>> WE WELCOME YOU
TO WHAT SURELY WILL BE AN
EXCITING AND STIMULATING
PRESENTATION. AND RAISE YOUR
SIGHTS TO ISSUES IN BIOLOGY THAT
OFTEN EXCEED THOSE AT THE LEVEL
AT WHICH WE NORMALLY WORK
WHETHER MORE CLINICALLY OR EVEN
IN THE LABORATORY. SO THIS
PROGRAM IS ACTUALLY TRIPLY
SPONSORED BY THE FAES WHICH
KINDLY IS GOING TO SPONSOR A
RECEPTION AT THE END OF TODAY'S
SESSION IN THE RECEPTION AREA
AROUND HERE. AND IN ADDITION IT
IS SPONSORED BY THE INTRAMURAL
PROGRAM OF THE NIH. AND BY THE
DEMYSTIFYING MEDICINE COURSE.
LET ME SAY A WORD ABOUT THAT.
THOSE OF YOU WHO IF THERE ARE
ANY WHO HAVE NEVER BEEN TO ANY
OF OUR SESSIONS I WOULD TELL YOU
THAT THIS COURSE IS NOW ENDING
ITS 23RD YEAR. ITS GOAL IS TO
BRIDGE EXCITING DEVELOPMENTS IN
BIOLOGY AND ENGINEERING WITH
MEDICINE. NORMALLY IT IS ON
TUESDAYS FROM 4 TO 6 FROM
JANUARY TO SOMETIME IN MAY. AND
IT CAN BE WATCHED ON THE NIH
VIDEOCAST, THIS YEAR IT WAS ALL
VIRTUAL AND WE HAD ATTENDANCE
RANGING UP INTO THE THOUSANDS
BECAUSE IT GOES GLOBALLY. MANY
OF OUR PARTICIPANTS WERE GLOBAL
WHEREAS IN PREVIOUS YEARS
EVERYONE WAS HERE ON SITE. WE
THINK NEXT YEAR THE PROGRAM WILL
BE A HYBRID ONE INCORPORATED BY
ASPECTS.
THE PICTURE IN THE UPPER RIGHT
IS WHAT MANY OF US IN EAST OF
THE ROCKY MOUNTAINS THINK IS THE
GREATEST BRIDGE IN THE WORLD.
THAT'S THE BROOKLYN BRIDGE. AND
THE REASON WE SHOW IT IS BECAUSE
THE WHO GENERALMEN ON THE CAT
WALK ARE ESSENTIALLY BRIDGING.
SO FOR TODAY, OUR SPEAKER IS AN
EVOLUTIONARY BIOCHEMIST AND WE
ARE ONE OF THOSE INDIVIDUALS WHO
ARE GOING TO LISTEN, LEARN,
THINK AND MAYBE INFLUENCE SOME
OF OUR EXPERIMENTAL WORKS. THIS
IS ESSENTIALLY IN BRIDGE
BUILDING. NORMALLY WE TRIED TO
HAVE A LIVE PATIENT, A CLINICAL
-- CLINICIAN, INVESTIGATOR AND
BASIC SCIENTIST WHO SHARE NOT
LAST WE CAN'S RESEARCH SEMINAR
BUT ONE OF THE BIG CHALLENGING
THAT CONFRONT THE TOPIC AT HAND.
MANY TIMES WE ARE FORTUNATE BY
HAVING ESSENTIALLY A SINGLE
SPEAKER SUCH AS TODAY. BECAUSE
THE BRIDGES THAT THOSE PEOPLE
ARE INVOLVED IN ARE QUITE
DIFFERENT FROM THE ONES WE
NORMALLY CONSIDER AT BENCH TO
BEDSIDE. SO WE HAVE HAD SPEAKERS
FROM NASA TALK ABOUT BIOLOGY AND
SPACE, WE HAVE HAD SPEAKERS FROM
THE OCEAN GRAPHIC TALK ABOUT
BIOLOGY ON THE SEA FLOOR, AND A
GREAT VARIETY OF BIG BRIDGERS IN
BIOLOGY ALL OF THOSE SPIN OFF TO
MEDICINE. OKAY. ENOUGH. SO
TODAY'S SPEAKER YOU KNOW IS NICK
LANE, WHO I SUSPECT IS WELL
KNOWN TO ALL OF YOU. LARGELY
BECAUSE OF HIS RESEARCH AND
PARTICULARLY HIS BOOKS. I BRING
YOUR ATTENTION THERE WILL BE A
BOOK SIGNING AT THE CONCLUSION
OF TODAY'S PROGRAM OF NICK'S
FIFTH BOOK CALLED TRANSFORMING.
MAY WE HAVE THE NEXT SLIDE
PLEASE. THANK YOU. SO NICK IS
PROFESSOR OF EVOLUTIONARY
BIOCHEMISTRY IN THE DEPARTMENT
OF GENETICS, EVOLUTION AND
ENVIRONMENT AT THE UNIVERSITY
COLLEGE LONDON IN THE UK. HIS
RESEARCH THROUGH THE YEARS HAS
CONCERNED MAJOR ISSUES LIKE THE
ORIGIN OF LIFE, THE ORIGIN OF
THE EUKARYOTIC CELL, THE ORIGIN
OF SEX OF SPECIESATION, AND
AGING, NOT SO MUCH TO GENOMICS
AS RELATED TO BIOENERGETICS.
THE ENERGY THAT PRESUMABLY
PRECEDES THE GENOME. DOES IT? WE
WILL HEAR DISCUSSION OF THAT.
NICK IS FOUNDER OF IT WILL
COLLEGE OF LONDON CONSORTIUM FOR
MITOCHONDRIAL RESEARCH AND FOR
THE RESEARCH FRONTIERS ORIGIN OF
LIFE PROGRAM AT THAT UNIVERSITY
HE TEACHES ENERGY AND EVOLUTION
TO WHICH I'M SURE ARE VERY
EXCITED STUDENTS. AND WELL KNOWN
IS HE IS AUTHOR OF FIVE
ACCLAIMED BOOKS ON EVOLUTIONARY
BIOCHEMISTRY. THIS IF YOU HAVE
NEVER READ ANY OF HIS BOOKS YOU
SHOULD READ ANY ONE OF THEM
BECAUSE THEY CONVERT
BIOCHEMISTRY FROM SOMETHING LIKE
A COMPLEX PATHWAY OF THINGS
INTERACTING IN AN IMPOSSIBLE
SCENARIO TO UNDERSTAND,
CONVERTED INTO DYNAMIC, WHAT IS
GOING ON EVERY SECOND IF NOT
MILLISECOND WITHIN OUR CELLS.
HIS MOST RECENT BOOK IS
TRANSFORMER WHICH I MENTIONED.
NICK IS RECEIVED MANY AWARDS
INCLUDING THE ROYAL SOCIETY
PRIZE FOR SCIENCE BOOKS, ONE OF
HIS EARLY BOOKS CALLED LIFE
ASCENDING. HE RECEIVED A
BIOCHEMICAL SOCIETY AWARD AND IN
2016 THE ROYAL SOCIETY MICHAEL
(INAUDIBLE) PRIZE FOR SCIENTIFIC
WRITING. HE IS A FELLOW OF THE
(INAUDIBLE) SOCIETY THE ROLE
SOCIETY OF BIOLOGY, THE
BIOCHEMICAL SOCIETY AND WE ARE
EXTREMELY GRATEFUL TO HIM FOR
COMING TO VISIT NIH FOR THE
FIRST TIME. WHICH WE HOPE WILL
BE PERHAPS NOT JUST THE FIRST
TIME BUT ONE OF MANY YET TO
COME. SO NICK WELCOME TO THE
NIH. AND THE TOPIC OF HIS TALK
IS THE ORIGIN OF CELLS AND GENES
AND WHY IT MATTERS TO MEDICINE.
[APPLAUSE]
>> THANK YOU VERY MUCH FOR THAT
EXTREMELY GENEROUS AND KIND
INTRODUCTION. THANK YOU ALL FOR
BEING HERE. IT FEELS
PRESUMPTIONS TO SAY THE LEAST TO
COME TO NIH AND TALK ABOUT IN
THIS RELATED TO MEDICINE SO I
WILL TELL YOU ORIGIN OF LIFE
INSTEAD BECAUSE MAYBE I CAN TELL
YOU SOMETHING YOU DON'T KNOW.
BUT I DON'T WANT TO BORE YOU TO
TEARS EITHER, FOR THE LAST HALF
OF THE TALK OR THIRD OF THE TALK
I WILL TRY TO PUT TOGETHER WHY
ACTUALLY MATTER AND SEEM AS
STRETCH TO CONNECT THE ORIGIN OF
LIFE WITH MEDICINE TODAY. BUT
THERE ARE GROUNDS FOR DOING SO,
I HOPE WHAT I CAN DO IS NOT TO
TELL YOU THINGS THAT YOU DON'T
KNOW SO MUCH AS PERHAPS GET YOU
TO SEE THINGS YOU DO ALREADY
KNOW ABOUT IN A SLIGHTLY
DIFFERENT WAY SO THAT IS WHAT I
HOPE TO DO TODAY. SO THE ORIGIN
OF LIFE, I'LL VULNERABLE
IMMEDIATELY TO A CHARGE OF
MAKING IT ALL UP. HOW CAN WE
POSSIBLY KNOW? THE ANSWER, WE
CAN'T POSSIBLY KNOW, WE'LL NEVER
KNOW. EASY TO SAY IF WE INVENTED
A TIME MACHINE WE CAN GO BACK 4
BILLION YEARS TO ORIGIN OF LIFE
THEN WE CAN KNOW BUT IT IS A
HISTORICAL QUESTION. NO, I DON'T
THINK SO BECAUSE IF WE INVENT A
TIME MACHINE BACK TO 4 BILLION
YEARS THIS IS ONLY 3 AND A HALF
BILLION YEARS WHAT WOULD WE LOOK
FOR? IF WE FIND IT HOW WOULD WOE
KNOW? SO THESE I'M SURE YOU KNOW
ARE STROMATOLITESS. LIVING
SYSTEMS THOUGH THEY LOOK LIKE
ROCKS, MOST PEOPLE NOT FOUNDED
IN PALEONTOLOGY WOULD UNDERSTAND
THAT IS A LIVING SYSTEM AND IF
WE FIND SOME GREEN SLIME
SOMEWHERE NOT OBVIOUSLY CELLULAR
WOULD THAT BE A STEPPINGSTONE ON
ROOT TO LIFE OR WOULD IT BE A
NON-LIVING -- WHAT WOULD IT BE?
THE ANSWER IS WE HAVE NO IDEA.
THE ONLY WAY WE COULD FIGURE IT
OUT AT ALL IS BY AN INTELLECTUAL
FRAMEWORK WHICH TELL US WHAT WE
ARE ACTUALLY LOOKING FOR. A
FRAMEWORK WHICH SAYS HOW CAN A
STERILE INORGANIC WET ROCKK
PLANET GIVE RISE TO LIFE? HOW
CAN WE GO FROM ONE PLACE TO
LIVING WORLD THAT WE KNOW? AND
THAT, SO MANY IDEAS ON HOW THIS
HAPPENS. MOST OF THEM ARE WRONG.
LET'S FACE IT WE ARE MOSTLY
WRONG ABOUT MOST STUFF. A LOT
HAS CHANGED IN THE LAST FEW
YEARS. I'M NOT TELLING YOU WE
ARE RIGHT ALL OF A SUDDEN BUT
WHAT WE HAVE BEEN DOING, NOT
JUST US, PLENTY OF PEOPLE IS
THINKING ABOUT LIFE AS A GUIDE
TO ITS OWN ORIGIN. YOU SEE
TURTLES ALL THE WAY DOWN. CAN
WE, SEEMS CIRCULAR. CAN E USE
LIFE AS A GUIDE TO ITS OWN
ORIGIN?
I THINK WE CAN. I WILL SHOW YOU
WHY. THIS IS IN THREE WAYS I
WILL TALK ABOUT. ENERGY, THE WAY
CELLS POWER WORK, IS NOT HOW YOU
MIGHT IMAGINE, IT IS NOT JUST
ABOUT ATP NOT JUST CHEMISTRY IN
A BUCK, IT IS ABOUT ELECTRIC
MEMBRANES POWER WORK SO HOW DID
THAT COME TO BE? SECOND,
METABOLISM, WE THINK IN COMPLEX
MEDICAL SYSTEMS OF ALL KINDS OF
DIFFERENT ASPECTS OF METABOLISM
BUT THERE IS A SMALL CORE SHED
BY LIFE ON EFFORT INCLUDING
BACTERIA AND EARLIEST FORMS OF
LIFE. THERE IS COMMONALITY TO
THAT SO THIS UNIVERSAL CORE IS
TELLING US SOMETHING ABOUT THE
CONDITIONS UNDER WHICH LIFE
MIGHT HAVE STARTED. GENES,
GENETIC INFORMATION. WHERE DOES
THAT COME FROM? BUN ONE OF THE
BIGGEST QUESTIONS IN BIOLOGY.
THERE'S PATTERNS IN THE GENETIC
CODE REINTERPRETED NOW WHICH WE
HAVE KNOWN FOR DECADES WHICH
ARELINGING BINGING TO POINT TO A
-- BEGINNING TO POINT TO A
POSSIBLE ANSWER. THIS IS ALL
VERY EXCITING STUFF. IT MIGHT BE
WRONG BUT IT MIGHT BE RIGHT AND
FUN TO THINK ABOUT AND FUN TO
COME HERE TO TELL YOU ABOUT IT
SO QUICKLY, LIFE IS ELECTRIC.
JUST TO GET USED TO MY DIAGRAMS
BECAUSE YOU CAN SEE IMMEDIATELY
I'M NOT GOOD AT POWERPOINT.
KREBS CYCLE RIGHT IN THE MIDDLE
THERE. NOT GOING TO GO INTO VERY
MANY DETAILS BUT YOU WILL KNOW
THE WORLD -- WE ARE STRIPPING
GLUCOSE DOWN. SOMETHING HAS GONE
WRONG. STRIPPING GLUCOSE NOW TO
ACETYLC, OA FEEDING TO THE KREBS
CYCLE. ALL I WANT YOU TO TAKE
NOTE IS PULLING OUT HYDROGEN,
NOT AS THE GASES NEDH BUT JUST
PUT THE TERMINOLOGY TO ONE SIDE.
HYDROGEN ATOMS COMING OUT OF THE
KREBS CYCLE. THEY ARE BEING FED
TO OXYGEN, NO AS HYDROGEN ATOM
BUS ELECTRONS AND PROTONS WHICH
POLYSEPARATE PATHS SO CO 2 AND
HYDROGEN ARE COMING OUT OF THE
KREBS CYCLE, THAT IS A KEY THING
TO KEEP IN MIND. THE CURRENT OF
ELECTRONS FLOWING THROUGH
OXYGEN, IT THE USN'T HAVE TO BE
OXYGEN, IT COULD BE NITRATE OR
NITRITE OR ANY NUMBER OF
DIFFERENT INORGANIC MOLECULES.
THE CURRENT OF ELECTRONS FLOWING
TO LEK ELECTRONIC ACCEPTOR
POWERS THE EXTRUSION OF IONS, IT
CAN BE SODIUM IONS AND OTHERS
BUT NORMALLY PROTONS. THIS IDEA
GOES BACK TO PREFER MITCHELL IN
THE 1960s. THIS PROBABLY LOOKS
THE SAME. IT IS DIFFERENT IN ONE
KEY WAY, THOSE ARROWS MANY ON
THE KREBS CYCLE ARE INVERTED
THEIR DIRECTION. THEY ARE NOW
GOING OPPOSITE DIRECTION AND WE
HAVE HYDROGEN BEING SUCKED IN
AND CO 2 BEING SUCKED IN. THIS
IS THE REVERSE KREBS CYCLE,
PLENTY OF BACTERIA LIVING IN
HYDRO THERMAL SYSTEMS AND
GEOTHERMAL SYSTEMS AND STAGNANT
MUGS AND ALL PLACES THAT HAVE A
REVERSE KREBS CYCLE, IT
SURPRISES ME THAT IS NOT COMMON
KNOWLEDGE IN THE BIOCHEMISTRY
TEXTBOOKS MORE MEDICALLY
INCLINED TEXTBOOKS IT TENDS TO
MENTION EXISTENCE, I KNEW
NOTHING ABOUT IT UNTIL YEARS
AFTER MY DEGREE IN BIOCHEMISTRY.
THEY ARE DOING EXACTLY THE
OPPOSITE. THEY ARE SUCKING IN
HYDROGEN CO 2 REACTING THEM
TOGETHER TO FORM KREBS CYCLE
INTERMEDIATES. IT IS LONGER
THAN THE KREBS CYCLE AND
INCLUDES ACETYLCOA AND PYRUVATE
AND PHOSPHOTEAL PYRUVATE AS
WELL. SO ENENCOMPASSING AND IT
IS ABOUT THE CORE OF
BIOCHEMISTRY. SO SLIGHTRY
UNSTABLE ME DOING SOMETHING OR
WHAT. FROM ACIDS IN THE KREBS
CYCLE WE ARE MAKING AMINO ACIDS,
SUGARS LIPIDS, HS THE HEART OF
ANN BOLLIC METABOLISM, AND IT IS
LESS OBVIOUS WITHIN MEDICINE
BECAUSE WE SEE THE KREBS CYCLE
AS THE OXIDATIVE KREBS CYCLE
WITHIN CELLS, CYTOPLASM IS
DIFFERENT, PYRUVATE AND
GLYCOLYSIS ARE OUTSIDE THE SIGH
SOL SO IT IS NOT OBVIOUS --
CYTOSOL SO NOT OBVIOUS THIS IS
THE HEART OF ANN BOLLIC
METABOLISM BUT STEP BACK TO
THINK ABOUT THE BACTERIA THAT IS
WHAT IT IS. SO THE THIRD THING,
THIS IS JUST A TASTE OF ARGUMENT
LATER ON, THESE PATTERNS IN THE
GENETIC CODE THAT HAVE BEEN
KNOWN ABOUT REALLY SINCE THE
1960s, CARL WOES IN THE
1960s POINTING THIS OUT IN
1965, 1966 PAPERS IN PNAS. THERE
ARE EFFECTIVELY SEVERAL PATTERNS
THAT SUGGEST THAT THE
RELATIONSHIP WITH METABOLISM
WITH THE PRECURSOR OF THE AMINO
ACID BUT ALSO WITH THE HYDRO FOR
BUSINESSTY OF THE AMINO AND SIZE
OF AMINO ACID. I'M SUGGESTING
SYSTEM -- AM I STEPPING ON A
POWER CABLE SOMEWHERE? WHICH
MEANS ALL I WANT TO GO I A CROSS
IN THIS MOMENT IS IF YOU HAVE A
COMPLETELY RANDOM PIECE OF RNA
AN YOU HAVE SOME KIND OF
PHYSICAL TEMPLATING HYDRO FOLKIC
BASE WILL INTERACT WITH
HYDROPHOBIC AMINO ACID AND IF
THAT POLYMERIZES YOU HAVE A
POLYMERIC PEPTIDE WHICH IS
TEMPLATED BY THE RNA IN SOME WAY
SO RANDOM RNA WILL GIVE RISE TO
NON-RANDOM PEPTIDE THAT HAS
FUNCTION DEPENDING ON THE
SETTING. SO THE ORIGIN OF
INFORMATION IN BIOLOGY IS VERY,
VERY CONTEXT IN SETTING
DEPENDENT AND I WILL SUGGEST TO
YOU HOW THAT COMES ABOUT.
ANOTHER INTERESTING POINT ABOUT
THIS. WHAT I'M SAYING HERE IS
THAT EFFECTIVELY ELECTRICITY ONE
FORM OR ANOTHER IS DRIVING
METABOLISM CORE ANN BOLLIC
METABOLISM GIVING TO GENES AND
IS ALL HAPPENING IN THE SAME
PLACE. IT IS NOT AS IF YOU MAKE
GENES OVER THERE AND YOU MAKE
SOMETHING ELSE OVER HERE AND
THEY COME TOGETHER SOMEHOW. TO
HAVE ANION GRADIENT ACROSS
MEMBRANE DRIVING METABOLISM,
THEY HAVE TO BE NEXT TO ETCH OOH
OTHER SAME PLACE SAME TIME AND
IF GENES RESEARCH MANYING THEY
HAVE TO EMERGE IN THE SAME
ENVIRONMENT AT THE SAME PLACE
SAME TIME, GREAT TO DO LAB WORK
ON THESE THINGS BECAUSE WE CAN
DO IT SAME PLACE SAME TIME. IT
IS NOT THE PREDOMINANT IDEA IN
THE FIELD I WOULD SAY. YOU
SHOULD BE -- I HAVE TO WARN YOU
UP FRONT THIS IS LIGHTLY
HIERATICAL. I SAID REALLY? IT IS
ACTUALLY FEASIBLE BELIEVABLE?
RATIONALE OR RANNABLE TO SAY --
RASHABLE TO SAY THESE THINGS CAN
TAKE PLACE SAME TIME SAME PLACE?
I HAVE TO ADMIT A POINT. I KIND
OF AGREE WITH YOU IT DOESN'T
SEEM PLAUSIBLE, DOES IT? THERE
IS A PLACE, NOT WEDDED TO THIS
AS A PLACE FOR THE ORIGIN OF
LIFE BUT IT WORKS WELL AND THERE
MIGHT BE OR SETSINGS EQUIVALENT
TO THIS. -- SETTINGS EQUIVALENT.
THIS WAS DISCOVERED BY DEB KELLY
ON THE ALVIN SUBMERSIBLE IN THE
YEAR 2000. THIS IS LOST FITTING
WHICH IS A HYDRO THERMAL VENT
SYSTEM OFF AXIS OF THE MID
ATLANTIC RIDGE 15 MILES AFTER
AXIS. AND IT IS NOT LIKE THE
BLACK SMOKE EVENTS MOST OF US
ARE FAMILIAR WITH. IT IS NO
SMOKE COMING OUT OF IT AT ALL,
THEY LOOK ALMOST INACTIVE BUT
THESE ARE ACTIVE VENTING
SYSTEMS. AND SHE IS HOLDING IN
HER LEFT HAND A LUNCH OF BLACK
SMOKE WHICH LOOKS ACHE A CAN
IMNY THE WAY SMOKE COMES OUT.
IN HER RIGHT HAND SHE IS HOLDING
A PIECE OF LOST CITY, IT LOOKS
LIKE POUR OUT POWER OUTSID POURS
WAS THIS PICTURE OF HIM PHOTO
SHOPPED UP WAS IN A NATURE
FEATURE IN 2009 UNBELIEVE BY
THEY DRESSED HIM UP AS A
RENAISSANCE MAN, THEY DRESSED
HIM UP AS BIRTH OF LIFE, AND
THEY GOT A LITTLE BIT OF
REACTOR, HE WAS IN JET
PROPULSION SO BIT OF HIS REACTOR
THERE, THIS IS A SECTION OF LOSS
CITY SHOWI SHOWING THE MINERALID
SPONGE STRUCTURE. THE KEY POINT
HE DESCRIBED THESE SYSTEMS AS
EFFECTIVELY ELECTROCHEMICAL FLOW
REACTORS YOU HAVE FLUIDS WINDING
THROUGH -- ALKALINE HYDRO
THERMAL FLUID COMING,K AING OUT
OF OCEAN WATER, THE WATERS WERE
PROBABLY ACIDIC SO THEY WOULD
HAVE BEEN MIXING WITHIN THOSE
SYSTESYSTEMS. NO OXYGEN. THE ABE
OF OXYGEN MEANS PLENTY OF
DISSOLVED IRON AND OTHER
TRANSITION METALS NICKEL AND
THINGS LIKE THAT SO CATALYTIC
WALLS NOT JUST ION SUR FEED BUT
INCLUDING IRON SKULL VIED. THE
OTHER IS THE FLUIDS ARE
ALKALINE. HYDRO HER MALL FLUIDS
ARE WITHOUT PH 11 WHICH SHOULD
UNDERSTAND EXTREME AND THEY ARE
BUBBLING WITH HIGH ROW GENERAL
GAS SO THEY -- HYDROGEN GAS. SO
THEY ARE HYDROGENATED -- NOT
SURE YOU WANT TO DRINK IT AND
THE OCEAN I MENTION REDIRECT
EXAMINATION ACIDIC. SO WE HAVE
PH GRADIENTS ACROSS THE
BARRIERS. PH GRADIANS IS SEVEN
ORDERS OF MEMBER TUESDAY
DIFFERENT IN PROTONE STRUCTU ST.
IT IS SAY IT IS A NATURAL
PROTONE MOTOR FORCE AND THAT IS
WHERE I'M GOING WITH THIS. HERE
IS HYPOTHESIS. BE INTERESTING TO
KNOW WHAT YOU MAKE OF THIS BY
THE END OF THE LECTURE BUT WE
START WITH THINK OF GRAY AS THE
PORE IN ONE OF THESE HYDRO
THERMAL VENTSS. WE HAVE HYDROGEN
IONS OUTSIDE, FLUIDS INSIDE, WE
HAVE PROTONS CROSSING THE
BARRIER, NOT SURE WHAT IS GOING
ON THERE. EFFECTIVELY DRIVING
REACTION BETWEEN HYDROGEN AN CO
2 LOWERING KINETIC BARRIER TO
THAT REACTION HAPPENING AND
DRIVING THE REACTION TO MAKE C
CYCLE INTERMEDIATES AND AMINO
ACIDS AND LIPIDS IN THAT SYSTEM.
IF WE ARE MAKING LIBBEDS WE
EXPECT TO FORM A BIOLAYER
MEMBRANE THAT WILL PLATE ITSELF,
SHOWING YOUR HERE BECAUSE IT
LOOKS NICE THAT WAY. SO WE HAVE
A PROTO CELL INSIDE THE HYDRO
THERMAL CORE. NOW WE HAVE A
PARTIALLY CLOSED SYSTEM, THE
CONCENTRATION IS A BIT HIGHER
MAYBE THE DRIVING FORCE GETS
BETTER SO PERHAPS WE CAN PUSH A
LITTLE BIT FURTHER THROUGH
BIOCHEMISTRY TO MAKE NOT JUST
APPLY KNOW ACIDS AN LIPIDS BUT
SUGARS AND ULTIMATELY
NUCLEOTIDES. YOU ARE THINKING
WHAT A HAND WAVING GUY TELLING
YOU THIS STUFF HOW IS THAT
BELIEVABLE? HOPE TO CHANGE YOUR
MIND OVER THE NEXT TEN MINUTES.
FINALLY IN THE RIGHT HAND SIDE
THERE,S WE HAVE SOME RNA IN THIS
SYSTEM, WE HAVE AN RNA WORLD THE
FIRST POLYMERS INTERACTING WITH
AMINO ASSISTEDS FORMING SHORT
PEPTIDES, EFFECTIVELY A DIRTY
RNA WORLD INSIDE GROWING PROTON
CELLS INSIDE A HYDRO THERMAL
VENT. THE HYPOTHESIS. THE GOOD
THING IS EVERY STEP IS TESTABLE,
AT LEAST IN PRINCIPLE. SO I
WILL TALK ABOUT EACH BIG IDEA IN
TURN BEFORE I COME INTO MY --
ENERGY FLOW. PETER MITCHELL AND
JENNIFER ARE BEING GOING OUT OF
MY WAY TO DO ACOLYTE TO JENNIFER
BECAUSE WITHOUT HER DO A CALL
OUT, MITCHELL HAD BRILLIANT
IDEAS BUT HE WASLESS IN THE AND
IT WAS JENNIFER WHO DID THE
EXPERIMENTS, IT WASN'T MITCHELL
SAID YOU DO THIS EXPERIMENT OR
THAT ONE, JENNIFER WAS
INTELLECTUALLY SHE WAS COMING UP
WITH THE EXPERIMENTS AND THE ONE
WHO NAILED THE IDEA SO PEOPLE
LIKE (INAUDIBLE) HERE IF THE
U.S. BEGAN TO TAKE IT SERIOUSLY.
I DON'T THINK SHE GOT ANYTHING
LIKE THE CREDIT SHE DESERVES IS.
MITCHELL GOT THE NOBEL PRIZE BY
HIMSELF IN 1978, IT CERTAINLY
WAS A WORLD CHANGING IDEA. IT
WAS A REMARKABLE IDEA AND THE
IDEA WAS MITCHELL'S IDEA BUT THE
DEMONSTRATION WAS IT WAS REAL
SCIENCE WAS COMING FROM
JENNIFER, SHE WAS REMARKABLE
WOMAN. PUTTING THAT ASIDE, HERE
IS A QUOTE FROM MITCHELL, AS A
CONFERENCE IN 1957 IN MOSCOW. ON
THE ORIGIN OF LIFE. HE SAID THIS
WAS FOUR YEARS BEFORE THE
HYPOTHESIS IN NATURE IN 1961. HE
SAID I CANNOT CONSIDER THE
ORGANISM WITHOUT ITS ENVIRONMENT
FROM A FORMAL POINT OF VIEW TWO
MAY BE REGARDED EQUIVALENT
PHASES WHICH DYNAMIC CONTACT IS
MAINTAIND BY THE MEMBRANES THAT
SEPARATE AND LINK THEM. SO WHEN
I SAY WHEN HE SAYS ORGANISM,
THINK BACTERIAL CELL, FORGET
CELL WALL JUST THINK BACTERIAL
WITH CELL MEMBRANE AND IT IS
EQUIVALENT PHASE INSIDE OF THE
CELL AND OUTSIDE ARE E REQUEST
I'VE LENT FADES. STRANGE TO SAY
BUT -- PHASES. -- EQUIVALENT
PHASES.
IF THERE IS A CELL OR ORGANISM
IT IS HELPFUL TO THINK
EQUIVALENT PHASES WITH BARRIER
SEPARATING THEM. IT IS A
PRODUCTIVE WAY OF SEEING THE
QUESTION. A LOT OF WHAT I AM
GOING TO PUT TO YOU NOW THE SEED
REALLY CAME FROM MITCHELL'S
THINKING BACK IN THE 1950s. I
THOUGHT FOR A LONG TIME WHAT IS
IT -- WHAT CAN I DO? IN AN
INORGANIC WORLD WHAT CAN A
Ph.D. GRADIENT ACROSS
INORGANIC BARRIER DO? NOT GOING
TO MAKE ATP. WHAT IT CAN DO IS
DRIVE REACTION BETWEEN
HYDROGENND A CO 2. THIS WAS
PURE SIMPLE PHYSICAL CHEMISTRY.
THIS IS NOT GOING TO GO INTO THE
REDOX POTENTIAL UNLESS YOU ASK
ME SPECIFICALLY AFTERWARD BUT
JUST KNOW UPHILL HYDROGEN WON'T
REACT WITH CO 2 FOR,
FORMALDEHYDE BECAUSE IT IS NOT
DATED THERMODYNAMICALLY, THAT IS
PH 7 OR ANY OTHER PH YOU WISH TO
CHOOSE. THE REDOX POTENTIAL OF
GAS DEPENDS ON PH. PH 11 IS THE
-- PH OFFER THESE FLUIDS, THAT
MAKES HYDROGEN MORE REACTIVE,
THE REDOX POTENTIALS IS
BASICALLY 60 MILIVOLETS PER PH
UNIT SO CERTAINLY MORE REDUCING.
CO 2 IN ACIDIC ENVIRONMENT IS
EASIER TO PUSH ELECTRONS INTO IT
SO IT IS DOWNHILL, SPONTANEOUS
GOING TO HAPPEN, YOU HAVE BROKEN
DOWN THE ENERGETIC BARRIER TO
REACTION BETWEEN HYDROGEN AND CO
2 THEY ARE BUBBLING OUT OF THE
GROUND CO 2 COMING IN FROM OCEAN
WORTH OF CO 2 AND JUST LOWERED
THE BARRIER TO THEIR REACTION.
SO HIGHER PROPORTION WILL REACT
TO FORM, THE MOLECULES OF LIFE
KREBS CYCLE INTERMEDIAS SO YOU
NEED A -- INTERMEDIATES. YOU
NEED A BARRIER AND SOMETHING
CROSSING IT, YOU SHOW ELECTRONS
CROSSING THE BARRIER, MAYBE
PROTONS THE OTHER WAY. THIS WAS
FROM A EXPERIMENT DONE BY FORMER
Ph.D. STUDENT REUBEN HUDSON. I
HAVE BEEN TRYING TO DO THIS IN
THE LAB FOR FIVE YEARS BEFORE
THAT, I NEVER MANAGED TO GET
CONTROLS RIGHT AND HE DID IT
AFTER HE LEFT MY LAB. GREAT FOR
HIM. HE WAS KIND ENOUGH TO
INCLUDE ME ON THE PAPER BUT AID
NOTHING TO DO WITH THE SCIENCE
BEYOND HOW WE HAVE THE IDEAS IN
THE FIRST PLACE. ON THE HYDROGEN
SIDE, THE ELECTRONS ARE PASSING
TO THE BARRIER,S SOMETHING
DODGEY ABOUT THAT SPOT. THE
PROTONS ARE REACTING IMMEDIATELY
WITH HYDROXIDE IONS JUST A
NEUTRALIZATION REACTION, GOING
TO HAPPEN IMMEDIATELY AND GIVE
OFF HEAT. OTHER SIDE YOU PICK UP
ELECTRONS TO, CO 2, PICKING UP
PROTONS TO FORM ORGANIC
MOLECULES, FORMIC ACID IN THAT
CASE, MAYBE NOT QUITE LIKE H
WITH PROTONS THE OTHER WAY, A
QUESTION FOR DISCUSSION
AFTERWARD IF INTERESTED. THIS
HEARSAY THE SETUP IN MY LAB,
THIS HAS TO BE DONE INSIDE AN AN
AEROBIC BOX, THIS IS SPATIALLY,
THE TWO POST-DOCS DOING THIS IN
MY LAB, THIS IS A MICROFLUIDIC
CHIP BUT WE HAVE LAMINAR FLOW,
ACID FLOW THAT PRECIPITATES
BARRIER IN THE MIDDLE AND THE
QUESTION IS WHETHER THAT DRIVE
CO 2 REDUCTION TO FORM ORGANIC
MOLECULES? THE ANSWER IS YES,
NOT IN HUGE AMOUNTS MIGHT NOT BE
IMPRESS WITH THAT BUT THIS IS
FORMATE HERE, AND ACETATE, TINY
AMOUNTS OF METHANOL, PYRUVATE
TOO BUT NOT ON A REGULAR BASI B.
SO IT WORKS. IT DOESN'T WORK IN
A HUGE WAY BUT H IS ATMOSPHERIC
PRESSURE, OTHER WORK FROM TOM
COLLIN'S GROUP FROM 20 YEARS AGO
WHICH WORKED IN A STEEL REACTOR
BUT NOT GLASS INTERESTINGLY SO
IT IS PARTIALLY NOT QUITE
BELIEVABLE BUT WHAT THEY START
WITH IN THIS CASE WAS HIGH
TEMPERATURES, HIGH PRESSURE, AND
FORMIC ACID INSTEAD OF HYDROGEN
CO 2, IDEA WAS HAVE THE
DISPROPORTION NATION OF FOR MATE
TO FORM HYDROGEN AND CO 2 WHICH
REACT TO FORM LONG CHAIN HYDRO
CARBONS AND LIPIDS. I DON'T KNOW
IF THIS IT SEEMS TO ME OR IF
THIS IS THE PROJECTOR. THE
NUMBERS YOU CAN SEE THERE, 15,
THE NUMBER OF CARBON ATOMS IN A
HYDRO CARBON CHAIN. I'M GOING TO
COME OVER HERE AND SEE IF IT
STOPS FLASHING IF I STAND HERE
FOR A WHILE. SO YOU CAN GET
RELATIVELY LONG CHAIN FATTY
ACIDS FORMING IN THOSE UNDER
THOSE CONDITIONS. WE TOOK
SAMPLES OF THOSE, MIXED TOGETHER
AND LOOKED TO SEE CAN WE MAKE
UNDER THESE CONDITIONS STARTING
WITH THOSE PROTO CELLS UNDER THE
HARSH CONDITIONS IN HYDRO
THERMAL VENT?
I WON'T GO THROUGH THE DELL
TAILS ON DETAIL, NOT JUST ME. I
WILL COME BACK OVER HERE IN THAT
CASE. ALL I WANT TO TAKE HOME
FROM THIS 70 CENTIGRADE MODERN
NOTION -- THIS IS GOT CALCIUM
MAGNESIUM IONS AN STRONGLY
ALKALINE PH 12. CRYOELECTRON
MICROSCOPY AND CONFOCAL
MICROSCOPY, BASICALLY PICTURES
YOU CAN SEE THE OPTICAL DENSITY
THESE ARE MIXTURES OF FATTY
ACIDS AND LONG CHAIN FATTY
ALCOHOLS FORMING BIOLAYER
MEMBRANE AROUND IT AND AQUEOUS
INTERIOR UNDER THE HARSH
ALKALINE HYDRO THERMAL
CONDITIONS. THE OTHER THING --
THANK YOU. SO THE OTHER THING
YOU WOULD REQUIRE FOR CO 2
FIXATION INSIDE PROTO CELLS
WOULD BE SOMETHING LIKETHER RA
DOCK SIN, IRON SULFUR PROTEINS
WE HAVE THE IRON SULFUR MINERALS
IN BARRIERS HOW WE GO FROM
MINERAL TO MORE LIKE A PROTEIN
NEXT TO MEMBRANE? THE ANSWER IS
IRON SULFUR CLUSTERS, CAN WE
MAKE SOMETHING MORE LIKE IRON
SULFUR CLUSTER, AND I WAS
SHOCKED TO SEE THIS SHOULDER
WHICH IS OR HERE YOU CAN SEE IT
SLIGHTLY BETTER. THAT IS ON UV
SPECK TROUGHSSCOPY, IT IS THE
CLASSIC 4FV 4S CLUSTER SO
CYSTEINE WITH IRON CHLORIDE AND
SODIUM SULFIDE GIVES RISE TO
4FE. WE DID MASS SPECTROSCOPY
AND LOOKED AT THE REDOX
POTENTIAL, IT IS THE SAME AS
MINUS 450 MILIVOLTS SO THE SAME
REDUCTION POTENTIALS. WE
HAVEN'T SHOWNED IN CO 2 BUT IN
PRINCIPLE SHOULD AND COULD.
SIMPLE MIXTURE OF THE SIMPLEST
AMINO ACIDS, AND SOME IRONS ARE
CAPABLE ARE CAPABLE OF MOVING
CLUSTERS IN CO 2 IN MODERN FIXED
CELLS. SO EXTRAORDINARY THAT
THAT WORKS. I HARDLY NAILED THE
CASE BUT WHAT I HAVE SHOWN YOU
IS THAT CO 2 AND HYDROGEN CAN BE
MADE TO REACT BY PH GRADIENTS
WITH IRON SULFUR MINERALS THAT
GIVE RISE IN PRINCIPLE TO
ORGANICS INCLUDING LONG CHAIN
CAR BOXIC ACID TO MAKE IRON
SULFUR CLUSTERS TO DRIVE CO 2
FIXATION INSIDE THE CELLS SO A
LOT OF MISSING HOLES THERE. BUT
THERE IS ALSO A FEW MARKERS OF A
POSSIBLE PATH THAT I WOULD SAY
IT IS WORTH CONTINUE MANAGE THE
LAB WITH THESE EXPERIMENTS
BECAUSE I THIS I WE CAN NAIL IT
BUT I AM ALSO PRONE TO SEL
SELF-DELUSION. WHO CAN SAY,
METABOLISM. SORRY ABOUT THIS. IT
IS NOT AS CO COMPLICATED AS IT
LOOKS. ONLY COUPLE OF THINGS TO
NOTICE. THE IT IS CORE OF
METABOLISM AS WE KNOW IT. I
WOULD SAY IT IS OLDER AN GENES,
I SAY THAT BECAUSE BACTERIA HAVE
THE SAME CHEMISTRY GOING ON BUT
THE GENES THAT CODE THE ENZYMES
THAT CATALYZE ARE NOT CONSERVED
IN BACTERIA AND ARCHEIIA SO YOU
HAVE DIFFERENT GENES THAT
CATALYZE THE SAME CHEMISTRY.
EAST YESTERDAYS EXPLANATION IS
CHEMISTRY CAME BEFORE THE EVEN
GOOS WHICH IS A SWAGGERING CLAIM
BUT LOOK WHAT IS GOING ON HERE
IN BROWN WE HAVE HYDRO WREN SO
CO 2 TOP LEFT HAND CORNER IN
BROWN ORANGE COLOR, HYDROGEN
BEING GREEN WE HAVE CO 2 AND
TAKE NOTICE STRAIGHT TO THE
CENTS CYCLE, ACETYLCOA IT COULD
BE BOUND TO MINERAL SURFACE OR
BOUND ON ACETATE. PYRUVATE,
ALPHA KETO GLUTERATE, A FEW
STEPS BEFORE WE ARE AT THE HEART
OF METABOLISM, IT IS THE
CHEMISTRY OF HYDROGEN AND CO 2
AND LITTLE ELSE. SOME AMOAN YAW
TO GET O THE AMINO ACIDS. SO NOT
A LONG WAY. MOST -- THE BLUE
ARROWS BEING DONE IN THE LAB
OVER THE LAST SEVEN OR EIGHT
YEARS. NONE OF THAT WAS DONE
EIGHT YEARS AGO BUT LAST 7, 8
YEARS,S CENTS CYCLE
GLYCOGENESIS, THE ACETYLCOA
PATHWAY ARE NONE IN THE LAB
UNDER CONDITIONS WITH METAL IONS
AS CATALYSTS WITH THE STEPS YOU
SEE IN MODERN PATHWAYS AND THE
CENTS CYCLE IS NOT CLOSED AND
COMPLETE 9 OF 10 REACTIONS ARE
DONE IN THE LAB NOW BY THREE OR
FOUR DIFFERENT GROUPS. IT IS NO
LONGER HAND WAVIN WAVING. IT ISL
CHEMISTRY. THE IT WILL HAPPEN IN
THE RIGHT CONDITIONS. THIS IS
THE RED MUCH MORE DIFFICULT
PROBLEM. YOU HAVE TO GET TO THE
RED BOXES BEFORE YOU CAN BEGIN
TO SYNTHESIZE NUCLEOTIDE
BUSINESS THE BIOCHEMICAL
PATHWAYS. WE LOOKED AT LATER
STEPS SO THIS IS ASPAR AT A TIME
IS A KEY AMINO ACID NEVER
SYNTHESIZED UNDER CONDITIONS
BEFORE. THERE IT IS. WE
PUBLISHED THIS RECENTLY, A
LITTLE BIT OF A CON BECAUSE WE
STARTED WITH ACETATE ONE STOP
BEFORE ASPAR AT A TIME. THE
QUESTION IS COULD WE DO THAT
STEP USING A CO-FACTOR PARADOCKS
MEAN, WE NEED TO MAKE IT TO SHOW
IT WORKS. BUT INTERESTING THIS
IS WITH PARADOCKS MEAN YOU DON'T
GET ANY ASPARTATE WITH THAT
ALONE BUT WITH COPPER SULFATE OR
IRON CHLORIDE YOU GET A
REASONABLE PEAK. IT HAS TO BE
KINETICALLY FAST. IT IS STRIKING
METAL IRONS TURN OUT THE ONE
WHAT IS ARE DRIVING THIS
CHEMISTRY. THIS THIS IS ALANINE
SO OXALLO ACETATE, THE PYRUVATE
BECOMES CONVERTED INTO ALANINE.
THAT HAPPENS SPONTANEOUSLY, IT
IS FASCINATING THAT (INAUDIBLE)
INHIBITS THAT PROCESS, PARADOX
MEAN BY ITSELF. WE LOOKED AT
GCMS, NOT LONG ON THIS BUT WHAT
YOU HAVE SEEN ALANINE ASPARTATE.
WE GET LYSINE BETA ALANINE AND
SERINE IN TRACE AMOUNTS BUT
INTERESTING GET -- RECOVER IING
THE AMINO ACID PART OF
METABOLISM, SO LOOKS LIKE
RECOVERING THE METABOLIC MAP. I
MENTION CYSTEINE TO MAKE
CYSTEINE TO MAKE IRON SULFUR
CLUSTER NOBODY MADE CYSTEINE
UNDER THESE CONDITIONS EITHER.
THAT IS IT HERE. THAT IS THE
GAME, ONLY ONE STEP COMING FROM
SERINE BUT WE MADE GLYCENE
SERINE AND CYSTEINE WE ARE
TRYING TO DO THAT AS ONE POT
SYNTHESIS SO IT LOOKS THE MORE
INTRACTABLE ARE BEGINNING TO
HAPPEN. THIS IS ONE OF MY
FAVORITES FROM THE LAB IN THE
LAST YEAR, THIS IS YOUR SILL,
THIS IS THE BIOCHEMICAL PATHWAY
STARTING WITH AKNOWNIA AND
CARBONATE AND ASPARTATE. THIS IS
A ONE STOP SYNTHESIS AND
SYNTHESIS A STEP BEFORE THATMENT
IN THE PRESENCE ONLY METAL IONS,
COPPER IN THIS CASE. WE TRIED
DIFFERENT PH DIFFERENT
TEMPERATURES, WHOLE SET OF METAL
IONS, DIFFERENT PRESSURES AND SO
ON. AND WE OPTIMIZE THE BEST
CONDITIONS AND THIS IS A
SYNTHESIS OF YOUR SILL WITHIN
THE ONMIZED SET OF CONDITIONS
AND GOT TENFOLD THE YIELD. I WAS
PLEASED THAT IT TURNS OUT THE PH
9, 90 DEGREES CENTIGRADE, IN THE
PRESENCE OF COPPER SULFIDE OF
ALL THINGS. SO ALKALINE HYDRO
THERMAL CONDITIONS OPTIMIZES THE
SYNTHESIS OF URASIL. WE HAVE
NOT MADE ATP OR NOT MADE ADEN
SCENE, NOT PURINE NUCLEOTIDES SO
LOT TO DO BUT ENOUGH
ENCOURAGEMENT TO MAKE ME THINK
IT IS WORTH PURSUING THIS. NOT
MADE ATP, NOT MADE ADEN SCENE
BUT WE CAN PHOSPHORYLATE ADP TO
ATP, THAT IS INTERESTING.
DOESN'T REQUIRE THE ATP
SYNTHASE, SPINNING THERE IN THE
MIDDLE, IT CAN BE DONE WITH AS
TILE PHOSPHATE A TWO CARBON AND
WE GET ABOUT A 20 PERCENT YIELD.
THIS IS QUITE OLD WORK WE
REPEATED, IT TOOK A WHILE TO
REPEAT BUT ONCE WE DID, WE FOUND
TEN OTHER PHOSPHORYLATING AGENTS
DIDN'T WORK ONLY AS TEAL
PHOSPHATE WORKED. WE FOUND
ABOUT TEN METAL IRONS ONLY
(INAUDIBLE) WORKED IT WORKS FOR
ARCDP, WE CAN PHOSPHORYLATE ADP
TO ATP BURKS NOT GTP TO UDP SO
WHY IS ATP UNIVERSAL ENERGY?
BECAUSE YOU CAN MAKE IT IN
WATER, YOU CAN PHOSPHORYLATE IT
IN WATER WITH (INAUDIBLE) AS THE
ONLY CATALYST, 20% YIELD. SO IT
IS AGAIN FAVORED CHEMISTRY. IT
WORKS BECAUSE THE GOD OF
THERMODYNAMICS SAYS IT SHALL BE.
IT IS ALMOST QUITE SCARY IF YOU
THINK THAT WAY. INFORMATION. I
HAVE INSINUATED THIS, THIS IS A
MAP OF METABOLISM THAT MAYBE
SLIGHTLY FAMILIAR NOW, COLOR
CODED HERE ARE AMINO ACIDS SO
GLYCENE, ALANINE, ASPARTATE ALL
IN GRAY, THEY HAVE A G AT THE
FIRST POSITION OF THEIR CODON.
THEY ARE ALL A SINGLE STEP FROM
CARBOXYLIC ACID. A SINGLE
REDUCTIVE AM NATION FROM A
CARBOXYLIC ACID TO FORM THOSE.
THEY HAVE THE SAME GENE AT THE
FIRST POSITION. IN YELLOW, IS
A, THE FIRST POSITION OF THE
CODON. IN BLUE IT IS CYTOKINE
AND IN GREEN IT IS YOU. SO
DOESN'T TELL AS MUMP BUT TELLS
US THE SOME STRUCTURE, SOME
RELATIONSHIP WEAN THE CODONS AND
-- BETWEEN CODONS AND AUTOTROPIC
METABOLISM LIMB WHICH IS
INTERESTING AS A STARTING POINT.
IF WE STRUCTURE -- SO THE TOP
BOX THERE AT THE LEFT, THAT IS
WITH THE G AT THE FIRST POSITION
OF THE CODON, THEN FIRST
POSITION, THIS IS NOW HYDRO FOE
BUSINESSTY, SO JUST TO SHOW OWE,
VALENE IS A -- AND THE SECOND
POSITION OF ANTI-CODON IS A,
WHICH IS THE MOST HYDROPHOBIC
BASE. ASPARTATE HERE,
HYDROPHILIC AMINO ACID BY YOU,
THE SECOND CODON HYDROPHILIC
BASE. THEY ARE INTEREST
INTERACTIONS HYDROPHOBIC
INTERACTIONS OR SOMETHING
SIMILAR GOING ON. WORKS BEST
WITH PURINE AT THE FIRST
POSITION OF THE CODON, WE SEE A
STROLL RELATIONSHIP, LESS WELL
WITH PRIM DEA DEAN. THESE PATTEN
SUGGEST DON'T NAIL BUT SUGGEST
BIOPHYSICAL REACTIONS. THIS IS
THE THIRD POSITION AND EVERYBODY
HEAR SAY THE THIRD POSITION IS
REDUNDANT. THERE IS NO PATTERN
THERE BUT WILL IS. THIS IS JUST
TO GIVE ONE EXAMPLE AGAIN, THIS
IS AN INVERTED CODON TABLE, THIS
IS A G THE FIRST POSITION, A AT
THE SECOND POSITION OF THE
CODON, THAT IS TRUE FOR
ASPARTATE AND GLUTAMATE BUT A
PRIM DEAN AT THIRD POSITION OF
CODON. AND INVERT FORD THE
UNDERCODON. THE DIFFERENCE IS
SIZE. IF THERE IS A SMALL PRIM
DEAN AT THIRD POSITION OF
ANTI-CODON YOU HAVE LARGER AMINO
ACID THERE AND VICE VERSA, IF
YOU GO TO LARGE PURINE THAT
THIRD POSITION ANTI-CODON YOU
HAVE A SMALLER AMINO ACID THERE.
SO THESE PATTERNS ALL -- DON'T
NAIL ANYTHING BUT SAY THERE ARE
DIRECT INTERACTIONS GOING ON.
WRONG DIRECTION HERE. THIS SLIDE
IS OUT OF PLACE. GOING TO P WHO
TO THAT ONE. DON'T KNOW HOW THAT
HAPPENED. THIS IS MOLECULAR
DYNAMIC SIMULATIONS IN THE LAB.
OVER LAST YEAR OR SO. AND SO
JUST TO SHOW YOU HERE, SO THIS
IS THE PROPORTION OF TIME SPENT
BY PROLINE NEXT TO ONE OF THE
FOUR BASES AMP CMP GMP OR UMP AN
IT SPENDS TIME BIG PEAK HERE
NEXT TO GMP WHICH IS THE BASE
THAT CODES FOR IT. THE SECULAR
POSITION OF THE ANTI-CODON
SUGGESTING A RELATIONSHIP THERE.
WE GETS -- WE DO BETTER THAN 99%
OF RANDOM ALLOCATION SO WE CAN
PREDICT 50% OF THE ANTI-CODONS
FROM MOLECULAR DYNAMICS AND
RELATIONS. WE CAN DO SAME THING
WITH ONLY DOING FIVE AMINO ACIDS
SO FAR, THIS IS NMR, BINDING
STRENGTH AND INTERACTIONS WITH
NMR, SHOWING THE SAME THING, THE
INTERACTIONS ARE STRONGEST
BETWEEN NUCLEOTIDE THAT CODES
FOR AMINO ACID AND THE AMINO
ACID ITSELF. I HAVE HOPPED A
SLIDE BUT I WILL LEAVE THAT
SLIDE BEHIND. AND MOVE ON. WHAT
DOES THAT SHOW? IN MY MIND THAT
SHOWS THAT CO 2 FIXATION CAN BE
DRIVEN TO GIVE RISE TO
METABOLISM WHICH IS CAPABLE OF
POTENTIALLY GIVING RISE TO
NUCLEOTIDE WHICH WILL INTERACT
WITH AMINO ACIDS IN A WAY WHICH
PREFIGURES THE CODE AND GENES
ARE THERE ARE LIKELY TO ARISE IN
THE CONTEXT OF A AUTO TROPIC
METABOLISM GROWING PROTO CELLS
SO NOT UNREASONABLE CONTEXT FOR
THE ORIGIN OF LIFE LIFE. MAY OY
NOT BE REAL BUT ENOUGH SUBSTANCE
TO MAKE IT LOOK PLAUSIBLE OR
FEASIBLE. SO WHY ANY OF THAT
MATTER? TO YOU? LET'S FAST
FORWARD AROUND 3 1/2 BILLION
YEARS TO THE EXPLOSION WHERE WE
SEE FIRST ANIMALS IN -- NOT THE
FIRST ANIMALS THESE ARE THE
LEFT-HAND SIDE, THESE ARE FILTER
CREATURES MORE STUCK TO THE
BOTTOM OF THE OCEAN, OFTEN 200
METERS DOWN IN BLACKNESS MEANING
NOT PHOTO SYNTHETIC THEY LOOK
LIKE PLANTS BUT NOT, THEY ARE A
BIT LIKE SPONGES. THEN WE HAVE A
EXPLOSION, WHAT WE ARE SEEING IS
REALLY PREDATION, WE ARE SEEING
CLAWS AN EYES YOU WILL KINDS OF
ARMER PLATING, WE ARE SEEING
PREDATORS PREY, MODERN ECO
SYSTEMS AS WE UNDERSTAND IT. TO
RUN AROUND AND DO THOSE THINGS
WE CAN BE VIRTUALLY CERTAIN THAT
THEY WERE AEROBIC, QUITE A LOT
OF EVIDENCE THAT OXYGEN WAS
ARISING IN THE ATMOSPHERE AROUND
THAT TIME BECAUSE AEROBIC
RESPIRATION GIVES ENOUGH POWER
TO HAVE THAT MANY TROPIC LEVELS.
SO ROUGHLY 40% EFFICIENCY YOU
GET 40% ENERGY FROM WHATEVER
YOU'S, YOU CAN CONSERVE THAT.
THAT ALLOWS YOU AROUND 6 TROPIC
LEVELS IF YOU JUST TAKE A RANDOM
STAB IN THE DARK AND SAY YOU
NEED 1% ENERGY AVAILABLE IN THE
SYSTEM PASS THROUGH, YOU CAN
HAVE SIX TROPIC LEVELS WITH
RESERVATION. SOMETHING LIKE
FERMENTATION OR ANY OTHER
ELECTRON ACCEPTORS THERE IS NOT
OXYGEN THEY TEN NOT TO
ACCUMULATE IN ABSENCE OF OXYGEN,
YOU ONLY GET TWO OR THREE TROPIC
LEVEL WHICH IS MEANS YOU CAN'T
HAVE PREDATION IN THE ABSENCE OF
A MODERN AEROBIC RESPIRATORY
SYSTEM. YOU CAN BE CERTAIN THE
ANIMALS HAD A MODERN KREBS CYCLE
AS WE KNOW IT. AND THE
SURPRISING THING THERE IS WHAT
WE START OUT WITH ESSENTIALLY
COUPLE OF THESE SLIDES OUT OF
ORDER. WE START WITH REDUCTIVE
KREBS CYCLE ON THE LEFT HAHN
SIDE I SHOWED YOU AT THE
BEGINNING BASICALLY A
BIOSYNTHETIC ENGINE MAKING
ORGANICS, THE RIGHT HAND SIDE WE
HAVE THE OXIDATIVE KREBS CYCLE,
BURNING THOSE ORGANICS TO
GENERATE MEMBRANE POTENTIAL. YOU
WONDER WELL, FOR THE FIRST TWO
BILLION YEARS OR MORE OF LIFE WE
HAVE GOT -- WE HAVE THESE
CRYOSEN SYNTHETIC ENGINES MAKING
MOLECULES THEN IT SCREECHES TO A
HALT AND CHANGES DIRECTIONS?
CAN'T BE DOING THAT. HOW DOES IT
CHANGE? THESE SLIDES ARE OUT OF
ORDER. THIS IS A INSIGHT INTO
HOW IT HAPPENS BECAUSE THIS
HAPPENS IN MOST BACTERIA, THAT I
DON'T HAVE A COMPLETE CENTS
PSYCH MILLION THE WAY WE
RECOGNIZE IT. THEY HAVE THEY ARE
A TWO PRONGED PATHWAY, THEY HAVE
AN OXIDATIVE PRONG AT THE TOP
AND PULLING OUT HYDROGEN HERE IN
THE WAY OF A MODERN SYSTEM, BUT
THEY ALSO HAVE A REDUCTIVE
PRONG. THIS GOES BACK OF COURSE
TO (INAUDIBLE) SAINT GEORGE AND
KREBS HIMSELF IN 190s WHO KNEW
VERY -- 1930s, WHO KNEW THAT
IT GIVES RISE TO SUCCINATE AND
SO ON. IT CAN BE OPERATING
EITHER DIRECTION ON THAT PART OF
THE PATHWAY. SO IT IS REDUCTION
BALANCE, NADH AND REDUCTION,
WHETHER YOU ARE SUCKING IN
HYDROGENS OR SPITTING THEM OUT
AND BURNING THEM. THIS PART HERE
IS THE INTERESTING BIT BECAUSE
IT POINTS TO SUCCINATE. WHAT IS
HAPPENING THERE? DOES IT GO THAT
WHICHER THIS WAY? A COMPLETE
SICKLE OR NOTHING AT ALL?
SUCCINATE IS CENTRAL TO HOW THAT
WORKS. HERE IS WHAT HAPPENS IN
THINGS LIKE SEA TURTLES TODAY
THIS WAS DISCOVERED BY KEN STORY
IN THE '70s, IF I REMEMBER
RIGHTLY. THEY DON'T HAVE A
SUCCINATE DEHYDROGENASE, THEY
HAVE A FUME RATE REDUCTASE. THE
FUME RATE KREBS CYCLE
INTERMEDIATE IS THE ELECTRON
ACCEPTOR SO TAKING FROM NADH
INTO THE RESPIRATORY CHAIN TO
MAKE ATP BUT INSTEAD OF GOING
THROUGH THE CHAIN TO OXYGEN IT
COMES TO FUME RATE. AND MAKES
SUCCINATE AS A WASTE PRODUCT. SO
KNOWN FOR DECADES. ONLY RECENTLY
MIKE MURPHY AN COLLEAGUES IN
CAMBRIDGE HAD A NATURE PAPER
NEARLY TEN YEARS AGO SHOWING
THAT IN REPROFUSION INJURY YOU
TEND TO ACCUMULATE SUCCINATE
THROUGH SOMETHING SIMILAR TO
THAT AND AS SOON AS YOU
REINTRODUCE OXYGEN YOU OXIDIZE
THAT SUCCINATE BACK TO FUME RATE
AND IT IS POWERING ELECTRON
TRANSFER BACK TO COMPLEX 1 SO A
HEART OF ISCHEMIA REPROFUSION
INJURY, I DUD MY Ph.D. ON AND
WISH I HAD MADE THAT DISCOVERY
BUT HE -- IT WAS 20 YEARS AFTER
WORKING ON THE SAME QUESTIONS
AND I WAS BEFUDDLED BY MY OWN
DATA WHICH POINTED STRAIGHT TO
THAT AND NEVER SAW IT. SO THIS
IS REALLY, COMPLEX 2 FUME RATE
REDUCTASE OR SUCCINATE
DEHYDROGENASE IS THE ONLY ENZYME
IN THE KREBS CYCLE THAT STILL IN
THE MEMBRANE AND IT IS GIVING
YOU EFFECTIVELY A READ OUT ON
HOW YOU ARE DOING WHAT IS THE
REDOX STATE OF THE MITOCHONDRIA
AS A WHOLE? THE REDOX STATE OF
THE CELL? HOW ARE YOU DOING? IN
A HYPOXIC SITUATION OR A
SITUATION WHICH A FALSE HYPOXIA?
ARE YOU DOING ALL RIGHT? IT
TELLS YOU A LOT ABOUT THE
ENVIRONMENT YOU ARE IN. SO
INTERESTING SUCCINATE IS A
REALLY POTENT EPIGENETIC SIGNAL
AND FUMARATE AS WELL. IF YOU
THINK IN THAT WAY HOW THE KREBS
CYCLE IS WORKING, THIS IS MY BAD
ATTEMPT TO DO A RESPIRATORY
CHAINS HERE COMPLEX 1, COMPLEX
2, COMPLEX 3 AND 4 AND ATP
SYNTHASE AND THE KREBS PSYCH
WILL THE MORE DETAIL MAKING NADH
WHICH GETS OXIDIZED IN COMPLEX
1. THAT IS WHAT ALL THE
TEXTBOOKS WILL SHOW. BUT NOW WE
IMAGINE THERE IS DAMAGE TO
COMPLEX 1. AND WHENEVER WE SEE
DAMAGE TO COMPLEX 1 WE TEND TO
THINK OKAY RESPIRATION IS GOING
TO BE IN SOME WAY, NOT GREAT FOR
RESPIRATION, IT IS NOT THAT BAD
NECESSARILY FOR PERSPIRATION, WE
CAN PUT ELECTRONS IN FROM VISUAL
3 PHOSPHATE FROM THE OUTSIDE
FROM THE CYTOSOL BY PHOSPHATE
DEHYDROGENASE STRAIGHT INTO
COMPLEX 3 SO ACTUALLY TERMS OF
ATP SYNTHESIS IT DOESN'T MATTER
MUCH IF COMPLEX 1 GOES DOWN, YOU
ARE OKAY FOR ENERGY AND A LOT OF
CANCER CELLS PROBABLY WORK THAT
WAY. IT DOES MARY FOR THE
OXIDATION OF NADH. THERE AREN'T
MANY OTHER SINKS FOR THE NADH SO
IT WILL BUILD UP AND YOU CAN
SHOW USING SURFACE THAT IT
BUILDS UP. IF IT IS BUILDING UP
IT WILL PUSH THE KREBS CYCLE IN
REVERSE. WHAT WE HAVE IS
ESPECIALLY SUCCINATE AND
CITRATE, THE LAST STEP FROM
CITRATE TO CITRATE TO ALPHA KETO
GLUTERATE THROUGH TO CITRATE, IS
COMMON IN CANCER, DRIVING PARTS
OF THE KREBS CYCLE USUALLY NOT
THE WHOLE CYCLE BUT PARTS
BACKWARDS. SO CITRATE AND
SUCCINATE WILL DISPERSE FROM THE
MITOCHONDRIA. SO WE HAVE A
PARTIAL REVERSAL OF THE KREBS
CYCLE, WHAT IS HAPPENING THERE,
ACETATE NOT GOING TO TALK ABOUT
THAT BUT THAT IS CENTRAL TO ALL
METABOLISM AND ACETYLCOA HISTONE
ACETYLATION, WE ARE DRIVING
GROWTH AXIS HERE. SIMILARLY FOR
SUCCINATE, THAT IS BOUNDING TO
PROLINE HYDROXYLASE, HIF 1 AL PA
IS ACTIVATED. SO DAMAGE TO
COMPLEX 1 IS GOING TO FLUX
THROUGH THE KREBS CYCLE WHICH
WILL GIVE A FALSE SIGNAL TO SAY
YOU ARE IN A HYPOXIC SITUATION
AND THE EPIGENETIC SIGNAL FROM
THAT IS GROW. THAT'S EXACTLY
WHAT CANCER CELLS WANT TO HEAR.
IT IS ALL COMING FROM THE SIMPLE
MECHANICS OF HOW THE ELECTRICAL
MEMBRANE POTENTIAL IS
INTERACTING WITH THE KREBS CYCLE
AND POTENTIAL FOR REVERSAL TO
THE KREBS CYCLE WHICH CAME AS A
SHOCK IN THE CANCER FIELD TEN
YEARS AGO WHEN THIS KIND OF
THING WAS FIRST DISCOVERED IT
WAS A SHOCK FOR THE KREBS CYCLE
BEING INVOLVED IN CANCER. WHEN
WE TAKE A FEW STEP BACKS AND
THINK, IT MAKES PERFECT SENSE
THAT IT'S CENTRAL TO AXIS. SO IT
IS NOT BY NO MEANS SAYING THIS
IS DRIVING CANCER, IT IS
PROVIDING I WOULD SAY A
PERMISSIVE ENVIRONMENT THAT
CANCER CELLS CAN TAKE ADVANTAGE
OF. WE ARE NOT A MILLION MILES
FROM THE WARBURG EFFECT WHICH IS
PROBABLY ONE OF THE THINGS THAT
MEANS THE MOST THING TO THE
LARGEST NUMBER OF PEOPLE, I
DON'T KNOW THAT ANY TWO PEOPLE
IN THIS ROOM WOULDN'T UNDERSTAND
EXACTLY THE SAME THING BY THE
WARBURG EFFEC EFFECT. BUT WHAT K
IT MEANS IS NOT REALLY WHAT
WARBURG HIMSELF MEANT BUT AS
TONY PUT IT IT IS BIOSYNTHETIC
MITOCHONDRIA, IT IS WORKING
LARGELY IN REVERSE LARGELY ABOUT
BIOSYNTHESIS AND LITTLE TO DO
WITH ATP AND IF WE THINK THAT
ANY OXIDATIVE ATP TO GROWS THAT
THE WRONG WAY, YOU NEED LOTS OF
NAPH, YOU NEED SOME ATP BUT NOT
TOO MUCH. YOU NEED PA MEMBRANE
POTENTIAL CERTAINLY BUT YOU CAN
MAINTAIN WITHOUT INVOLVING THE
KREBS CYCLE FROM THINGS LIKE
GLYCEROL PHOSPHATE. SO A
DIFFERENT WAY OF SEEING THIS
WIRING AND IF YOU THINK ABOUT IT
IN TERMS OF BIOSYNTHESIS YOU CAN
SEE WHY CANCER CELLS SOME CANCER
CELLS WOULD GRAB ON TO THAT FORM
OF WIRING. THIS IS THE -- NO,
OKAY. SO I SUSPECT THAT AS WE
GET OLDER, WE END UP WITH THE
SLIDE I SHOWED YOU WE END WITH
KREBS CYCLE WHICH IS SLOWING
DOWN, BEGINNING TO GO INTO
REVERSE WHICH IS BEGINNING TO
HAVE ACCUMULATION OF THINGS LIKE
CITRATE AND SUCCINATE. WHICH IS
TENDING TO MAKE US PUT ON WEIGHT
AS WE GET OLDER AND SLIGHTLY
LOWER OUR ENERGY LEVELS, STRIKES
ME NOT A MILLION MILE ACE WAY
FROM HOW I FEEL, IN MY MID
50s. AND I SUSPECT THAT IS A
PERMISSIVE ENVIRONMENT FOR
CANCER CELLS MUTATIONS AND SO ON
TO NAIL THAT METABOLISM IN AND
MAKE IT GO FORWARD. BUT NOT
EVERYTHING CAN ADAPT IN THAT
WAWAY. SOME CELLS ARE STUCK WITA
PARTICULAR SUBSTRATE. AND CANCER
CELLS LOVE GLUTAMINE AND IT WILL
DRIVE THE REVERSE KREBS CYCLE
WELL. BUT THE BETA CELLS WELL,
THEY ARE DETECTING GLUCOSE
LEVELS. I IMAGINE SOME PEOPLE
CAN TELL ME WHERE I GO WRONG
WITH THIS BUT MY UNDERSTANDING
IS THAT THE WAY THEY DETECT
GLUCOSE LEVELS IS BY MEMBRANE
POTENTIAL, THE ACTUAL SECRETION
OF INSULIN DEPENDS ON
MITOCHONDRIAL MEMBRANE
POTENTIAL. DON'T KNOW THERE IS
LARGE AM OF WORK ON THIS SO
INTERESTING TO HEAR FROM YOU
ABOUT THIS. BUT LET'S PRETEND IT
IS TRUE BECAUSE IT WOULD BE
INTERESTING IF IT WAS, WE HAVE
AN INCREASE IN GLUCOSE, IT GOES
STRAIGHT INTO THE MITOCHONDRIA,
THAT RAMPS UP KREBS CYCLE, THAT
RAMPS UP MEMBRANE POTENTIAL,
THAT LEADS TO RELEASE OF
SECRETION OF INSULIN. IF WE HAVE
DAMAGE TO THE RESPIRATORY CHAIN,
WHATEVER THAT DAMAGE MAYBE
CAUSED BY THEN THE GLUCOSE
DOESN'T -- MAY GET MANY THE SAME
WAY BUT IF THIS DAMAGE TO
COMPLEX 1 WE WON'T GENERATE
MEMBRANE POTENTIAL IN THE SAME
WAY. THEREFORE WE ARE NOT GOING
TO BE SECRETING INSULIN OR GOING
TO START SEEING ALL KINDS OF
PROBLEMS WITH DIABETES. MAYBE,
MAYBE NOT. THAT IS NOT MY MAIN
POINT, MY MAIN POINT IS WHY DO
NEURONS LOVE GLUCOSE? BECAUSE
MAYBE THEY ARE SIMILAR. MAYBE
THERE'S SOMETHING ABOUT RAMPING
UP MEMBRANE MANY POTENTIAL IN
GLUCOSE OR COULD BE LACTATE BUT
BASICALLY THE FORWARD KREBS
CYCLE AS WE KNOW IT, THAT IS
WHAT THEY WAN, THEY CAN WORK
FROM AS MATERIAL COA FROM
KETONES FINAL LACTATE, WORK FROM
GLUCOSE BUT ALL ARE COMPLEX SUB
INVESTIGATES THAT GO STRAIGHT
IN. THIS IS WORK THAT IS COMING
REALLY FROM ESTEL GOMEZ AND ERIC
SHOWN, I DON'T KNOW HOW WIDELY
ACCEPTED THIS IS BUT IT MAKES
SENSE TO ME. THEY ARE TALKING
THE MITOCHONDRIA ASSOCIATED
MEMBRANES WHICH IS THE PART OF
THE ENDOPLASMIC RETICULUM
SYNAPSING WITH MYCHON DRYIA AND
PROCESSING OF THINGS LIKE
AMYLOID PRECURSOR PROTEIN, AND
ALL KINDS OF OTHER THINGS ARE
HAPPENING I UNDERSTAND IN THE
MITOCHONDRIA ASSOCIATED
MEMBRANES. THEY ARE PUTTING
CALCIUM INTO THE MITOCHONDRIA.
AND WE HAVE THIS SAME SITUATION,
SOON AS CAPILLARIES OPEN UP,
GLUCOSE MOVES IN TO CELLS THE
CALCIUM MOVES IN, PYRUVATE
DEHYDROGENASE RAMPED UP, KREBS
CYCLE SPINS, WE HAVE A MEMBRANE
POTENTIAL SO WE HAVE A SUDDEN
INCREASE IN MEMBRANE POTENTIAL.
I WON'T TALK ABOUT THIS NOW BUT
I SUSPECT THAT IS GENERATING
ELECTROMAGNETIC FIELDS WHICH
WILL DO SIGNALING BUT WE WON'T
TALK ABOUT THAT SO MUCH AS WE
HAVE THE SAME PROBLEM AS IF
THERE IS DAMAGE TO COMPLEX 1,
THEN WE CAN'T BOOT UP THE SYSTEM
IN THE SAME WAY. WE STILL WE ARE
RELIANT ON ONE SUBSTRATE GLUCOSE
DAMAGE TO COMPLEX 1 MEANS NO
INCREASING MEMBRANE POTENTIAL
AND WE POTENTIALLY ARE GOING TO
BECOME VULNERABLE TO ALZHEIMER'S
DISEASE. ONE WAY OUT OF THAT IS
TO PUMP MORE CALCIUM IN. TO TRY
AND GET MORE BANG FOR YOUR BUCK
IF YOU LIKE AND JUST INCREASE
THE CALCIUM LEVELS, INCREASE THE
ACTIVATION OF PYRUVATE
DEHYDROGENASE AND PUMP UP
MEMBRANE POTENTIAL THAT WAY
WAY.ERRATIC SHOWN AND GOMEZ
THEIR ARGUMENT ISN'T THAT HIGH
PER TROPHY WITH MITOCHONDRIA
ASSOCIATED MEMBRANES IF IT IS
DRIVING ALZHEIMER'S DISEASE SO
IN THE A PROBLEM WITH
MITOCHONDRIA DIRECTLY SO MUCH
PROBLEM WITH OVERACCUMULATION OF
CALCIUM IN THE ENDO E PALACE MIC
RETICULUM SURROUNDING THE
MITOCHONDRIA. YOU TELL ME, BUT
IT LINKS IN NICELY AND WHETHER
RIGHT OR WRONG, THESE THINGS
SEEM TO BE VERY CLOSELY LINKED
NOT ONLY TO CANCER AS I
SUGGESTED OR TO DIABETES BUT
ALSO NEURODEGENERATIVE
CONDITIONS LIKE ALZHEIMER'S.
I'M USING THE SAME DIAGRAMS THAT
I WAS FOR THE ORIGIN OF LIFE.
BASICALLY NO CHANGE THERE. SO IT
IS NOT THAT I'M TELLING YOU THIS
IS RIGHT OR WRONG, TELLING YOU
HERE IS HOW WE SEE IT, MAY I
HOPE GIVE YOU SOME IMPULSE TO
THINK ABOUT THESE QUESTIONS. I
THINK I DON'T NEED TO CLOSE
PROPERLY, ELECTRIC MEMBRANES
DRIVE CO 2 FIXATION, METABOLISM
SPONTANEOUS, GENES AMPLIFY THIS
METABOLIC NETWORK. THAT MEANS
METABOLISM GIVES MEANING TO
GENETIC INFORMATION UNDISTILLED
DOES. RESPIRATION IS -- AND
STILL DOES. AND DAMAGE TO
RESERVATION WHICH ACCUMULATES IN
ALL OF US -- RESPIRATION LEADING
TO EPIGENETIC SHIFT IN ADDITION
TO WHAT IS GOING WRONG WITH
AGING. I WANT TO CALL ATTENTION
TO MY LAB. THE SPY GOODBYES IN
THE MIDDLE, SOME ARE STILL IN
THE LAB, SOME HAVE LEFT. THIS IS
A BIRTHDAY PRESENT, THEY ARE
HOLDING A KREBS CYCLE, I LOVE
THAT SO MUCH, AID TO PUT THE
NEWER MEMBERS OF THE LAB AROUND
THE EDGE. BUT THEY ARE BRAVE
PEOPLE TO BECOME ASSOCIATED
SEARCH WARRANT WITH SOMEONE LIKE
ME AND WORK ON QUESTIONS LIKE
THE ORIGIN OF LIFE, THEY HAVE
BEEN DOING BEAUTIFUL SCIENCE,
THE WORK ON ORIGIN OF LIFE IS
ENTIRELY DOWN TO THEM AND I FIND
IT INSPIRING TO BE WORKING WITH
THEM EVERY DAY. SO THANK YOU TO
THEM AND THE FUNDERS AND THANK
YOU FOR LISTENING.
[APPLAUSE]
>> THANK YOU, NICK, FOR THIS
REALLY VERY EXCITING PROVOCATIVE
TALK. WE HAVE A SERIES OF
QUESTIONS.
>> SO I THINK IT IS VERY
INTERESTING WHAT YOU TOLD US
TODAY AND AS FAR AS I UNDERSTOOD
BASICALLY THE MAIN IDEA IS THAT
FIRST CHEMISTRY THEN THERE WERE
GENES THAT WERE PRODUCING
PROTEINS THAT MADE THE CHEMISTRY
THE MOST EFFICIENT IN THIS
PARTICULAR ENVIRONMENT FOR THE
UNICELLULAR ORGANISMS BUT THEN
FOR THE MULTI-CELLULAR ORGANISMS
BASICALLY WHAT THIS LAST PART
YOU SHOWED THAT ALL DIFFERENT
TISSUES LIKE HAVE DIFFERENT
CHEMISTRY ENVIRONMENTS
BASICALLY, WAS THIS RELATED TO
THE FUNCTIONING ORION LIKE SOME
PROCESS CANCER AGING AND SO
FORTH. SO THE BASICALLY
DIFFERENT CELLS IN THE ORGANISM
THEY HAVE THE SAME GENES BECAUSE
THEY COME FROM THE SAME GENOME
SO THEY CAN GET STUCK WITH SAME
GENES THAT HAVE TO WORK IN
DIFFERENT ENVIRONMENTS,
MULTI-CELLULAR ORGANISMS, THEY
THINK ANY EVIDENCE
MULTI-CELLULAR ORGANISM THERE IS
IS MORE REGULATION IN TERMS OF
GENE EXPRESSION OR SOMETHING
LIKE THIS TO MAKE SURE THAT ALL
THE DIFFERENT CELLS IN THE SAME
ORGANISM FUNCTION IN DIFFERENT
CHEMICAL ENVIRONMENTS CAN STILL
FUNCTION AT THE MOST OPTIMALLY.
>> YES, I MEAN OBVIOUSLY THERE
IS A HUGE REQUIREMENT FOR GENE
REMEMBER RATION AND SO ON. AND I
THINK THAT IS WHAT BIOMEDICAL
SCIENCES OVER THE LAST FEW
DECADES HAS BEEN STUDYING TO A
LARGE EXTENT. OF COURSE, IT IS A
VITAL IMPORTANCE TO HOW THINGS
WORK. BUT I THINK THIS MAYBE A
BLIND SPOT FOR SOME OF THE MORE
OBVIOUS THINGS THAT UNDERPIN IN
PART BECAUSE THEY -- THEY SEE
THE DUSTY TEXTBOOK BIOCHEMISTRY,
THE IDEA THE KREB CYCLE IS THE
CENTER OF METABOLISM IN THE CELL
Z IN SOME SENSE EVERYBODY KNOWS
THAT AND SOME OTHER SENSE NOT
ACTUALLY SO OBVIOUS AS YOU MIGHT
THINK BECAUSE OF THE
PARTITIONING OF CELLS, BETWEEN
DIFFERENT ORGANELLES AND SO ON
SO IT IS -- AND I THINK OLD
IDEAINGS LIKE KREBS PSYCH
MILLION BIOLOGY TEND TO BE
FORGOTTEN BECAUSE THEY ARE OLD.
AND IT TAKES A WHILE FOR PEOPLE
TO SEE IT WITH FRESH EYES SO I
THINK A CHANGE THAT HAPPENED IS
REGULATION IS LARGELY ABOUT
LARGELY IS TOO STRONG A WORD BUT
ABOUT MAKING SURE THAT OF THE
KIND OF MAINTAINIOUS FLUXES MOST
LIKELY TO HAPPEN THE FORMS YOU
DON'T WANT DON'T HAPPEN IN THIS
PLACE. SO AS WE SEE REGULATION
BREAKING DOWN WHAT YOU SEE IS A
REASSERTION OF SPONTANEOUS
METABOLISM THERE FROM THE VERY
BEGINNING WHICH HAS A TENDENCY
TO DO CERTAIN THINGS, THE THINGS
IT DOES WILL DEPEND ON AGAIN
ANOTHER OLD FASHIONED ASPECT OF
SCIENCE WHICH IS WHAT IS THE
NADH TO NAD RATIO? WHAT IS
ACETYLCO TO COA RATIO? VARIOUS
RATIOS ARCTP TO ADP RATIO. THEY
ARE GIVING A GROUND STATE OF THE
CELL AND IF YOU ARE LOOSING
REGULATORY CONTROL THE GROUND
STATE DRIVES THINGS AND
COMPENSATION IS EPIGENETIC
COMPENSATION, ABOUT WHICH PART
OF THE NUCLEUS IS CLOSED DOWN
AND WHICH BITS ARE UPREGULATED
SO ON. AND SUDDENLY IN A WAY
OUTSIDE THE DOMAIN OF REGULATION
AND INTO DOMAIN OF COMPENSATION
FOR A PROBLEM AND COMPENSATION
ON A FAIRLY GRANULAR SCALE
ACROSS THE NUCLEUS IS NOT ONE
PATHWAY OR DIFFERENT PATHWAY, IT
IS A STRESS RESPONSE TO ENTIRE
SYSTEM WHICH IS NOW OUT OF ORDER
OUT OF SYNC. SO IT IS NOT THAT
I'M TELLING YOU ANYTHING YOU
DON'T KNOW, IT IS JUST THAT I'M
TRYING TO GET YOU TO SEE IT
THROUGH SLIGHTLY FRESH EYES
BECAUSE IT IS UNDERNEATH THIS
BEAUTIFUL FINES REGULAR
REGULATION OF A SYSTEM IS DOING
REGARDLESS. FROM A TOP DOWN VIEW
WE THINK GENES INVENTED
METABOLISM AND THE REGULATION
CONTROLS FLUX. I WOULD SAY THE
OTHER WAY UP, METABOLISM
INVENTED GENE, AND YES GENES
CONTROL FLUX BUT THE FLUX CAN
REASSERT ITSELF IN INTERESTING
AND UNUSUAL WAYS.
>> THANK YOU, VERY INTERESTING.
>> LET ME REMINDER, THERE IS A
RECEPTION RIGHT AFTER THIS, SO
IF YOU HAVE MORE DETAILED
QUESTIONS, YOU WANT TO DISCUSS
AT LENGTH THAT IS THE PLACE.
MEANWHILE WE HAVE SEVERAL SHORT
QUESTIONS.
>> THANK YOU VERY MUCH. IS THIS
WORKING?
>> YES.
>> FANTASTIC, FANTASTIC
PRESENTATION. I'M (INAUDIBLE)
IMMUNOLOGIST WITH 40 YEARS OF
PROTEIN CHEMISTRY IMMUNOLOGY AND
CANCER AN VACCINE SCIENCES.
(INAUDIBLE) PROCESS AND A LOT OF
QUESTION, BUT MY PRINCIPLE
QUESTION IS, DO YOU THINK THAT
THE MYCHON DEAL FUNCTIONALITY
WHICH IS MITOCHONDRIAL
FUNCTIONALITY AFTER EXPOSURE OF
THE NEWBORN WOULD BE COMPLETED
ALONG WITH ORGAN GENESIS AND
ANGIOGENESIS, WHICH PART OF
MITOCHONDRIA MAY BILL NOT
FUNCTIONAL AND.
THE EXPOSURE TO OXYGEN HAPPENS
IT TAKES STILL A FEW MONTHS FOR
THE MITOCHONDRIA TO BE FULLY
FUNCTIONAL BECAUSE THE NEWBORN
BABY IMMUNE SYSTEM IS DEPENDENT
STILL ON THE MOTHERS IMMUNITY.
AND ANOTHER MAYBE INTERESTING
THING IS WE HAVE COMPARED THE
GROWTH -- UNIGROWTH OF EMBRYO TO
THE CANCER --
>> WE ARE RUNNING OUT OF TIME,
COULD YOU ASK YOUR QUESTION?
>> THAT IS WHAT I WAS ASKING. I
THINK HE HEARD ME.
>> SO INTERPLAY BETWEEN OXYGEN
AND THE IMMUNE SYSTEM AND
MITOCHONDRIA ESPECIALLY DURING
EARLY LIFE AND EMBRYONIC
DEVELOPMENT AND BIRTH. I THINK
IT IS BECOME INCREASINGLY CLEAR
THE LAST FEW YEARS MITOCHONDRIA
SENTRA TO THE INFLAMMASOME, I
DON'T THINK WE KNOW A GREAT DEAL
ABOUT IT BUT A LOT OF WORK WITH
COVID IN RECENT TIMES OBVIOUSLY
HAS SUGGESTED THAT THE
UPREGULATION OF ANNA BOWISM BY
CANCER CELLS IS WHAT VIRUSES
WANT AS WELL, I JUST VISITED
DOUG WALLACE IN PHILADELPHIA AND
HE IS WORKING A LOT. WHAT I
FOUND IS DOWN REGULATION OF
OXIDATIVE PHOSPHORYLATION,
UPREGULATION OF GLYCOLYSIS AND
REVERSE FLUX IN GENES SO HIF 1
ALPHA INVOLVED AND SO ON, AND
THE LOSS OF OXIDIZE
MITOCHONDRIAL DNA TO ACTIVATING
THE INFLAMMASOME SO THESE
PROCESSES ARE AGAIN CENTRAL AND
REALLY STRONGLY CONSERVED, IT IS
INTERESTING TO ME THAT THE
MITOCHONDRIA SEEM TO PLAY A
CRITICAL AND CENTRAL ROLE IN
IMMUNE ACTIVATION.
>> THANK YOU SO MUCH.
>> THANK YOU.
>> THANKS THAT WAS A BEAUTIFUL
TALK.
>> THANK YOU.
>> I MANY NAME IS DAVID L -- MY
NAME IS DAVID LEVIN BIOCHEMIST
IN UCI WHO USED TO FOLLOW THESE
THINGS CLOSELY. TWO SMALL
QUESTIONS. THE FIRST ONE, GIVEN
THAT YOU ARE SAYING LIFE BEGAN
ON EARTH AND OCEAN COOL OCEAN
AVENA I ASSUME, HOW DOES THAT
SPEAK TO THE NOTION OF PAN
SPERMIA AND IS THE UNIVERSE
TEAMING WITH LIFE? THAT'S
QUESTION ONE.
>> I WILL ANSWER QUESTION ONE
QUICKLY. I CAN'T DISPROVE PAN
SPERMIA BUT DON'T THINK IT IS A
HELPFUL HIGH POTSIES BECAUSE IT
PUSHES THE QUESTION TO SOMEWHERE
ELSELSE. MAY WELL BE LIFE WAS
SEEDED FROM SOMEWHERE ELSE IN
THE UNIVERSE, WHERE UNDER WHAT
CONDITIONS WHEN, HOW LONG DID IT
TAKE? IT CEASES TO BECOME
SCIENCE. I DON'T KNOW WHY IT IS
SO POPULAR BECAUSE IT DOESN'T --
EVERYTHING I SAID MAYBE WRONG
BECAUSE IT IS UNDERPIND BY
ASSUMPTION THAT LIFE STARTED ON
EARTH WHICH MAYBE WRONG BUT WE
HAVE TO START SOMEWHERE. AND
SCIENCE IS UNDERPINNED BY AN
AIONAL WHICH IS THAT THE WORLD
IS EXPLICABLE BY NON-MIRACULOUS
FORCES AND LAWS OF NATURE DON'T
BROADLY CHANGE VERY MUCH OVER
TIME. AND THOSE ARE KIND OF
ASSUMPTIONS AS WELL, AND SO I
THINK HOPKINS RAISED THE IDEA
YOU CHOOSE THE SIMPLEST ANSWER
IS AGAIN AN ASSUMPTION, NOT
PROVED. SO I CAN'T SAY THAT PAN
SPERMIA DIDN'T HAPPEN AN LIFE
WASN'T SEEDED FROM SOMEWHERE
ELSE BUT THAT MEANS NO POINT
DOING ANYTHING IN THE LAB. IF I
A MAKE THE ACHUM SHUN LIFE
STARTED ON EARTH WE USE LIFE
EFFORTS ON EFFORT TO POINT US TO
THE KIND OF ENVIRONMENT WHERE IT
MAY HAVE STARTED, THEN I HAVE A
REASON TO GET UP IN THE MORNING
AND STUDY IT AND IT IS GREAT
FUN. AND I'M QUITE AWARE I MAYBE
DILUTING MYSELF BUT IT IS FUN
AND MAYBE EVERYONE RELEVANT.
>> SO THAT LEADS THE SECOND --
THE SECOND QUESTION IS THAT
RELATES TO EXPERIMENT THAT YOU
CAN DO. SO THE INITIAL CARBON
FIXATION THAT YOU ARE TALKING
ABOUT, THESE ARE DONE WITH
PRESUMABLY THE INITIAL COMPOUNDS
ALL MIXTURES AND YET YOUR LATER
EXPERIMENTS AND QUITE SURE YOU
HAVE BEEN PUTTING THE
APPROPRIATE STEREO ISOMERS NOT
GLYCEMIC MIXTURES HOW DO YOU
SEE, WHAT PROCESS DO YOU SEE
EVOLVING THE TENDENCY TOWARD THE
AMINO ACID?
>> THE PROTERM METABOLISM, I
TALKED ABOUT IS NOT OBVIOUS TO
ME THERE WOULD BE ANY STRONG
PROCESSES FOR GENERATING
ANYTHING OTHER THAN MIXTURES.
SOON AS WE HAVE PEPTIDES AS A
MIMICKING ACTIVE SITE RIBOSYMES
AT KEY EARLY POINTS IN
METABOLISM, SO WE HAVE SOMETHING
APPROXIMATING A PROTEIN EARLY
STAGE METABOLISM, THAT HAS A
NECESSARY HAND IN GLOVE
MECHANISM AND YOU HAVE NO LONGER
CAN HAVE GLYCEMIC MIXTURES YOU
ARE OBLIGED TO FORCE METABOLISM
--
>> GO COULD YOU MAKE THE ENZYMES
--
>> IT COULD HAVE GONE OATHER
WAY. FOR SOME LIPIDS SO VISCERAL
PHOSPHATE IS WHAT IS SOMETIMES
CALLED DUAL HOMOCOMMONALITY, ALL
HAVE GLYCEROL 1 PHOSPHATES, ALL
BACTERIA HAVE GLYCEROL 3
PHOSPHATE, THE SAME AS THE D
AMINO -- L AMINO ACIDS AND L
SUGARS. I GET THAT THE RIGHT WAY
AROUND. IT WOULD HAVE BEEN THE
OTHER WAY. I PERMLY THINK THAT
THAT KIND OF (INAUDIBLE) AROSE
WITH GENES AND PROTEINS AND
GENETICALLY ENCODED METABOLISM,
THAT IS MY OPINION, BY NO MEANS
DEMONSTRATESSED.
>> OKAY. -- DEMONSTRATED.
>> REMEMBER WE CAN HOPEFULLY
EVERYBODY CONTINUE THE
DISCUSSION. WE HAVE SEVERAL
OTHER QUESTIONS AND FIND ONE
THAT INTRIGUES ME BUT I DON'T
THINK YOU CAN ANSWER THIS IN
THREE MINUTES. BUT MAYBE YOU
CAN. SO DOES ENERGETICS PLAY A
ROLE IN IT WILL CARALITY, NAMELY
DNA, RNA, NUCLEOTIDES, THEY ARE
ALL D. AND AMINO ACIDS AND
PROTEINS ARE --
>> SOON AS YOU --
>> IS THERE A ROLE FOR
BIOENERGETICS IN THAT PHENOMENA
>> I WOULD SAY NOT A DIRECT
ROLE. I WOULD SAY THAT AS SOON
AS YOU YOU ARE BEGINNING TO HAVE
ENZYMES THAT HAVE A POCKET THAT
A SUBSTRATE BINDS TO THAT POCKET
ONLY ONE FORM BIND TO THAT
POCKET SO THE FORM THAT BINDS IS
GOING TO DEPEND ON WHATEVER THE
MOST LIKELY CONFIRMATION OF
SMALL PEPTIDE THAT CAME OUT AND
I US SUSPECT YOU COME WITH
RATHER BLACK AN WHITE IT'S ALL L
OR ALL D, YOU PROBABLY HAVE SOME
BIAS OR SHIFT TOWARDS ONE OR THE
OTHER BUT YOU ONLY NEED HANDFUL
OF PLACES IN METABOLISM TO HAVE
PEPTIDES THAT WILL BIND ONLY ONE
OF THE ISOMERS TO GIVE YOU
CARALITY AS WE KNOW IT. I DON'T
THINK THERE'S A NEED TO SAY YOU
CAN HAVE SLIGHT BIAS IN L VERSUS
D FORMS ON MYYOURATE IN SPACE
AND BECAME AMPLIFIED, THAT COULD
BE OVERWRITTEN SOON AS YOU HAVE
ENZYMES THEY ARE GOING TO IMPOSE
A -- ON YOU WHETHER YOU LIKE T
OR NOT. PROBABLY AMPLIFY
PRE-EXISTING BIAS BUT THAT IS
NOT DIRECTLY ENERGETIC BUT FLUX
HAS TO GO THROUGH THE SYSTEM SO
IT IS INDIRECTLY.
>> OKAY. CHRIS, FROM THE -- NICK
FROM THE QUESTIONS AND
ALL WE HAVE RECEIVED THE
UNDERLYING MESSAGE IS WE HAVE TO
HAVE YOU COME VISIT HERE AGAIN.
>> THAT WOULD BE GREAT.
>> OPENED UP AN ENORMOUS AREAS
THAT NORMALLY I THINK MOST OF US
DON'T REGULARLY THINK ABOUT. BUT
SHOULD. ON BEHALF OF EVERYBODY
HERE, OUT THERE, THE NIH, WE ARE
MOST DELIGHTED YOU ARE HERE,
THANK YOU VERY MUCH FOR A VERY
EXCITING PRESENTATION AND
EVERYONE IS NOW WELCOME TO A
BOOK SIGNING WHICH IS OUTSIDE IN
THE RECEPTION AREA. THANK YOU.
[APPLAUSE]