO THE QUESTION IS, SO WE KNOW,
WE NEED MORE THAN ONE MUTATION.
THE QUESTION IS, WHAT IS THE
MINIMUM NUMBER.
SOME PEOPLE FROM JOHNS HOPKINS,
THEY SUGGESTED THREE, OTHERS
SUGGESTED MORE.
ETCETERA.
I DON'T KNOW, OBVIOUSLY AND
PROBABLY DEPENDS ON CONTEXT,
PROBABLY MORE.
WHAT MY FEELING IS THAT JUST
LIKE CANCER REQUIRES MORE THAN
ONE DRIVER MUTATION,
NEURODEVELOPMENTAL DISORDERS
ALSO REQUIRE MORE THAN ONE
MUTATION.
AND SOME MUTATIONS ARE NOT KNOWN
TO BE HARBORED BY CERTAIN
INDIVIDUALS BECAUSE THEY DON'T
HAVE -- THEY HAVE SAY ONE
MUTATION OR TWO MUTATIONS, IT
STILL DOESN'T SHOW, BUT NO
SYMPTOMS.
RIGHT?
BUT WHAT -- AND I THINK THIS IS
THE KEY HERE, HOWEVER, SINCE IT
IS THE SAME PROTEIN AND THE SAME
MUTATIONS, THE CHANCE, THE
PROBABILITY OF THAT INDIVIDUAL
HAVING ANOTHER MUTATION WHICH
WOULD ENHANCE THESE IS HIGHER
THAN IF YOU DON'T HAVE THESE
MUTATIONS.
THESE MUTATIONS ARE OFTEN
INHERITED, SO THEY CAN COME FROM
BOTH PARENTS, FROM ONE OF THE
PARENTS, BUT THE PARENTS DOESN'T
SHOW ANY FOR EXAMPLE, AUTISM, NO
AUTISM SYMPTOMS.
RIGHT?
BUT MAYBE THE CHILD, THE
OFFSPRING, IF HE INHERITS MORE
MUTATIONS, IT CAN -- OR OTHER
MUTATION DURING DEVELOPMENT
COMES EMBRYO DEVELOPMENT COMES
UP, THEN IT WILL SHOW AND THEN
SIMILARLY FOR CANCER, SEEMS
MUTANT, WHICH I SHOWED, SEEMS
MUTATIONS ARE THE SAME, THEY
ALWAYS HAVE SOME MUTATIONS THAT
ENCAPSULATE CANCER SO
PROBABILITY OF HAVING ANOTHER
MUTATION IS HIGHER THAN
ACQUIRING THREE, FOUR, FIVE NEW
MUTATIONS, RIGHT?
OUR VIEW IS THE PROTEINS ARE THE
SAME, MUTATIONS ARE THE SAME,
PATHWAYS ARE THE SAME.
SO IT IS A QUESTION OF THE
PROBABILITY, THE INHERITED, YOU
KNOW, MUTATIONS AND THEN THE
PROBABILITY AND THE SAME RELATED
TO WHAT YOU WERE ASKING.
>> RIGHT.
SO THE NUMBER OF MUTATIONS, ONE
IN CANCER, AT LEAST,
EPIDEMIOLOGICAL CURVES SHOW A
CERTAIN GROWTH, RIGHT? AND THAT
GROWTH USUALLY HINTS AT FIVE OR
SIX MUTATIONS IN TERMS OF ADULT
CANCERS, NOT CHILDHOOD CANCERS.
IS THERE ANY SIMILAR
EPIDEMIOLOGY ON
NEURODEVELOPMENTAL DISORDERS?
>> EPIDEMIOLOGY, WE SHOULD
ALWAYS, OR AT LEAST I
PERSONALLY, THERE IS SOME -- YOU
TAKE IT WITH A GRAIN OF SALT,
RIGHT?
BECAUSE HOW DO YOU -- SOME
PEOPLE FOR EXAMPLE, SOCIAL, DOES
IT MEAN THEY HAVE AUTISM?
I DON'T KNOW.
IT THEN DEPENDS HOW EXACTLY YOU
DEFINE, RIGHT? SO YOU DON'T
KNOW, THIS IS NUMBER ONE.
AND NUMBER TWO, OVER THE YEARS,
THERE WAS NO AWARENESS,
EPIDEMIOLOGICAL STUDIES, I DON'T
KNOW, PEOPLE COMPLAIN LESS, THEY
WENT LESS TO MAYBE YOU KNOW
PHYSICIANS, DOCTORS, ETCETERA.
SO IT WAS LESS NOW THERE IS
INCREASING AWARENESS, RIGHT?
SO I THINK IT IS THE DEFINITION
OF THE SYMPTOMS, ETCETERA, AND I
DON'T KNOW THAT THERE IS A CL
CLEAR -- YEAH.
THIS IS ALL VERY -- SO WE DON'T
GO INTO THIS, WE JUST, THIS IS
JUST OUR THINKING, WE DO
SIMULATIONS.
CURIOSITY.
>> WHAT WE OBSERVE IS THAT IN
CAN
CANCER, THE MUTATIONS PROMOTE A
HIGHER PROPENSITY OF THE ACTIVE
C
CONFORMATION AS COMPARED TO THAT
OF OTHERS FOR EXAMPLE, THERE IS
STILL A RANGE FOR SURE.
YEAH.
>> EXCELLENT TALK, THANK YOU, I
LEARNED A LOT.
ONE EARLIER SLIDE, YOU SHOWED
DISTANCE BETWEEN TWO --
>> CAN YOU SPEAK LOUDER?
>> MEASURED IN EXTREMES FROM THE
CRYSTAL STRUCTURE AS COMPARED TO
MAGNITUDE OF MEASUREMENT FROM
YOUR SIMULATION, WHAT GAVE YOU
MORE CONFIDENCE IN --
>> WHAT, WHAT?
>> WHAT GAVE YOU MORE CONFIDENCE
IN THE MAGNITUDE OF THE
MEASUREMENT OF THE GAP?
>> I DON'T KNOW, WHAT I'M SAYING
IS ONE HAS TO CONSIDER AND ONE
HAS TO CHECK SIMULATIONS IS
DEFINITELY ONE WAY AND NMR IS
ANOTHER.
YEAH.
WE KNOW CRYSTAL STRUCTURES
AFTERALL WE, DO SIMULATIONS, WE
KNOW ALL OF THESE PROTEINS ARE
HIGHLY DYNAMIC, CRYSTAL
STRUCTURE EVENTUAL LY CAPTURE OE
STATE, RIGHT? THAT PARTICULAR
STATE IS THE ONE THAT'S FAVORED
UNDER THE CRYSTALLIZATION
CONDITIONS, PERIOD.
FOR MANY YEARS PEOPLE, WE HAD
ISSUES WITH THAT THINKING,
CRYSTAL STRUCTURE IS THIS
STRUCTURE.
NO SUCH THING AS THIS STRUCTURE.
IT IS A SNAPSHOT.
>> THANK YOU VERY MUCH.
>> WE KNOW THIS AND CRYSTAL
STRUCTURE DO NOT EXPLAIN, YOU
KNOW, THOSE FOR EXAMPLE, WHAT I
SKIPPED OVER HERE, HERE FOR
EXAMPLE, THE DIFFERENCE HERE
BETWEEN THE ACTIVE CRYSTAL
STRUCTURE AND WHAT NEEDS TO BE
IS VERY LARGE.
THIS IS THE PI3K, YEAH.
SO THIS IS, YEAH, I MEAN, WE
WERE ASKING HERE, THE DISTANCE
IS NOT THAT DISTANCE.
OKAY.
THIS IS DURING CATA LYSIS, THIS
IS KRI CRYSTAL STRUCTURE AND
CRYSTAL STRUCTURE DID NOT
EXPLAIN.
THIS IS LIPID LIP2.
YEAH.
ANYWAY.
>> THANK YOU FOR THE TALK, IT
WAS VERY INTERESTING.
I ACTUALLY HAVE A VERY SIMILAR
QUESTION REGARDING CRYSTAL
STRUCTURE VERSUS SIMULATIONS.
I UNDERSTAND YOU USE --
SOMETHING LIKE THAT?
>> YES.
MY QUESTION IS, CAN YOU ACTUALLY
REPRODUCE THE CRYSTAL STRUCTURES
AND THE CONDITIONS WHICH ARE
PRESENT WHEN YOU DO
CRYSTALLIZATION?
CAN YOU FIRST PROVE YOU CAN
REPRODUCE CRYSTAL STRUCTURE IN
CONCERN CONDITIONS AND MOVE ON
TO CONDITIONS IN REAL LIFE CELL?
>> SO THIS IS A FANTASTIC
QUESTION, BUT WHAT WE DO USUALLY
IS OTHER WAY AROUND, WE START
WITH THE CRYSTAL STRUCTURE,
RIGHT?
WE CAN START WITH A MODEL
STRUCTURE, RIGHT? THERE ARE
MANY, DEPENDING ON ACCURACY OF
THE MODELING AND AS WE KNOW,
THERE WOULD BE SOME BARRIERS,
RIGHT?
THE QUESTION OF SIMULATION TIME,
MULTIPLE TRAJECTORIES, ETCETERA,
ETCETERA.
BUT THERE ARE CASES WE HAVE
LOOKED AND WE HAVE CAPTURED OVER
THE YEARS, WE STARTED FOR
EXAMPLE MODELING BASED ON CRY-OM
OR VICE VERSA, I CAN'T REMEMBER
FOR SURE, QUITE A NUMBER OF
YEARS AGO.
YEAH.
>> YOU USUALLY TREAT WATER AS
EXPLICIT OR IMPLICIT?
>> EXPLICIT, ALWAYS EXPLICIT.
>> HOW ABOUT IONS PRESENT?
>> ALWAYS, WE ARE PARTICULAR
ABOUT EXPERIMENTAL, SIMULATION
CONDITION, ALWAYS EXPLICIT.
YES, I GUESS THAT IS WHAT YOU
ARE INTO.
[LAUGHTER]
>> WE SHARE THIS.
IT IS FASTER IF IT IS NOT
EXPLICIT, RIGHT? BUT, USING THE
BIOWULF, WE ARE ABLE TO DO THIS.
YES.
>> LAST QUESTION FROM THE
VIDEOCAST.
RAS AND GRAPH MUTATIONS THAT
OCCUR IN EMBRYONIC SITES DO NOT
CAUSE MELANOMA IN ADULT CYTES DO
LEAD TO MELANOMA, WHAT IS
DIFFERENCE IN EMBRYO AND ADULT
CELLS?
>> I DON'T EXACTLY KNOW WHAT IS
THE DIFFERENCE BETWEEN THE
EMBRYO AND THE ADULT AS FAR AS
CELL CYCLE, IT IS ACTUALLY VERY
IMPORTANT QUESTION.
I DON'T EXACTLY KNOW.
BUT WE KNOW THAT AS I SAY
DIFFERENTIATION IS VERY
IMPORTANT.
THIS IS IN THE EMBRYO CELLS HAVE
TO DIFFERENTIATE, RIGHT? COMING
BACK TO CANCER, IN CANCER, IN
TUMORS, CELLS DIFFERENTIATE AND
GO BACK.
RIGHT?
THEY GO BACK IN EVOLUTION.
YEAH.
SO --
>> THANK YOU.
>> AND THANK YOU VERY MUCH.
[APPLAUSE]
>> SO I GUESS I CLOSE.