>> THIS IS WIN ARIAS WELCOMING
YOU TO THE NINTH SESSION OF THE
21ST YEAR OF THE NIH COURSE
CALLED DEMYSTIFYING MEDICINE.
THIS IS REALLY A COURSE IN
BRIDGE-BUILDING.
THE LOGO, WHICH AT LEAST FOR
THOSE ON THIS SIDE OF THE
ATLANTIC IS ALMOST CONSIDERED
THE MOST FAMOUS BRIDGE IN THE
WORLD IS MY GRANDFATHER'S
PHOTOGRAPH OF THE CONSTRUCTION
OF THE BROOKLYN BRIDGE.
NORMALLY THE TWO INDIVIDUALS ON
THE BRIDGE COME FROM DIFFERENT
SIDES OF THE RIVER, THE EAST
RIVER, AND ARE DISCUSSING ISSUES
OF MAJOR IMPORTANCE, EACH
REPRESENTING A DIFFERENT POINT
OF VIEW AND A DIFFERENT
EXPERTISE.
IT'S AN EXERCISE IN
COMMUNICATION.
TODAY'S BRIDGE IS PROBABLY THE
LONGEST -- WELL, IT'S CERTAINLY
THE LONGEST AND MOST EXTENSIVE
BRIDGE AND PROBABLY THE MOST
IMPORTANT THAT WE COULD EVER
CONSIDER, AND THAT'S THE ORIGIN
OF LIFE.
SO TODAY'S SPEAKERS WILL ADDRESS
THIS.
ONE IS AN EVOLUTIONARY
BIOCHEMIST AND THE OTHER A CELL
BIOLOGIST.
I CAME UPON THIS QUOTATION FROM
SYDNEY BRENNER.
I THINK ONE OF THE THINGS ABOUT
CREATIVITY IS NOT TO BE AFRAID
OF SAYING THE WRONG THING.
TO A CERTAIN EXTENT, THAT WILL
INFLUENCE THE ENTIRE
PRESENTATION TODAY.
NOW THIS TOPIC REALLY BEGINS
ABOUT 4 BILLION YEARS AGO, WHEN
LIFE AROSE ON EARTH FROM
NON-LIVING MATTER.
BUT HOW, WHERE, AND WHY ARE
MYSTERIES.
THE EARLIEST LIFE FORMS WERE
SIMPLE AND MICROSCOPIC, YET THEY
HAD TWO PROPERTIES THAT SET THEM
APART FROM OTHER ORGANIC
CHEMICAL CHAINS IN THE
ENVIRONMENT, AND THESE
PROPERTIES COULD METABOLIZE AND
THEY COULD REPLICATE.
THIS IS THE ORIGIN OF LIFE,
WHICH WILL BE DISCUSSED IN THE
FIRST TALK BY DR. NICK LANE,
WHO'S A PROFESSOR OF
EVOLUTIONARY BIOCHEMISTRY IN THE
DIVISION OF BIOSCIENCES AT THE
UNIVERSITY COLLEGE LONDON.
NICK'S RESEARCH IS DIRECTED
TOWARD A BIOCHEMICAL EXPLANATION
FOR THE ORIGIN OF LIFE AND THE
EMERGENCE OF THE EUKARYOTIC
CELL.
THE GENERAL FOCUS OF HIS WORK
HAS BEEN ON THE ROLE OF
CHEMIOSMOSIS, THE GENERATION OF
ATP BY WAY OF PROTON GRADIENTS.
NICK IS AN OUTSTANDING TEACHER.
AND IS AN AWARD-RIN WINNING
AUTHOR -WINNING AUTHOR
OF FOUR BOOKS, THE MOST RECENT
PUBLISHED IN 2015 IS AN
EXTRAORDINARY BOOK CALLED "THE
VITAL QUESTION: WHY IS LIFE THE
WAY IT IS?"
A NEW BOOK WILL BE COMING OUT IN
JULY, ENTITLED "TRANSFORMER:
THE DEEP CHEMISTRY OF LIFE AND
DEATH."
AND SO NICK WILL BE THE FIRST
SPEAKER, WHO WILL TALK ABOUT THE
ORIGIN OF LIFE IN AN
EVOLUTIONARY SENSE.
NOW ABOUT 2 BILLION YEARS AGO,
LIFE EXPLODED WITH A DAZZLING
VARIETY -- WITH A VARIETY AND
COMPLEXITY TO INCLUDE NOW
MULTICELLULAR LIFE IN THE FORM
OF THE EUKARYOTIC CELL.
WELL, MANY THINGS HAPPENED
BETWEEN ABIOGENESIS AND THE RISE
OF THE FIRST EUKARYOTIC
ANCESTOR.
THIS WILL BE THE SUBJECT OF
DR. JENNIFER
LIPPINCOTT-SCHWARTZ'S
PRESENTATION.
JENNIFER, YOU KNOW, IS A SENIOR
GROUP LEADER AT THE HOWARD
HUGHES MEDICAL INSTITUTE AT
JANELIA FARMS CAMPUS, AND
FORMERLY, FROM 1993 TO 2015, SHE
WAS CHIEF OF THE NIH NATIONAL
INSTITUTE OF CHILD HEALTH AND
DEVELOPMENT SECTION ON ORGANELLE
BIOLOGY.
JENNIFER'S APPROACH HAS BEEN
TOTALLY DYNAMIC IN TERMS OF
SCIENCE AND PERSONALITY.
SHE DOES RESEARCH ON THE
EUKARYOTIC CELL ORGANELLES AS
DYNAMIC STRUCTURES, AND IN PART,
THIS IS BECAUSE SHE HAS BEEN AN
INNOVATOR IN LIVE, SUBSELL SUBCELLULAR
AND SUPER-RESOLUTION MICROSCOPY,
USING PHOTOACTIVATABLE
ORGANELLE-SPECIFIC PROBES
DEVELOPED AT NIH WITH THE LATE
GEORGE PATTERSON.
JENNIFER HAS RECEIVED NUMEROUS
NATIONAL AND INTERNATIONAL
AWARDS, INCLUDING ELECTION TO
THE NATIONAL ACADEMY OF SCIENCE,
THE NATIONAL ACADEMY OF
MEDICINE, AND THE NATIONAL
ACADEMY OF ARTS AND SCIENCES.
AND SHE WILL BE DISCUSSING THE
EMERGENCE OF THE EUKARYOTIC
CELL.
SO JOIN US IN A $4 BILLION
JOURNEY TODAY, AS WE PROBE
THEORIES AS TO HOW LIFE
ORIGINATED, AND HOW IT BECAME
MORE COMPLEX.
SO PROFESSOR LANE, WOULD YOU
PLEASE BEGIN.
>> THANK YOU VERY MUCH FOR THE
VERY KIND INTRODUCTION.
AND FOR THE HUGE HONOR OF BEING
HERE AT ALL.
IT REALLY IS AN IMMENSE HONOR
AND PLEASURE, AND I'M REALLY
LOOKING FORWARD TO SPEAKING TO
YOU.
SO I'M GOING TO TALK ABOUT
ENERGY AND MATTER AT THE ORIGIN
OF LIFE.
THESE ARE, I SHOULD SAY UP
FRONT, IDEAS THAT I'VE BEEN
CONJURING WITH FOR A LONG TIME,
BUT LOTS OF PEOPLE WOULD NOT
AGREE WITH ME AND YOU SHOULD BE
AWARE OF THAT UP FRONT.
SO I HAVE NO CONFLICTS OF
INTEREST.
THIS WAS FOR THE CME PROGRAM
WHICH APPARENTLY IS NOT GOING
AHEAD, SO YOUR LEARNING
OBJECTIVE, YOU NO LONGER NEED TO
UNDERSTAND THE ORIGIN OF LIFE,
WHICH I'M SURE SOME OF YOU WILL
BE PLEASED TO HEAR.
BUT I LO DO MY WILL DO MY BEST TO MAKE IT
INTELLIGIBLE ANYWAY.
THE FIRST PROBLEM WE ALL HAVE
WHEN WE TALK ABOUT THE ORIGIN OF
LIFE IS TO WRESTLE WITH SOME
DEFINITION OF WHAT IS LIFE
ANYWAY, AND THERE ISN'T A GOOD
DEFINITION OF IT.
THERE ARE ACTUALLY SCORES OF BAD
DEFINITIONS OF IT, AND I THINK
PART OF THE PROBLEM, LIFE IS NOT
A NOUN, IT'S A VERB, IT'S A
PROCESS OVER TIME, IT'S AN
ACTIVITY, AND REALLY A BETTER
QUESTION IS WHAT IS LIVING.
A LOT OF PEOPLE, I HOPE, MIGHT
HAVE READ THIS FAMOUS BOOK BY
ERWIN SCHRODINGER CALLED WHAT IS
LIFE, A BEAUTIFUL BOOK, DATING
BACK TO BEFORE THE TIME ANYBODY
REALIZED THAT GENES WERE MADE OF
DNA.
MOST CERTAINLY IT WAS NOT
ESTABLISHED IN THE FIELD IN THE
EARLY 1940s.
AND HE TALKED IN -- THIS IS
APPARENTLY THE FIRST USE OF THE
WORD CODE SCRIPT IN BIOLOGY.
DURING THE SECOND WORLD WAR, AT
A TIME WHEN CRYPTOGRAPHY WAS
VERY MUCH IN THE AIR.
HE ALSO TALKED ABOUT ENTROPY,
LIFE FEEDING ON NEGATIVE
ENTROPY, AND HERE QUITE
ANTIQUATED, HE SAYS LIFE
MAINTAINS ITSELF AS A FAIRLY
HIGH LEVEL OF ORDERLINESS
THROUGH CONTINUALLY SUCKING
ORDERLINESS FROM ITS
ENVIRONMENT.
I DON'T KNOW WHAT HE HAD IN MIND
WHEN HE SAID THAT.
HE SAID IF I WAS CATERING FOR
PHYSICISTS ALONE, I SHOULD HAVE
LET THE DISCUSSION TURN TO FREE
ENERGY INSTEAD.
SO JUST TO MAKE SURE WE'RE ALL
ON THE SAME PAGE, HE DIDN'T TALK
ABOUT FREE ENERGY BECAUSE HE
THOUGHT IT WAS A MORE COMPLEX
TERM THAN ENTROPY.
I THINK MOST BIOLOGISTS WOULD
PROBABLY SEE IT THE OTHER WAY
AROUND, FREE ENERGY SIMPLY AS I
SEE IT, THE ENERGY AVAILABLE TO
POWER WORK, MUSCLE CONTRACTION,
CONFORMATIONAL CHANGES IN PLEK
NAR
MOLECULAR MACHINES, SO ON,
GENERATING ATP, I'M SURE I'M
TALKING THE LANGUAGE OF
EVERYBODY ON THIS CALL.
AND OF COURSE WE TURN OVER
SOMETHING APPROXIMATING TO OUR
OWN BODY WEIGHT IN ATP EVERY
DAY.
IT'S VERY DIFFICULT TO CONVEY
JUST HOW MUCH ENERGY IT COSTS
JUST TO STAY ALIVE.
AND IF YOU START TO THINK ABOUT
THE ORIGIN OF LIFE, THEN WE HAVE
TO THINK ABOUT UNIVERSALS ACROSS
LIFE, AND WE ALL KNOW ABOUT DNA
AND THE UNIVERSAL GENETIC CODE,
AND IT'S PERHAPS LESS OBVIOUS
THAT THERE ISS IS ALSO A UNIVERSAL
FORM OF FREE ENERGY CONSERVATION
ACROSS ALL LIVING THINGS.
IT GOES BEYOND ATP, IT'S ALSO
THE MECHANISM IN WHICH OUR
MITOCHONDRIA AND CELLS IN
GENERAL, BACTERIA AND SO ON, ARE
POWERING THE SYNTHESIS OF ATP
THROUGH THE USE OF ION GRADE
YANTS AND ESPECIALLY PROTON
GRADIENTS ACROSS MEMBRANES.
THAT'S REALLY A VERY SIMPLE
DIFFERENCE IN THE CONCENTRATION
AND THEREFORE THE CHARGE BETWEEN
ONE SIDE OF THE MEMBRANE AND THE
OTHER SIDE OF THE MEMBRANE.
THE USE OF THESE GRADE YANTS IS
AS UNIVERSAL AS THE GENETIC CODE
ITSELF ACROSS ALL OF LIFEMENT
BUT THE MACHINERY THAT'S
POWERING THIS IS EXTRAORDINARILY
COMPLEX AND I'M JUST GOING TO
GIVE YOU A SNAPSHOT.
I'M SURE MANY OF YOU ARE MORE
FAMILIAR WITH THESE KIND OF
MOLECULAR MACHINES THAN I AM
BECAUSE I DON'T SPECIFICALLY
WORK ON THESE, BUT THEY ARE
ABSOLUTELY GLORIOUS, MARVELOUS,
AND PROMOTE FROM THE POINT OF
VIEW OF A BIOCHEMIST WONDERING
ABOUT HOW SUCH MACHINERY AROSE
AT THE ORIGIN OF LIFE DUMB
FOUNDING, REALLY.
THEY'RE PLAINLY A PRODUCT OF
GENES AND NATURAL SELECTION, AND
SO THEY SEEM TO HAVE NOTHING
WHATSOEVER TO DO WITH PREBIOTIC
CHEMISTRY.
THESE ARE THE PINNACLES OF
EVOLUTION, NOT THE BEGINNINGS OF
EVOLUTION.
FOR THAT REASON, MOST PEOPLE
HAVE PUT IT ASIDE AND DON'T
WORRY ABOUT IT AND TEND TO
DISMISS MEMBRANE -- SOMETHING
THAT AROSE MUCH LATER IN
EVOLUTION AND WE HAVE TO LOOK AT
SIMPLE THINGS AT THE ORIGIN OF
LIFE.
AND THERE'S PLENTY OF IDEAS OUT
THERE.
REACTIVE GASES, CYANIDE OR
CYANOD ACETYLENE, SO ON,
ENERGIZING LIGHT, UV RADIATION,
LIGHTNING, ALL KINDS OF DYNAMIC
ENVIRONMENTS, WET/DRY CYCLES,
THIS IS THE PREDOMINANT AREA OF
THIS FIELD RIGHT NOW AND THIS
HAS BEEN GOING FOR 50 OR 60
YEARS GOING BACK, REALLY, TO THE
EXPERIMENT WITH BOLTS OF
LIGHTNING TO TRY AND EFFECTIVELY
ENERGIZE THE GASES IN THOSE
EARLY ATMOSPHERES.
AND IT'S WORKED EXTREMELY WELL
AND THE CHEMISTS THINK THEY'VE
SOLVED THE PROBLEM, BUT FROM A
BIOLOGIST'S POINT OF VIEW, IT'S
TO MY MIND FRANKENSTEIN
CHEMISTRY.
IT LOOKS NOTHING LIKE THE
CHEMISTRY OF LIFE AS I
UNDERSTAND IT.
SO I SUPPOSE AT THE VERY LEAST,
EVEN IF THIS CHEMISTRY IS, IN
FACT, ALL THE RIGHT CHEMISTRY,
AND LIFE REALLY DID START IN
THIS WAY, WE STILL HAVE A GAP.
WE STILL HAVE TO EXPLAIN, OKAY,
SO WE'VE GOT ALL OF THESE
CHEMICALS, HOW DID METABOLISM
THEN START, HOW DID GENES INVENT
METABOLISM, AND METABOLISM AS WE
KNOW IT IN CELLS TODAY, BECAUSE
THIS IS NOTHING LIKE THE
METABOLISM OF CELLS AS WE KNOW
THEM.
SO FROM A BIOLOGIST'S POINT OF
VIEW, I AM VERY UNCOMFORTABLE
WITH THOSE ANSWERS.
AND I TURN TO PEOPLE LIKE
CHRISTIAN DE DUVE WHO TRIED TO
USE BIOLOGY RATHER THAN
CHEMISTRY AS A GUIDE TO LIFE'S
ORIGINS.
THERE'S A LOVELY QUOTE FROM DE
DUVE HERE, HE SAYS HOW DID
PROTOMETABOLISM, BY WHICH HE
MEANT GEOLOGICAL CHEMISTRY, THE
GEOCHEMISTRY HAPPENING IN SOME
ENVIRONMENTAL CONTEXT, HOW DID
THAT KIND OF DYNAMIC CHEMISTRY,
PROTO METABOLISM, COME TO BE
REPLACED BY METABOLISM AS WE
KNOW IT?
HE SAYS THE OBVIOUS ANSWER IS
THAT THE APPEARANCE OF
CATALYSTS, WHETHER RIBOZYMES,
PROTEIN ENZYMES OR BOTH, WAS
RESPONSIBLE FOR THE TRANSITION.
WE HAVE TO ASK HOW CATALYSTS
WITH THE APPROPRIATE PROPERTIES
CAME TO APPEAR.
WHY DO THEY CATALYZE THE RIGHT
REACTIONS?
HE SAYS THE ONLY SCIENTIFICALLY
PLAUSIBLE EXPLANATION IS THE
CATALYSTS AROSE THROUGH
SELECTION.
THEN IN THE KILLER LINE, ENZYMES
ARE SELECTED ONLY IF THEY FIT
INTO PROTO METABOLISM.
NOW THIS IS HARDLY AN EAR
REFUSABLE ARGUMENT BUT IT
CERTAINLY A POWERFUL CASE, HE'S
BASICALLY ARGUING THAT
METABOLISM AMPLIFIED THE
GEOCHEMICAL PATHWAYS THAT
PRECEDED IT.
AND THAT MAKES A LOT OF SENSE TO
ME.
THE ONLY PROBLEM IS, THEY NEVER
REALLY SEEM TO WORK.
PEOPLE HAVE TRIED THESE
EXPERIMENTS AND UNTIL RECENTLY,
THEY HAVEN'T WORKED WELL, BUT
RECENTLY, THINGS HAVE REALLY
CHANGED AND I'M GOING TO TELL
YOU MORE ABOUT THAT IN THIS
TALK.
BUT WHAT KIND OF CHEMISTRY DO WE
ACTUALLY NEED TO TALK ABOUT?
TO DO THAT, WE NEED TO GET BACK
TO THE ROOTS OF THE TREE OF LIFE
AND ONE OF THE MOST BRILLIANT
SCIENTISTS WORKING IN THIS FIELD
FOR MANY YEARS NOW, OVER SEVERAL
DECADES, IS BILL MARTIN.
NOW, HE HAS SOME VERY RADICAL
IDEAS.
A LOT OF PEOPLE FIND HIS IDEAS
VERY UNCOMFORTABLE.
I CERTAINLY DID MYSELF, BUT THE
LONGER I'VE LIVED WITH THEM, THE
MORE I THINK HE'S BANG-ON.
NOW THIS TREE I'M SHOWING YOU
HERE IS FROM ONE OF BILL'S
PAPERS FROM MORE THAN 20 YEARS
AGO NOW.
IT'S BASICALLY A CONCEPTUAL
TREE.
WHAT HE'S SHOWING IS THE
EUKARYOTES UP HERE, WHICH
JENNIFER WILL TALK ABOUT IN A
WHILE, AND THE YOU'RE CARE YOTS,
YOU THEY'RE GIVING
RISE TO -- DEEPER DOWN IN THE
TREE BETWEEN BACTERIUM OF SOME
SORT THAT BECAME THE
MITOCHONDRIA, THEN A HOST CELL.
SO THE POINT FOR MY TALK IS THAT
EUKARYOTES ARE A DERIVED DOMAIN.
THEY DON'T SPEAK DIRECTLY TO
WHAT WAS HAPPENING RIGHT DOWN AT
THE BASE OF THE TREE DOWN HERE.
NOW AGAIN, NOT EVERYBODY AGREES
WITH THAT STATEMENT, BUT
PROBABLY THAT WOULD BE A
CONSENSUS IN THIS FIELD NOW.
SO LUCA IS THE LAST UNIVERSAL
COMMON ANCESTOR OF ALL OF LIFE,
AND IT'S THE ANCESTOR OF THE
BACTERIA AND THE ARCHAEA, WHICH
LOOKED A LOT ALIKE IN TERMS OF
THEIR GROSS OVERALL MORPHOLOGY.
AND BILL HAS LUCA DOWN HERE WITH
TWO SEPARATE EMERGENCES FROM
THIS VENT WHICH IS ITSELF A VERY
RADICAL IDEA.
HE'S NOT SAYING THEY ORIGINATED
INDEPENDENTLY, HE SAID THEY
SHARED A COMMON ANCESTOR THAT
LIVED IN A ROCKY HYDROTHERMAL
SYSTEM.
WHY WOULD HE SAY SUCH A THING?
HE OOO ESSENTIALLY BECAUSE IT'S PLAIN
THAT LIFE SHARES A COMMON
ANCESTOR, AND THAT'S BECAUSE
LIFE SHARES THE UNIVERSAL
GENETIC CODE, THE STRUCTURE OF
THE PROTEIN FACTORIES, THE
PROTEIN-MAKING FACTORIES OF THE
RIBOSOMES, QUITE A LOT OF
INTERMEDIARY METABOLISM LIKE THE
KREBS CYCLE.
MOST IMPORTANTLY FROM THIS LEBLG
LECTURE, MEMBRANE BIOINER JE
TICS.
WHAT'S SHOCKING, THE CELL
MEMBRANE IS DIFFERENT IN ITS
CHEMISTRY, VERY DIFFERENT IN ITS
CHEMISTRY AND BACTERIA AND
ARCHAEA ALONG WITH ALL THE LIPID
SYNTHESIS REQUIRED TO GENERATE
THESE MEMBRANES ALONG WITH THE
CELL WALL.
SO BASICALLY THE BARRIER BETWEEN
THE INSIDE OF THE CELL AND THE
OUTSIDE OF THE CELL ARE NOT
HOMOLOGOUS, THEY HAVE APPEARED
TO EMERGE INDEPENDENTLY AND THAT
LEAVES YOU CONJURING WITH WHAT
ON EARTH DID THE COMMON ANCESTOR
HAVE THEN?
ALMOST CERTAINLY HAD A CELL
MEMBRANE, I DON'T KNOW IF IT HAD
A CELL WALL OR NOT BUT IT WAS
NOT LIKE A MODERN BACTERIA OR
MODERN -- MEMBRANE.
EVEN DNA REPLICATION, THE GENES
INVOLVED ARE NOT CONSERVED IN
BACTERIA -- ONLY ONE OR TWO OF
THEM.
VARIOUS PROTEINS OR GENES THAT
CAN MOVE AROUND INCLUDING THOSE
ENCODING THE RESPIRATORY CHAIN
IN RESPIRATION DON'T REALLY
APPEAR TO BE DEEPLY CONSERVED.
SO THIS LEAVES YOU WONDERING,
WHAT ON EARTH WAS LUCA, THIS
LAST UNIVERSAL COMMON ANCESTOR,
WHAT KIND OF A CELL WAS IT?
IT'S QUITE A PARADOX.
THE PARADOX AS I SEE IT IS,
MEMBRANE BIOINER JE TICS ENERGETICS -- TH E
PARADOX COULD BE RESOLVED IF
LIFE ORIGINATED IN AN
ENVIRONMENT WHERE THERE WERE
GEOLOGICAL PROTON GRADIENTS WITH
BARRIERS NOT NECESSARILY LIKE
MODERN MEMBRANES.
IS THERE SUCH A PLACE?
YES, THEY WERE DISCOVERED YEARS
AGO BY DEBORAH KELLEY,
DISCOVERED ABOUT 15 MILES AWAY
FROM THERE THIS COMPLETELY
DIFFERENT TYPE OF HYDROTHERMAL
SYSTEM.
THEY'RE NOW KNOWN AS ALKALINE
HYDROTHERMAL VENTS, LOST CITY
WAS THE ONE SHE DISCOVERED AND
IT'S NOT LIKE THE BLACK SMOKERS,
SO SHE'S HOLDING A LUMP OF A
BLACK SMOKER, YOU CAN SEE IT'S A
CHIMNEY, THE BLACK SMOKER WOBBLE
CH OUT WOULD
BELCH OUT.
THE HYDROTHERMAL FLUIDS WILL
PERCOLATE THROUGH THE SPONG,
THEY DON'T KIND OF BELCH OUT
THROUGH THE TOP.
INSTEAD OF BEING FORMED BY
DIRECT INTERACTIONS BETWEEN
OCEAN WATER AND MAGMA CHAMBERS
FROM THE THOUSANDS OF DEGREES,
THE MAGMA, THIS IS WATER
PERCOLATING DOWN.
LET ME PUT MY POINTER ON IT.
SO WATER WILL PERCOLATE DOWN
INTO THE SEA FLOOR 5 OR
6 KILOMETERS DEPTH, OXIDIZING
THE ION FROM FERROUS, AND THAT
PRODUCES WARM IN GEOLOGICAL
TERMS, 50 TO 100 DEGREES, FOR
EXAMPLE, STRONGLY ALKALINE, PH10
OR 11, AND SATURATED IN HYDROGEN
GAS, BUBBLING IN HYDROGEN GAS.
THIS IS KIND OF CAUSTIC SODA
BUBBLING WITH HYDROGEN GAS.
THEY BUBBLE BACK UP TO THE
BOTTOM OF THE OCEAN AND THERE,
THEY REACT WITH THE OCEAN WATERS
AND PRECIPITATE THESE
HYDROTHERMAL SYSTEMS.
AND THEY'RE FOUND NOT ONLY ON
EARTH BUT WE KNOW THESE PLUMES,
FOR EXAMPLE, ON ENCELADUS, THEY
ARE ALKALINE AND HYDROGEN RICH,
THEY CONTAIN ORGANICS, IT SEEMS
ALMOST CERTAIN NOW, BEE KNEAD
THE CRUST, THERE IS HYDROTHERMAL
SYSTEMS LIKE THESE ONES ON EARTH
THAT I'M TALKING ABOUT THAT I
THINK WHERE THE ENVIRONMENT --
WHERE LIFE STARTED.
WE FIND THEM AS WELL PROBABLY ON
ANY TRACES OF METHANE FOUND ON
MARS, IF THEY REALLY DO EXIST,
ARE ALMOST CERTAINLY THESE SAME
KIND OF REACTIONS BETWEEN TRACES
OF WATER AND MINERALS LIKE -- ON
MARS.
SO THESE ARE PROCESSS THAT
SHOULD HAPPEN ON ANY WET, ROCKY
PLANET OR MOON AND ARE COMMON
EVEN IN OUR OWN SOLAR SYSTEM AND
SHOULD HAPPEN PROBABLY TENS OF
BILLIONS OF PLANETS IN THE MILKY
WAY ALONE.
THE IDEA THAT LIFE MIGHT HAVE
STARTED IN THESE ENVIRONMENTS
WAS FIRST PUT FORWARD BY MIKE
RUSSELL BACK IN THE EARLY
1990s.
HE'S BEEN PIONEERING THESE
IDEAS, I DON'T ALWAYS AGREE WITH
WHAT HE HAS TO SAY BUT HE'S HAD
ABSOLUTELY STUPENDOUS IDEAS.
I'M WHITTLING THIS DOWN TO HIS
KEY POINTS.
HE SEES ELECTROCHEMICAL FLOW
REACTORS, FLUID PERCOLATING
THROUGH THIS LABYRINTH OF MICRO
PORES WITH CATALYTIC WALLS.
THE CATALYSTS IN THESE WALLS, IN
THE EARLY OCEANS, WHEN THERE WAS
NO OXYGEN AND LOTS OF IRON
AROUND, WERE PROBABLY IRON
SULFIDE MINERALS, PLENTY OF
OTHER THINGS IN THERE AS WELL,
SO WE HAVE ALKALINE FLUIDS, WARM
ALKALINE FLUIDS BUBBLING,
INTERACTING WITH THESE CATALYTIC
WALLS AND OCEAN WATER AS WELL,
PERCOLATING IN, FULL OF CO2,
SATURATED IN CO2, AND IN SOME
WAY, THIS ELECTROCHEMICAL FLOW
REACTOR IS GOING TO DRIVE THE
ORIGIN OF LIFE.
THAT'S WHAT I'M GOING TO TRY AND
TELL YOU IN THE REST OF THIS
TALK.
SO THESE VENT PORES ARE
ANALOGOUS TO CELLS.
THIS IS MY SIMPLE ATTEMPT TO
CONVEY WHAT A BACTERIAL CELL
LOOKS LIKE ATITY MOST ELEMENTARY
LEVEL.
IT BASICALLY GOT A MEMBRANE PUMP
HERE IN THE MEMBRANE, PUMPING
PROTONS OUT, SO WE HAVE A PROTON
GRADIENT ACROSS THIS MEMBRANE.
IT'S RELATIVELY ALKALINE INSIDE,
OF COURSE PUTTING A CHARGE ON
THIS MEMBRANE BECAUSE THE
PROTONS ARE MOVING OUT.
AND HERE WE HAVE AN INORGANIC
BARRIER, THICK IN COMPARISON, WE
HAVE ACIDIC OCEAN WATERS
PERCOLATING IN AND WE HAVE
ALKALINE FLUIDS.
SO WE HAVE A SIMILAR PH
DIFFERENCE, SIMILAR MAGNITUDE OF
PROBABLY PH UNITS AND IT SHOULD
ALSO BE SIMILAR IN POLARITY.
IT'S EFFECTIVELY ACID OUTSIDE,
ALKALINE INSIDE.
IS THIS JUST IMAGINATION?
AM I SEEING THINGS HERE, OR CAN
WE COME UP WITH A WAY OF GOING
FROM THIS SIMPLE INORGANIC
SYSTEM TO THE WAY THAT CELLS
WORK?
I'M ACTUALLY FOLLOWING HERE IN
THE FOOTSTEPS OF PETER MITCHELL
HIMSELF WHO DID WONDER AND WORK
A LITTLE BIT ON THE ORIGIN OF
LIFE, SO MITCHELL'S IDEAS, HE
WAS THE PERSON WHO CAME UP WITH
THESE IDEAS OF COUPLING AND
MEMBRANE BIOGENETICS.
THEY DIDN'T GO OVER WELL AT THE
TIME.
THERE'S A LOVELY QUOTE, NOT
SINCE DARWIN HAS BIOLOGY COME UP
WITH AN IDEA THAT'S AS
COUNTERINTUITIVE, AND IT WAS
REALLY JENNIFER MOYLE WHO DID
THE PIONEERING EXPERIMENTS.
MITCHELL HIMSELF WAS QUITE
CANDID IN THE LAB, AND IT WAS
JENNIFER MOYLE WHO DID THE
EXPERIMENTS THAT DEMONSTRATED TO
INITIALLY A VERY SKEPTICAL WORLD
THAT THERE WAS SOMETHING IN
THESE IDEAS.
MITCHELL HIMSELF WAS QUITE
PHILOSOPHICALLY-MINDED.
HERE'S A QUOTE WHICH I THINK IS
BEAUTIFUL, HE SAYS, I CANNOT
CONSIDER THE ORGANISM WITHOUT
THIS ENVIRONMENT.
FROM A FORMAL POINT OF VIEW, THE
TWO MAY BE REGARDED AS
EQUIVALENT PHASES BETWEEN WHICH
DYNAMIC CONTACT IS MAINTAINED BY
THE MEMBRANES THAT SEPARATE AND
LINK THEM.
SEPARATING THESE TWO DIFFERENT
PHASES.
NOW THE ORIGIN OF LIFE, THERE
ISN'T SUCH A THING YET AS A CELL
OR AS LIFE OR AS LIVING THINGS.
THESE TWO PHASES WITH A BARRIER
SEPARATING THEM MAKES MUCH MORE
SENSE WHEN WE'RE THINKING ABOUT
THE ORIGIN OF LIFE.
WE'RE BEGINNING TO SEE HOW THE
SYSTEM CAN ITSELF BE
COMPARTMENTALIZED.
SO MITCHELL WAS ASKING A VERY
SIMPLE QUESTION, WHICH WAS CASE
BACEICALLY, HOW WAS
BASICALLY, HOW DO BACTERIA KEEP
THESE TWO PHASES DIFFERENT?
AND HE RECOGNIZED THAT WHILE
THEY HAVE TO FIND PARTICULAR
MOLECULES, PROTONS IN THIS CASE,
RECOGNIZE THEM, THEN PHYSICALLY
PUMP THEM OUT, THAT'S GOING TO
COST ENERGY.
THEN CONVERSELY, IT WILL --
YOU'LL BE ABLE TO TAP THAT
ENERGY, IF YOU CAN CONSERVE THAT
ENERGY AS THEY ALLOW THEM TO
FLOW BACK IN AGAIN, YOU'LL BE
ABLE TO POWER WORK.
AND MOSTLY WHEN WE THINK ABOUT
THAT WORK, WE'RE THINKING ABOUT
ATP SYNTHESIS.
BUT IT'S NOT ONLY ATP SYNTHESIS.
IN BACTERIA, VERY OFTEN THE
PROTON GRADIENTS ARE DRIVING CO2
FIXATION, AND THAT, TO ME, IS
THE KEY TO THINKING ABOUT THIS.
SO THE MOST ANCIENT CELLS THAT
WE KNOW ABOUT GREW FROM HYDROGEN
AND CO2.
AND THEY'RE FIXING CO2 AND TO DO
THAT, THEY REQUIRE, THEY'RE
FULLY DEPENDENT ON COUPLING.
SO THESE CELLS AND METHANOGENS
AND ACETOGENS, THIS IS THE ONLY
PATHWAY FOUND IN BOTH BACTERIA
AND ARCHAEA, IT'S BASICALLY A
REACTION BETWEEN CO2 AND
HYDROGEN.
SO THESE ARE THE GASES WE HAVE
IN THESE VENTS.
WHEN THEY WORK TOGETHER, TO
PRODUCE METHANE AS A BYPRODUCT,
AND -- IT'S OVERALL EXOGONIC BUT
THEY DON'T REACT VERY EASILY.
THEY NEED A PROTON GRADIENT
ACROSS A MEMBRANE TO DRIVE THOSE
FIRST FEW STEPS.
AND WHAT THEY'RE DOING IS USING
A MEMBRANE PROTEIN, IN THIS
CASE, THE ENERGY CONVERTING HIGH
HYDROGENASE TO REDUCE FAIR -- TO MAKE
ORGANIC MOLECULES.
SO IT TAKING THE ELECTRONS FROM
HYDROGEN, MAKING ORGANIC
MOLECULES.
THAT DOESN'T HAPPEN
SPONTANEOUSLY, TO DRIVE THAT.
AND THIS SLIGHTLY MORE COMPLEX
DIAGRAM, I WOULDN'T TRY AND
EXPLAIN IT TO YOU, BUT IT'S
ESSENTIALLY SAYING THAT FIRST
STEP IS ELECTROCHEMICALLY NOT
FAVORED, THERE'S A DIFFERENCE OF
ABOUT 200 MILLIVOLTS THAT NEED
TO BE OVERCOME TO DRIVE THAT
REACTION.
WHEN YOU HAVE GOT THROUGH THAT
STEP, WE GET INTO THE CORE OF
BIOCHEMISTRY AS WE KNOW IT
ALMOST IMMEDIATELY.
SO DON'T WORRY ABOUT THE DETAILS
ON THIS SLIDE.
WHAT I'D LIKE YOU TO NOTICE IS
THE HYDROGEN IS IN BROWN.
STARTING WITH CO2 IN THIS
CORNER, WE'VE GOT HYDROGEN,
HYDROGEN, HYDROGEN, THROUGH TO A
METHYL GROUP, MORE HYDROGEN TO
MAKE CARBON DIOXIDE, AN
ACTIVATED ACETYL GROUP, THROUGH
TO GLYCINE PRETTY QUICKLY AS
WELL, MORE CO2, MORE HYDROGEN.
IS A LOW THIS IS THE KREBS CYCLE.
NOT THE KREBS CYCLE AS MOST
PEOPLE KNOW IT, AS AN OXIDATIVE
PROCESS, BUT THE REVERSE KREBS
CYCLE OR THESE FIRST STEPS ARE
BASICALLY TAKING HYDROGEN AND
CO2 FROM THE ENVIRONMENT,
REACTING THEM TOGETHER TO MAKE
KREBS CYCLE INTERMEDIATES.
THOSE ARE USED TO MAKE AMINO
ACIDS.
THEY'RE USED TO MAKE SUGARS FROM
PIE
PYRUVATE, TO MAKE AN ENERGY
CURRENCY, IN THIS CASE, ACETYL
PHOSPHATE.
NOW THE RED BOXES HERE, THESE
ARE THE PRECURSORS FOR AGAIN,
WE'RE BEGINNING TO MAKE --
REALLY VERY CLOSE TO THE CENTRAL
METABOLISM.
THE VERY CORE FROM THIS AUTO
TROPHIC POINT OF VIEW IS
HYDROGEN AND CO2 PRODUCING THESE
CARBON SKELETON RIGHT AT THE
HEART OF METABOLISM.
MOST OF IT, ALMOST ALL OF THESE
STEPS ARE ACTUALLY EXOTHERMIC.
THEY WILL -- IF YOU START WITH
HIDE JENS AND -- WARM THEM UP TO
50 DEGREES CENTIGRADE, AS YOU
CAN SEE ACROSS THE X AXIS HERE,
THE TOTAL CELL BIOMASS RELEASES
ENERGY.
THIS IS FREE ENERGY.
IT'S QUITE STRONGLY EXOTHERMIC.
IF WE SHAKE HYDROGEN AND CO2, WE
SHOULD GET CELLS DROPPING OUT.
THE THERMODYNAMICS, THAT SHOULD
HAPPEN.
OF COURSE IT DOESN'T HAPPEN.
THE MOST FAVORITE OF THE AMINO
ACIDS, NUCLEOTIDES COST SOME
ENERGIES TO MAYBE, BUT REALLY
THE ENERGETICALLY FAVORED STATE
OF CELLS IS HARD TO FATHOM, BUT
IT'S THE TRUTH.
THE REASON IT DOESN'T HAPPEN
SPONTANEOUSLY IS THIS BARRIER
HERE TO THE REACTION, TO GET
THROUGH THE FIRST COUPLE OF
STEPS TO FORMALDEHYDE, IT'S
UPHILL.
AND THEN AFTER THAT, IT'S
DOWNHILL ALL THE WAY.
AND THIS IS THE KIND OF THE
REDOX ZONE OF ORGANIC CHEMISTRY
INSIDE CELLS.
IT'S JUST SLIGHTLY LOWER THAN
CO2 ITSELF.
THE METHANOGENS ARE USING A
PROTON GRADIENT, DRIVING THE
REACTION BETWEEN CO2 AND
HYDROGEN.
THE QUESTION IS, IS THIS
SOMETHING THAT CAN HAPPEN IN A
PREBITE IK ENVIRONMENT AND THE
ANSWER IS YES, IT'S SIMPLE
PHYSICAL CHEMISTRY.
THE PROBLEM HERE IS THAT HIDE
JEB, IF YOU HEIDI --
THAT'S A PH7 OR ANY OTHER PH.
IN THE VENTS, HYDROGEN IS
BUBBLING OUT OF THE GROUND AT
PH11 IN -- THE REACTION
POTENTIAL IS MUCH LOWER.
CO2 IS PERCOLATING IN WITH THE
ACYTIC OCEAN WATERS, THESE EARLY
ACETIC OCEANS.
YOU CAN THINK OF IT REALLY
EASILY.
IF A HYDROGEN PUSHES ITS
ELECTRONS ON TO SOMETHING ELSE,
WHAT'S LEFT BEHIND?
THE PROTONS ARE LEFT BEHIND.
IN AN ALKALINE ENVIRONMENT, THE THIS
IS A PHYSICIANING NEUTRALIZATION
REACTION FIZZING REACTION, THERE'S
NO WAY YOU CAN STOP IT FROM
HAPPENING.
THE MORE -- IN AN ACIDIC
ENVIRONMENT, YOU'RE RELEASING
PROTONS INTO THE ACYTIC
ENVIRONMENT.
IF THERE'S A PROTON AVAILABLE,
IT BALANCES THE CHARGE, IT CAN
NOW PICK UP ANOTHER -- IT'S EASY
TO PRODUCE CO2 IN AN ACIDIC
ENVIRONMENT.
THIS IS JUST FORMALIZED.
THE DIFFERENCE IS ABOUT 60 MILL
EE VOLTS, SOCK WHAT WE HAVE IN
THESE VENTS IS MORE REACTIVE.
OCEAN WATERS, MORE REACTIVE, SO
AS LONG AS THEY STAY AS TWO
PHASES SEPARATED BY SOME KIND OF
A BARRIER, A MEMBRANE OF SOME
SORT, THEN THERE SHOULD BE
REACTION.
THIS MIM BRAIN NEEDS TO SEPARATE
AND LINK, REMEMBER WHAT PETER
MITCHELL SAID, IT NEEDS TO BE
SEPARATED AND -- -- ACROSS THE
BARRIER.
SO I CAN IMAGINE, I'M NOW GOING
TO SUGGEST A MECHANISM AND THEN
I'LL TALK ABOUT HOW WE CAN TEST
IN THE LAB.
I CAN IMAGINE, HERE IS A -- I'VE
GOT PROTONS CROSSING THIS
BARRIER AND DRIVING THE REACTION
BETWEEN HYDROGEN AND CO2, AND
THE PROTONS ARE PERPETUALLY
BEING FED IN FROM THE OCEANS,
HYDROXIDE IONS AND HYDROGEN
PERPETUALLY FED IN, IN THE --
THIS IS NOT FORMALDEHYDE, THIS
IS SUPPOSED TO BE ORGANIC
MOLECULES IN GENERAL.
THE LOGICAL END POINT IS WE END
UP WITH SOMETHING WITH FATTY
ACID MEMBRANES SURROUNDING IT.
SO THIS IS HOW I CAN IMAGINE THE
PROCESS MIGHT WORK.
QUESTION IS, AM I MAD?
AND THE ANSWER IS, WELL, QUITE
POSSIBLY YOU CAN ASK ME THAT
LATER ON, BUT WE CAN AT LEAST
TEST IT.
WE'RE NOW INTO SCIENCE.
I'VE BEEN TRYING TO TEST SOME OF
THESE IDEAS FOR MORE THAN A
DECADE.
THIS WAS ONE OF THE FIRST
REACTORS THAT WE BUILT, AND YOU
CAN SEE IT WAS VERY HOMEMADE AND
IT DIDN'T WORK VERY WELL.
WE TRIED PRECIPITATING ALL KINDS
OF VENT-LIKE STRUCTURES INSIDE
THIS AND THEY DIDN'T WORK VERY
WELL EITHER.
WE ENDED UP DOING A MICRO -- BUT
I
IRONICALLY, A PH.D. STUDENT FROM
MY LAB LEFT AND NAILS THIS A
YEAR OR TWO AGO.
ON THE LEFT-HAND SIDE HERE,
THERE'S A BARRIER -- WHICH CROSS
THE BARRIER TO REDUCE CO2 AT THE
OTHER SIDE IN AN ACYTIC
SOLUTION.
I WON'T GO THROUGH THE NMR DATA
WITH YOU, BUT BASICALLY WHAT
IT'S SHOWING YOU, IN 13C NMR AND
DEUT R
AND D UTERONS, IS THE -- FROM
THE ACIDIC SIDE.
IT REQUIRES A PH GRADIENT, SO IT
REALLY DOES REQUIRE THIS PH
DIFFERENCE IF YOU DON'T HAVE
THAT PH GAP THERE, THEN IT
DOESN'T WORK.
IF YOU DON'T HAVE THE BARRIER,
IT DOESN'T WORK.
IF YOU DON'T HAVE HYDROGEN GAS,
IT DOESN'T WORK AND SO ON.
SO IT REQUIRE THIS IS TOPOLOGY,
IT REQUIRES THIS SETUP.
BUT THESE EXPERIMENTS WEREN'T
CLEAR.
IS IT PROTONS OR IS IT ELECTRONS
CROSSING THIS BARRIER?
WE COULDN'T REALLY NAIL WHICH
WAY IT'S GOING.
I'VE BEEN TRYING TO DO THAT, AND
ONE THING THAT STRUCK ME EARLY
ON IS THAT THIS IS A MICRO
FLUIDIC CHIP AND WE'VE GOT ACID
FLOW ON THIS CHANNEL, WE'VE GOT
ALKALINE FLOW IN THIS CHANNEL.
THIS IS LAMINAR FLOW SO THERE'S
NOT MUCH MIXING GOING ON HERE,
THERE'S NO BARRIER HERE AT ALL,
THIS IS JUST THE MIXING ZONE.
AND IF WE ADD FERROUS CHLORIDE
AND SODIUM SULFIDE, THEN WE
PRECIPITATE AN IRON SULFIDE
BARRIER BETWEEN THE TWO.
IT CAN BE A KIND OF DIFFUSE,
WISPY BARRIER.
WE NOTICE IT TENDS TO BE ASSAY
DICK.
SO THEY TEND TO BE ACIDIC.
SO WE LOOK AT THAT A LITTLE MORE
CLOSELY AND HERE YOU CAN SEE
THIS IS THE ALKALINE PHASE, THIS
IS THE THE ACYTIC ACIDIC PHASE.
WE FOUND PROTONS CROSS THIS
BARRIER ABOUT 200 MILLION TIMES
FASTER, SO THESE BARRIERS REALLY
DO TRANSFER PROTONS.
IT'S PROBABLY TO DO WITH THE
STRUCTURE IN THE TRAPPED WATER
IN THE BARRIERS THEMSELVES.
THIS, AT LEAST, IS CONSISTENT
WITH THIS IDEA THAT WE CAN HAVE
PROTONS CROSSING THE BARRIER AND
ENTERING SOME SORT OF PROTO
CELL.
I SAY PROTOCELLS, BUT THIS IS AN
EXTREME ENVIRONMENT.
THIS HAS GOT PH 5 OR 6 IN THE
OCEANS, 10 OR 11 OVER HERE.
ALMOST CERTAINLY, THE EARLY
OCEANS WERE PRETTY SALINE, AND
MAGNESIUM AND CALCIUM AND SO ON.
THESE ARE SUPPOSED TO BE -- MADE
FROM FATTY ACID.
SO WE WANTED TO SEE FIRST OF
ALL, IS IT EVEN POSSIBLE TO HAVE
VESICLES UNDER THOSE CONDITIONS
THAT ARE STABLE?
NOW, FROM HAS BEEN SOME WORK
DONE BY TOM MCCOLLUM AND OTHERS
UNDER HYDROTHERMAL CONDITIONS
USING A PROCESS CALLED
FISCHER-TROPSCH REACTIONS.
THESE ARE FATTY ALCOHOLS AND
FATTY ACIDS WITH A GROUPMENT
AGAIN, 10, 11, 12 CARBONS, SO WE
USE THOSE MIXTURES TO TRY AND
MAKE PROAT CELLS FROM THEM, AND
THIS IS WITH A FRESH DYE TO SHOW
THE VESICLES THEM SELVES.
YOU CAN SEE WE'RE GETTING
VESICLES, I'M NOT GOING TO GO
THROUGH THE DETAILS OF THIS, WE
CAN COME BACK TO IT BUT TO SAVE
TIME, I'M GOING TO SKIP OVER IT.
BUT WE'RE GETTING STABLE
VESICLES AT PH12, 70 DEGREES
CENTIGRADE, 50, 10 OF CALCIUM
CHLORIDE, SO REALLY HARSH
CONDITIONS.
THE KIND OF CONDITIONS I WAS
SAYING THEY'RE SUPPOSED TO FALL
TO PIECES.
IF YOU JUST USE A SINGLE FATTY
ACID, THEY DO, INDEED, FALL TO
PIECES.
BUT WHEN WE HAVE THE MORE
COMPLEX MIXTURES, THEY'RE QUITE
ROBUST.
SO THIS WAS REALLY PLEASING.
WE CAN SEE STABLE PROTO CELLS
WITHIN THE ENVIRONMENTS.
EVEN MORE PLEASING, KIND OF THE
REDUCTION OF CO2.
THE ENERGY CONVERTING
HYDROGENASE.
THEY CONTAIN FOUR FE, AND WE'RE
WONDERING IN A PREBITE IK
ENVIRONMENT, I CAN IMAGINE
MINERALIZED, SO WE SIMPLY TRIED
MIXING CYSTINE IN WATER, PH9,
WITH FERRIC CHLORIDE AND SODIUM
SULFIDE, AND WE GOT THE
CHARACTERISTIC SHOULDER ON
U.S. -- ITS
CONCENTRATION-DEPENDENT, IT
DEPENDS ON THE CONCENTRATION OF
THE IRON AND THE SULFUR.
MOST CONFIRM NIECE ARE 4FE-4S
CLUSTERS, WE HAVE SOME OTHER
SPECIES IN THERE.
VOLTAMMETRY SHOWS THEY ARE NOT
AS REDUCING AS I'D LIKE THEM TO
BE.
MINUS 400 MILLIVOLTS IS
CERTAINLY NOT VERY REDUCING, NOT
FLUFF TO REDUCE CO2 BUT THIS IS
PROBABLY A COMPLEX PEAK AND WE
NEED TO TRY AND WORK OUT WHAT
ELSE IS IN THERE.
WE THINK THERE'S SEVERAL SPECIES
IN THERE SO WE'RE STILL WORKING
ON THAT.
BUT THE KEY THING IS JUST MIXING
MONOMERS, CYSTINE, IRON, SULFUR
IN SOLUTION, AND WE'RE GETTING
4FE-4S CLUSTERS, THE SAME AS
LIFE.
I'M JUST GOING TO SHOW YOU TWO
SLIDES ON SOME SLIGHTLY MORE
COMPLEX CHEMISTRY THAT WE'VE
BEEN WORKING ON.
IF THESE IDEAS ARE RIGHT, THEN
THE WHOLE OF METABOLIC
BIOCHEMISTRY OUGHT TO BE
HAPPENING SPONTANEOUSLY UNDER
THESE CONDITIONS.
PEOPLE HAVEN'T DONE MUCH WORK ON
THIS.
LOTS OF PEOPLE HAVE WORKED ON
CYANIDE CHEMISTRY AND SO ON.
THIS IS FOLLOWING THE PATHWAY OF
URACIL SYNTHESIS THAT CELLS USE,
AND THIS IS DOING IT IN THE
ABSENCE OF ENZYMES, JUST USING
METAL IONS AS CATALYSTS.
WE HAVE A BUNCH OF METAL ION
CATALYSTS, COPPER WORKS QUITE
WELL, WE'RE ABLE TO GENERATE
URACIL, WE CAN CHANGE THE
CONDITION, SWITCHING PH,
CHANGING PH.
WE WERE ABLE TO OPTIMIZE THE
CONDITIONS AND THE CONDITIONS
THAT WORK BEST TURNED OUT TO BE
BASICALLY ALKALINE HYDROTHERMAL
CONDITIONS.
PH9, 90 DEGREES CENTIGRADE, 100
BARS PRESSURE, MODERN OCEAN
SALINITY.
IT WORKED ABOUT TENFOLD BETTER,
IN FACT, THAN THE CONDITIONS IN
WHICH WE STARTED OUT.
AND THIS ONE I THOUGHT YOU MIGHT
LIKE.
THIS IS ATP.
IF WE START WITH ATP IN
SOLUTION, AND WE ADD ACETYL
PHOSPHATE -- THIS IS JUST IN
WATER, THERE'S NO ENZYMES, NO
OTHER CATALYSTS THERE, AND WE
GET 15 TO 20% YIELD.
THIS IS A PH5.5 TO 6, WORKS LESS
WELL IN ALKALINE CONDITIONS.
AND WE TRIED A WHOLE RANGE OF
DIFFERENT PHOSPHORYLATING AGENTS
AND REALLY ONLY ACETYL PHOSPHATE
AND CARBON PHOSPHATE WORKED AT
ALL.
THIS WAS THE REALLY BEAUTIFUL
THING I WANTED TO SHARE WITH
YOU.
PHOSPHORYLATING ADP TO ATP, WE
GET QUITE A NICE PEAK.
THAT'S WHAT WE'RE SEEING HERE.
BUT IF WE TRY TO LOOK FOR ITP OR
GTP OR CTP OR UTP, WE'RE GETTING
NO MORE THAN THE CONTROL VALUES.
IN OTHER WORDS, THERE'S
SOMETHING FAVORED IN WATER ABOUT
ATP ITSELF.
THIS IS WHY, IN MY MIND, WHY ATP
IS THE UNIVERSAL ENERGY CURB
CURRENCY.
YOU CAN PHOSPHORYLATE IN WATER
USING ACETYL PHOSPHATE WHICH IS
STILL USED IN BACTERIA TODAY AS
KIND OF THE LINCHPIN BETWEEN --
AND PHOSPHATE METABOLISM.
SO IT'S REALLY -- IT'S BEAUTIFUL
THAT IT HAPPENED SPONTANEOUSLY
IN VERY SIMPLE PREBIOTIC
CONDITIONS.
SO JUST TO FINISH WITH THE LAST
THREE OR FOUR MINUTES, IF I MAY,
I WANT TO JUST TALK ABOUT WHERE
IT GOES AND HOW THE CODE MIGHT
EMERGE, THE GENETIC CODE IN
THESE CONDITIONS.
HAVE I GOT THREE OR FOUR
MINUTES, WIN?
I HOPE I DO.
SO THIS IS MATHEMATICAL
MODELING.
WE'RE CONSIDERING IN A BARRIER
HERE FIXING CO2, TRAPPED BY
ORGANICS, AMINO ACIDS LIKE
CYSTINE, REDUCING CO2 TO AN
INTERMEDIATE LIKE A METHYL --
BRANCHING FROM THERE INTO AMINO
ACIDS, SUGARS, ACETYL PHOSPHATE
AND FATTY ACIDS.
SO THE FATTY ACIDS WOULD
PARTITION STRAIGHT TO THE
MEMBRANE, AMINO ACIDS CAN
INTERACT WITH THE IRON SULFUR
INCLUDES TURS AND DRIVE CO2
FIXATION AND SO ON.
WHAT HAPPENS IF WE ALLOW THIS
CHEMISTRY TO MOVE FORWARD RIGHT
THE WAY THROUGH TO NUCLEOTIDES?
AS I'VE JUN SHOWN YOU, IT SEEMS
TO BE POSSIBLE.
THEN WE ASSUME THERE'S POSITIVE
FEEDBACK, WE CAN ASSUME POSITIVE
FEEDBACK ON CO2 FIXATION.
THIS IS WHAT WE SEE WITH
FOLATES, FOR EXAMPLE,
METHANOGENS, THEY'RE INVOLVED IN
CO2 FIXATIONS.
SO WE CAN ASSUME POSITIVE
FEEDBACK THERE AND ASK WHAT
HAPPENS, OR WE CAN ASSUME ALL
OTHER KINDS OF POSITIVE
FEEDBACKS ON ANY OF THESE
PATHWAYS, SEE WHAT HAPPENS THEN,
OR WE CAN ASSUME AUTO CATALYSIS
JUST FAVORING NUCLEOTIDE
SYNTHESIS.
WHAT WE FIND, AND I'M NOT GOING
TO GO THROUGH ALL THE RESULTS
HERE, BUT WHAT WE'RE FINDING,
REALLY, IS THAT YES, IT CAN
DRIVE PROTOCELL GROWTH UNDER
SOME SETS OF CONDITIONS IF WE
HAVE THIS SITUATION WHERE IT'S
JUST, FOR EXAMPLE, FARING FAIR FAVORING
AMINO ACID -- THAT FOSTERS FLUX
DOWN ONE PATHWAY AT THE EXPENSE
OF THE OTHERS AND COLLAPSES
PROTOCELL GROWTH.
SO WE WANT GENERAL CATALYSIS,
THE KIND OF THINGS THAT KNEW
NUCLEOTIDE COFACTORS ARE IN
TODAY.
WE HOPED WE'D BE -- SOME SET OF
CONDITIONS WOULD ALLOW US TO
ACCUMULATE AND THEN THEY'D BE
MORE LIKELY POLYMERIZE.
BUT THE ASSUMPTION THAT THEY'RE
CATALYSTS MEANS ACTUALLY THEY
NEVER DO THAT BECAUSE THEY
CATALYZE THE GROWTH OF CELLS SO
THEY KEEP DIVIDING AND DILUTING
THE CONTENTS AT EVERY CELL
DIVISION.
SO IN PRINCIPLE, THIS CAN
HAPPEN.
HOW COULD GENES EMERGE IN THIS
ENVIRONMENT?
THIS IS JUST WHAT I'D LIKE TO
LEAVE YOU WITH, WE CAN COME BACK
AND ASK QUESTIONS LATER ON.
IN ARE THERE ARE PATTERNS IN THE
GENETIC CODE, I'M GOING TO POINT
TO THREE VERY QUICKLY.
THIS IS A QUICK SCHEME OF AUTO
TROPHIC METABOLISM, WHAT I
SHOWED YOU EARLIER ON.
IN GREY, THIS IS WHERE THE FIRST
SPACE OF THE CODON IS A G, AND
IN YELLOW, THIS IS WHERE THE
FIRST BASE OF THE CODON IS AN A.
SO THE FIRST STEPS OF PURINES,
ENCODED BY PURINES.
THEN WITH GREEN, THIS IS URACIL
AT THE FIRST BASE AND WITH BLUE,
IT'S A C FOR THAT FIRST BASE.
SO WE SEE THAT THERE IS -- THIS
IS THE MINIMUM NUMBER OF STEPS
FROM CO2 FIXATION, THERE'S A
VERY CLEAR RELATIONSHIP OF THE
ORDER OF THE BASES.
IT SEEMS TO SUGGEST THE PURINES
CAME FIRST, PURINES CAME BEFORE
PRIM DEANS, AND ESPECIALLY GWAS
EARLY.
THIS IS THE SECOND BASE IN THE
CODON, AND IF WE HAVE A G OR AN
A AT THE FIRST POSITION, WE SEE
QUITE A STRONG RELATIONSHIP.
THIS IS FROM 43 DIFFERENT
INDICES OF HYDROPHOBICITY OF THE
AMINO ACID AND THE BASE OF THAT
SECOND POSITION.
IT'S NOT NEARLY SO STRONG IF
THERE'S A -- THERE SEEMS TO BE
BOTH A TIME FACTOR AND A
BIOPHYSICAL INTERACTION GOING ON
HERE, AND THIS IS THE FINAL
THING I'D LIKE TO LEAVE YOU
WITH, THERE'S ALSO PATTERNS AT
THE THIRD POSITION IN THE CODE
WHICH WE THINK OTHER PEOPLE
HAVEN'T SPOTTED BEFORE
SURPRISINGLY, SO THIS IS AN
INVERTED CODON TABLE WHERE
POSITION THREE, WE EITHER HAVE A
A -- IF WE HAVE A G AND AN A AT
THE FIRST AND SECOND POSITIONS
AND A G AND AN A AT THE FIRST
AND SECOND POSITIONS, IT MATTERS
WHETHER THERE'S A PURINE OR
PYRIMIDINE AT THE THIRD
POSITION.
IF WE CAN PREDICT PURINE, --
THAT DIFFERENCE DEPENDS ON THE
SIZE OF THOSE AMINO ACIDS.
SO AGAIN, THERE'S A PHYSICAL
RELATIONSHIP BETWEEN THE SIZE
AND THE HYDRO -- PROBABLY A TIME
FACTOR.
WE CAN'T UNDERSTAND THE DETAILS
OF THIS YET, BUT ALL I NEED TO
DO IS POSIT THAT THERE ARE
NON-RANDOM RELATIONSHIPS BETWEEN
THE AMINO ACIDS AND RANDOM RNA
SEQUENCES.
SO IF WE HAVE BIOPHYSICAL
INTERACTIONS BETWEEN AMINO ACIDS
AND RANDOM RNA SEQUENCES, IF
WE'RE INTRODUCING RAN DONE RNA
POLYMERS INTO THESE PROTOCELLS,
THERE'S A PURELY RANDOM SEQUENCE
BUT WE HAVE A NON-RANDOM PEPTIDE
AND IN THE CONTEXT OF GROWING
PROTOCELLS, THAT HAS FUNCTION.
IF IT'S A HYDROPHOBIC PEPTIDE,
IT'S LIKELY TO GO TO THE
MEMBRANE, IT MAY BE INVOLVED IN
CO2 FIXATION.
IF IT'S A HYDROPHILIC PEPTIDE,
IT'S LIKELY TO COLLATE IONS LIKE
MAGNESIUM.
ASPARTATE WOULD INTERACT
DIRECTLY WITH MAGNESIUM.
IT'S JUST BIOPHYSICS.
ALL KINDS OF MIXED PEPTIDES ARE
LIKELY TO BIND NUCLEOTIDE
COFACTORS AND PROMOTE
PROTOMETABOLISM.
WE CAN EASILY SEE HOW FUNCTIONS
CAN EMERGE IN THE GROWING
PROTOCELL SYSTEM JUST SIMPLY
THROUGH BIOPHYSICAL
INTERACTIONS.
AND THAT MEANS THAT WE HAVE
SEQUENCE-DEPENDENT FUNCTIONS AND
THEY WILL BE INHERITED SO LONG
AS THAT SEQUENCE IS COPIED.
SO INFORMATION COMES INTO
BIOLOGY RIGHT FROM THE VERY
BEGINNING IN THIS PROTOCELL
CONTEXT.
AND I DON'T THINK IT DOES IN ANY
OTHER CONTEXT.
SO I'M GOING TO LEAVE WITH YOU
THAT, AND I HAVE TO SAY THANK
YOU ENORMOUSLY TO MY GROUP,
BECAUSE THEY'RE BRAVE PEOPLE TO
RISK THEIR CAREERS COMING TO
WORK WITH ME ON QUESTIONS LIKE
THE ORIGIN OF LIFE WHERE THERE'S
NO GUARANTEE THEY'RE GOING TO
FIND ANYTHING AT ALL, SO I THANK
THEM AND I THANK YOU, AND I'M
GOING TO PASS OVER TO JENNIFER.
I THINK QUESTIONS COME LATER.
THANK YOU.
I HOPE I DIDN'T OVERRUN TOO
MUCH.
>> PLEASE CONTINUE TO REMEMBER
TO SUBMIT YOUR QUESTIONS, AND WE
WILL HAVE QUESTION AND ANSWER AT
THE END OF JENNIFER'S TALK.
SO NOW WE'RE GOING TO TURN TO
THE EMERGENCE OF THE EU
KARYOCITE.
JENNIFER?
>>IT'S QUITE AN HONOR TO
FOLLOW NICK LANE, WHOSE WORK I
HAVE REALLY BEEN IN AWE.
A LOT OF THE IDEAS THAT I'M
GOING TO TALK ABOUT TODAY
ACTUALLY COME OUT OF HIS BOOK,
"THE VITAL QUESTION," WHICH
REALLY TRANSFORM MY THINKING
ABOUT EUKARYOTIC CELLS, AND THE
WAY THAT THEY'VE ORIGINATED.
SO THIS IS GOING TO BE A
PERSPECTIVE.
BASICALLY ALL THE IDEAS THAT I'M
GOING TO BE TALKING ABOUT ARE
ONES THAT WE REALLY NEED FURTHER
TESTING, BUT I AM GOING TO TAKE
THE HINT FROM WIN TO JUST THROW
OUT SOME OF THESE IDEAS JUST TO
START A CONVERSATION.
SO I THINK ONE OF THE THINGS
THAT REALLY FORCES YOU TO THINK
HARD ABOUT THE ORIGIN OF
EUKARYOTIC CELL IS TO FIRST LOOK
OUT AT A PLANET THAT HAS NO
LIFE, LIKE MARS, AND THEN MOVE
INTO A PLANET LIKE EARTH THAT IS
FULL OF LIFE.
WHEN YOU LOOK OUT AT THIS
PLANETARY LANDSCAPE, WHAT YOU'RE
SEEING IS HIDDEN UNDERNEATH
PLENTY OF PROKARYOTIC LIFE, BUT
ALSO AN INCREDIBLY EMERGENT
EUKARYOTIC SYSTEM.
THAT'S WHAT WE'RE LOOKING AT
HERE, AND THAT'S WHAT WE ALL ARE
OPERATING WITHIN AS PHYSICAL BIG
HUMAN,.
NOW
HUMAN BEINGS.
NOW THE EVOLUTION OF -- THERE'S
A LOT OF THINKING ABOUT NOT ONLY
THE TREE OF LIFE, YOU KNOW, HOW
WE MOVE INTO THIS LARGE
EUKARYOTIC WORLD, BUT I THINK
ONE OF THE THINGS THAT IS REALLY
SORT OF A STARTING QUESTION IS
FIRST WHY DID IT TAKE 2 BILLION
YEARS BEFORE WE REACHED THIS
SITE OF THE LAST EUKARYOTIC
COMMON AN SES ANCESTOR, AND THEN WHAT
ARE THE CHANGES THAT HAPPENED
OVER THE NEXT 2 BILLION YEARS TO
CREATE THIS INCREDIBLE DIVERSITY
AND STRUCTURE THAT WE SEE THAT'S
CHARACTERISTIC OF EUKARYOTIC
CELLS.
AND I THINK ONE OF THE CLEAR
POINTS THAT NICK'S PRESENTATION
REALLY MADE CLEAR IS THAT IN THE
PROKARYOTIC KINGDOM, IT'S REALLY
METABOLISM THAT IS AT THE HEART.
BASICALLY LIFE WAS GETTING HOLD
OF A RICH METABOLISM THAT
ULTIMATELY LED TO A NEW
INVENTION.
THIS INVENTION IS THE EUKARYOTIC
CELL.
WHICH THEN MOVED INTO A
DIFFERENT TYPE OF DIMENSION IN
TERMS OF EXPLORING SPACE ON A
MANET, AND
PLANET, AND THAT IS STRUCTURAL
DIVERSITY, WHERE WE HAVE
ANIMALS, PLANT, FUNGI, SEA WE'D
AND AMOEBA.
ONE OF THE THINGS THAT HAS
ALWAYS EXCITED ME IS THE
COMPLEXITY OF THEIR INTERNAL
COMPARTMENTALIZATION.
WHAT YOU'RE LOOKING AT IS AN EM
SLICE OF A MOUSE FIBROBLAST, AND
YOU CAN SEE THE HUGE DIVERSITY
OF SUBCELLULAR STRUCTURES OR
COMPARTMENTS THAT COMPRISE THIS
CELL SYSTEM.
WHAT'S QUITE AMAZING ABOUT
EUKARYOTIC CELLS IS THAT EVEN
SIMPLE, MORE SORT OF COMPACT
VERSIONS OF EUKARYOTIC CELLS,
INCLUDING THIS PARASITE,
TOXOPLASMA GONDII, HAS THE EXACT
SAME SET OF NINE ORGANELLES THAT
CHARACTERIZE THIS MUCH LARGER
FIBROBLAST.
SO BASICALLY THERE'S A
CONSERVATION IN THE
COMPARTMENTIZATION OF THESE
EUKARYOTIC CELLS, WHICH I THINK
DESERVES THINKING ABOUT WHEN WE
START COMING UP WITH MODELS FOR
HOW THE EUKARYOTIC CELL ITSELF
EVOLVED.
BASICALLY ALL EUKARYOTIC CELLS
HAVE CONSERVED MEMBRANE-BOUND
STRUCTURES THAT ARE PERFORMING
VERY SPECIFIC TASKS, WHICH RANGE
FROM ENERGY METABOLISM IN THE
CASE OF MITOCHONDRIA TO DELIVERY
OF MACROMOLECULES TO THE OUTSIDE
OF THE CELL TO DIFFERENT OTHER
SUBCELL COMPARTMENTS AND ALSO A
PROCESS OF ENDO CYTOSIS AND
UPTAKE OF MACRO MOLECULES.
NOW THERE ARE SEVERAL MODELS FOR
THE ORIGIN OF EUKARYOTIC CELLS,
BUT TWO OF THOSE, I'M GOING TO
FOCUS ON TODAY, AND PERHAPS THE
MOST WIDELY RECOGNIZED MODEL FOR
THE ORIGIN OF EUKARYOTES IS WHAT
WE CALL STEP DID WISE EVOLUTION.
BASICALLY THE IDEA BEHIND THIS
MODEL IS THAT PROKARYOTES
BASICALLY GOT TIRED OF BEING
SIMPLE AND STARTED ELABORATING
ITS INTERNAL MEMBRANES
POTENTIALLY BY INVAGINATION OF
THE MEMBRANE, BUT BASICALLY THAT
LED TO WHAT WE CALL A
PROTOEUKARYOTE WHICH ALREADY HAD
A SIMPLIFIED SET OF ENDO
MEMBRANES, ALREADY HAD SORT OF
PERHAPS A PRIMITIVE NUCLEUS, AND
BASICALLY ALL THAT WAS NEEDED IS
TO CREATE A MORE MODERN
EUKARYOTIC CELL WAS THE
INTERNALIZATION OR UPTAKE OF
BACTERIA, WHICH WOULD CREATE A
MITOCHONDRIA, WHICH ITSELF COULD
BECOME AN INTEGRATED PART OF
THAT EUKARYOTIC CELL BY
TRANSFERRING PART OF ITS DNA
INTO THE NUCLEUS OF THIS
PROTOEUKARYOTIC HOST.
AND ULTIMATELY, YOU WOULD THEN
GET THE COMPLEX EUKARYOTIC CELL.
NOW THE PROBLEM WITH THIS
STEP-WISE EVOLUTIONARY MODEL IS
THAT THERE ARE NO SURVIVING
PROTO EUKARYOTES TODAY THAT SHOW
ANY EVIDENCE FOR THIS PATHWAY.
WE CAN'T FIND PROTO EUKARYOTES,
WE CAN'T FIND EU CARE YOTS EUKARYOTES THA T
HAVE A SUBSET OF THE
COMPARTMENTS THAT I JUST SHOWED
YOU.
OR PROTOEUKARYOTES THAT LACK
MITOCHONDRIA OR SOME HEREDITARY
VESTIGE OF THE MITOCHONDRIA.
BASICALLY ALL EUKARYOTIC CELLS
NOW HAVE VERY SIMILAR IDENTICAL
SETS OF ORGANELLES.
WE ALSO KNOW THAT THESE
ORGANELLES, THESE INTERNAL OR
NELS OF THESE EUKARYOTES ARE ALL
DOING VERY SMALLER THINGS IN ALL
EUKARYOTES.
SO BASICALLY THESE ARE ARGUMENTS
THAT DOESN'T RULE OUT THE
STEPWISE EVOLUTION BUT MAKES YOU
START WONDERING WHETHER SOME
OTHER MODEL MIGHT FIT THE BILL
MORE SPECIFICALLY.
THAT OTHER MODEL THAT I WANT TO
TALK ABOUT TODAY, AND REALLY
BUILDS ON THE REALLY FASCINATING
IDEAS THAT NICK TALKED ABOUT
TODAY IS A TYPE OF METABOLIC
SYMBIOSIS.
AND IN THIS MODEL BASICALLY IS
THAT A EUKARYOTIC CELL IS
FUNDAMENTALLY A SYMBIOTIC
RELATIONSHIP BETWEEN THE TWO
TYPES OF VERY PRIMITIVE
PROKARYOTS THAT NICK TALKED
ABOUT, THE ME THAN GENERALS AND
THE ASSET GENERALS.
THEY'RE PRO DEUTING CARBON
DIOXIDE AND HYDROGEN, THEY ARE
THE BACTERIA, AND THE
METHANOGENS ARE PRODUCING
METHANE.
AND IT'S A COLLABORATION BETWEEN
THESE TWO DIFFERENT PROKARYOTS
THAT GIVES RISE TO AN ENDO
SYMBIOTIC SYSTEM THAT ULTIMATELY
MOVES INTO THE CREATION OF A
COMPLEX EUKARYOTIC CELL.
SO LET'S TAKE A CLOSER LOOK AT
THIS.
I DON'T KNOW WHETHER YOU CAN
SEE -- IS THIS -- IS THERE A
PANEL UP HERE THAT BLOCKS PEOPLE
FROM SEEING THE TITLE OF THESE
SLIDES?
I'M JUST CURIOUS.
I CAN'T GET RID OF IT.
ANYWAY, BEAR WITH ME.
BASICALLY THIS IS JUST A ZOOM-UP
OF THIS METABOLIC SIM BUY OH
CYST MODEL WHERE WE HAVE THESE
TWO DIFFERENT TYPES OF
PROKARYOTS THAT BASICALLY ONCE
THEY BEGIN SORT OF INTERACTING
METABOLICALLY AND ULTIMATELY
WHEN THE ALPHA -- THE ACETOGEN
GETS TAKEN UP INTO THAT, WHAT
EMERGES IS AN INCREASED ENERGY
DEPENDENCE AS WELL AS
POTENTIALLY ENERGY OUTPUT IN
THAT SYSTEM.
AND IT'S THIS ENERGY DEPENDENCE
AND OUTPUT THAT I WANT TO FOCUS
ON RIGHT NOW, BASICALLY WHAT'S
THE BASIS OF THIS INCREASE
ENERGY DEPENDENCE.
AND FOR THAT, I'M GOING TO SORT
OF MOVE TO WHAT NICK TALKED
ABOUT, WHICH IS THIS UNEXPECTED
ASPECT OF THE ENERGY OF LIFE.
WHICH IS THAT CELLS ARE DERIVING
ENERGY FROM REALLY ONE TYPE, ONE
MAJOR TYPE OF CHEMICAL REACTION,
AND THAT IS FLOW OF PROTONS
ACROSS A MEMBRANE.
THIS, AS NICK SAID, IS WHY MANY
PEOPLE THINK IS ONE OF THE MOST
COUNTERINTUITIVE IDEAS SINCE
DARWIN, BUT BASICALLY IT WAS
PROPOSED BY PETER MITCHELL, AND
IT'S THE CROSS MEMBRANE PROTEIN
GRADIENT THAT PETER PROPOSED
DROVE ENERGY METABOLISM WITHIN
CELLS.
IN PARTICULAR, HE WAS USING TO
DESCRIBE THE MITOCHONDRIAL
RESPIRATORY CHAIN AND THE WAY
THAT IT IS PRODUCING ATP
BASICALLY, THESE ARE THE VARIOUS
ENZYMES, SUBUNITS THAT ARE PART
OF THIS ELECTRON TRANSPORT
CHAIN, BUT BASE BASICALLY WHAT
THEY'RE DOING IS PUMPING PROTONS
ACROSS THIS MEMBRANE BILAYER
AND, AS A CONSEQUENCE, CREATING
AN ELECTROPOTENTIAL GRADIENT.
NOW, WE KNOW THAT ALL LIVING --
WELL, BASED ON WHAT NICK SAID,
ALL LIVING CELLS ARE POWERING
THEMSELVES THROUGH THIS TYPE OF
MECHANISM.
SO BOTH ARCHAEA AS WELL AS TACK
BACTERIA USE THIS TYPE OF CHEMO
OSMOTIC COUPLING TO DRIVE THEIR
ENERGY PRODUCTION.
SO A QUESTION IS WHETHER THERE
ARE DIFFERENCES IN THE WAY THAT
ARCHAEA AND BACTERIA ARE DOING
THIS, THAT MIGHT PROVIDE CLUES
AS TO WHY HAVING A SYMBIOTIC
RELATIONSHIP BETWEEN ARCHAEA AND
BACTERIA MIGHT PRODUCE A SYSTEM
THAT CAN GIVE EMERGENT
PROPERTIES TO LIFE, IE, A
EUKARYOTIC CELL.
SO LET'S LOOK AT LET'S LOOK AT
THE TWO DIFFERENT WAYS THAT
ARCHAEA AND BACTERIA ARE DOING
THIS.
ONE OF THE WAYS THAT I THINK
SORT OF POPS UP IS IF WE LOOK AT
THE PHOSPHOLIPIDS THAT ARE
CHARACTERIZING ARCHAEA VERSUS
BACTERIA, NICK MENTIONED THEY
ARE DIFFERENT, YES INDEED THEY
ARE, BUT WHAT'S REALLY
INTERESTING IS THE DIFFERENCE
BETWEEN THE LINKAGE OF THE
PHOSPHOLIPID SIDE CHAIN, TO THE
HEAD GROUP.
IN THE CASE OF ARCHAEA, IT IS
MEDIATED BY AN ETHER LINKAGE,
WHEREAS IN THE CASE OF BACTERIA,
IT'S AN ESTER LINKAGE.
AND THAT TURNS OUT TO
POTENTIALLY BE EXTREMELY
IMPORTANT IN TERMS OF REGULATING
THE FLOW OF PROTEINS -- PROTONS
ACROSS BACTERIAL MEMBRANES.
RECENTLY, MARIA MENCIA, A
THEORETICAL AND A BIOCHEMIST,
HAS PROPOSED THAT WITH ESTER
LINKAGES IN LIPIDS, THE
PROTONS COULD POTENTIALLY FLOW
MORE FLUIDLY THROUGH THE
MEMBRANE -- THE INNER PART OF
THE BILAYER, IN CONTRAST TO
PHOSPHOLIPIDS THAT HAVE ETHER
LINKAGES.
WHERE YOU DON'T HAVE THE ABILITY
TO JUST FLOW THESE PROTONS
ACROSS THE MEMBRANE.
AND THAT WOULD FACILITATE THE
ABILITY OF THE ENZYMES IN THE
ELECTRON TRANSPORT CHAIN TO BE
ABLE TO BE COUPLED TO DRIVE FAST
PROTON FLUX.
THIS COULD BE -- AND THIS IS
VERY SPECULATIVE, BUT THIS
DIFFERENCE IN PROTON PUMPING
EFFICIENCY, IT MIGHT HELP
EXPLAIN SOME OF THE DIFFERENCES
IN ARCHAEA AND BACTERIAL
HABITATS AND CHARACTERISTICS.
WE KNOW THAT AT LEAST TODAY,
ARCHAEA, IF YOU WANT TO FIND
THEM, YOU'VE GOT TO GO TO
EXTREME ENVIRONMENTS, EITHER
THESE SULFUR PONDS OR THESE HOT
POOLS, AND IF YOU TRY TO GROW
THESE ARCHAEA, YOU FIND THEY
TYPICALLY ARE EXTREMELY
SLOW-GROWING.
BACTERIA, ON THE OTHER HAND,
GROW EXTREMELY FAST, AND YOU CAN
FIND THEM ALL OVER THE PLACE.
THIS IS JUST IN THE SOIL,
BASICALLY YOU PICK UP SOME SOIL,
IT'S JUST FULL OF BACTERIA.
SO THAT RAISES OF QUESTION OF,
OKAY, IF BACTERIA IS SO GOOD AT
GROWING, AND CAN FLOW PROTON%
REALLY FAST TO GIVE YOU A LOT OF
ENERGY, WHY DIDN'T BACTERIA
BECOME A EUKARYOTIC CELL?
WHY CAN'T WE SCALE UP A BACTERIA
TO MAKE IT A EUKARYOTIC-LIKE
CELL?
THE PROBLEM IS THAT BACTERIA HAS
A VERY SMALL AMOUNT OF DNA.
AND THAT DNA IS LARGELY DEVOTED,
OR A LARGE CHUNK OF IT IS
DEVOTED TO DRIVING THE
PRODUCTION OF THE PROTEINS THAT
ARE COMPRISING THE ELECTRON
TRANSPORT CHAIN ON ITS SURFACE
FOR ENERGY PRODUCTION.
SO THE THINKING IS THAT THE
BACTERIA'S GENOME IS JUST TOO
SMALL TO SUPPORT THE ENERGY
NEEDS OF A CELL THAT SWELLS UP.
BASICALLY YOU'RE NOT GOING TO
GET THIS DNA TO BE ABLE TO
COUPLE ITSELF IN TERMS OF ITS
PRODUCTION OF PROTEINS,
TRANSCRIPTION AND TRANSLATION TO
MATCH WHAT'S GOING ON IN THIS
LARGE SYSTEM.
WHY NOT JUST PUT A WHOLE BUNCH
OF BACTERIA DNA INTO WHY DOESN'T
THE BACTERIA JUST SWELL, WITH
YOU BUT
ALSO JUST MAKE A WHOLE BUNCH OF
COPIES OF ITS GENOME.
THIS ALSO HAS A PROBLEM BECAUSE
ALSO WE KNOW COULD BE -- THE
PROTEINS THAT ULTIMATELY ARE
GOING TO BE READ OUT FROM THIS
GENOME AGAIN HAVE THE PROBLEM IN
THE CASE OF PROTEINS THAT ARE
INVOLVED IN THE ELECTRON
TRANSPORT CHAIN OF FINDING THIS
MEMBRANE OF ENERGY FLUX TO DRIVE
PRODUCTION.
SO BASICALLY WHAT THE ANSWER
SEEMS TO HAVE BEEN IN THE CASE
OF EUKARYOTIC EVOLUTION IS TO
KEEP THE SMALL SIZE OF A
BACTERIUM THAT IS REALLY
SUPPORTING THE ENERGY NEEDS OF
THE CELL, BUT IT JUST INHABIT A
LARGER VIERM.
AND THIS IS ENVIRONMENT.
THIS IS BASICALLY WHAT THE
EUKARYOTIC CELL IS.
IT'S A BIGGER CELL THAT'S RUN BY
MULTIPLE POWER UNITS, WHICH ARE
MITOCHONDRIA.
SO EACH OF THESE MITOCHONDRIA
HAVE THEIR MEMBRANE CLOSE AROUND
THEM, THEY'RE CHURNING OUT
PROTEINS THAT ARE GOING TO DRIVE
THE ENERGY PRODUCTION FOR THIS
EUKARYOTIC CELL.
SO THIS TYPE OF THINKING HAS
SOME IMPLICATIONS.
ONE IMPLICATION IS THAT THE
PROTEOBACTERIA THAT HAS BEEN
TAKEN UP BY THE ARCHAEA, WHICH
IS THE MITOCHONDRIA, MUST OR IS
LIKELY TO HAVE BEEN A MAJOR
DRIVER FOR EVOLUTION IN THE
EUKARYOTIC SYSTEM.
BASICALLY THAT MY TOE CON MITOCHONDRIA IS
GOING TO REALLY BE REGULATING A
LOT OF THINGS, AND IS THAT THE
CASE.
WELL, WE SHOULD SEE A LOT OF
FEATURES OF MITOCHONDRIA ALL
OVER -- OR MARKED ALL OVER THE
WAY THAT EUKARYOTIC SYSTEM IS
WORKING.
AND ONE THING THAT WE
IMMEDIATELY KNOW IS THAT
EUKARYOTIC MEMBRANES, AND I WISH
WE COULD GET RID OF THIS PANEL
HERE BECAUSE -- YOU CAN'T SEE
THE TITLE HERE, BUT BASICALLY
THIS IS JUST A SMALL MICRON
VOLUME OF A EUKARYOTIC CELL
WHERE WE'VE SEGMENTED OUT ALL OF
THE DIFFERENT ORGANELLES WITHIN
THE SYSTEM, AND WHAT I WANT TO
JUST DRAW YOUR ATTENTION TO IS
THAT THE MEMBRANES THAT COMPRISE
ALL OF THE EUKARYOTIC CELL ARE
ALL ESTER-LINKED, LIKE BACTERIA.
THEY'RE NOT ETHER-LINKED.
SO THE ESTER-LINKED FEATURE OF
PHOSPHOLIPIDS FOUND IN BACTERIA
HAS BEEN EMBRACED BY THE
EUKARYOTIC CELL.
ALL ITS MEMBRANES ARE
ESTER-LINKED, THERE'S NONE THAT
ARE ETHER-LINKED.
SO BASICALLY THE BACTERIA SORT
OF PUSHED OUT ANY ARCHAEA-TYPE
LIPID THAT WAS ETHER LINKED
DURING THIS EVOLUTIONARY
PROCESS.
WE ALSO SEE THE PREEMINENCE OF
MITOCHONDRIA IN CELL PHYSIOLOGY.
THIS IS JUST LIVE CELL IMAGING
OF MY TOE MITOCHONDRIA.
YOU CAN SEE MITOCHONDRIA ARE
JUST DISTRIBUTED ALL OVER THE
CYTOPLASM, THEY'RE HIGHLY
DYNAMIC, IF WE THEN INTERROGATE
ALL OF THE FEATURES OF THESE
MITOCHONDRIA IN TERMS OF THEIR
FUNCTIONALITIES, WE CAN SEE
BASICALLY ALL ASPECTS OF CELL
PHYSIOLOGY REALLY HAVE
MITOCHONDRIA AT THEIR CORE.
SO FOR INSTANCE, ALL THE
BUILDING BLOCKS OF THE CELL,
WHETHER IT BE NUCLEOTIDE,
PROTEINS, LIPIDS, ARE ALL MADE
FROM THE FUNDAMENTAL TCA CYCLE
OPERATING INSIDE THAT
MITOCHONDRIA.
THE MITOCHONDRIA ALSO CAN GIVE
RISE TO LIPIDS, IT CAN STORE
LIPIDS.
IT'S TAKING IN FATTY ACIDS AND
GLUCOSE THROUGH THIS GLYCOLYTIC
PATHWAY WHICH FEEDS INTO THIS
TCA CYCLE, BUT YOU CAN MOVE OUT
TO STORE LIPIDS, AND I'M GOING
TO BE TALKING ABOUT THIS LATER
IN MY PRESENTATION, WHICH PLAYS
A CRITICAL ROLE IN THE WAY THAT
CELLS CAN HANDLE STARVATION AND
DEAL WITH VERY DRAMATIC CHANGES
IN AVAILABILITY OF NUTRIENTS.
THE MITOCHONDRIA IS ALSO
CONTROLLING CELL DEATH, IT'S
CONTROLLING SIGNALING, IT HAS
CALCIUM STORAGE DEPOT.
BASICALLY ALL THE
CHARACTERISTICS, ALL OF THE
MACRO MOLECULES THAT ARE -- A
LOT OF THE METABOLISM OF THE
CELERILY ARE SN TERRED AROUND CENTERED ARO UND THE
MITOCHONDRIA AND THE WAY IT'S
FUNCTIONING.
SO BASICALLY ALL OF THIS IS
SUGGESTING THAT THE EUKARYOTIC
CELL AROSE THROUGH AN ENDO -- A
SINGLE SYMBIOTIC EVENT BETWEEN
AN ARCHAEA HOST AND THIS
MITOCHONDRIAL -- IT'S A
BACTERIUM THAT ULTIMATELY IS
GOING TO GIVE RISE TO THE
MITOCHONDRIA.
SO THAT THEN RAISES THE QUESTION
OF HOW DO EUKARYOTIC CELLS GET
BIG GENOMES AND HOW DO THEY
BECOME MORPHOLOGICALLY COMPLEX.
IS THERE A WAY THAT WE CAN START
THINKING ABOUT THAT TO GET A
BETTER UNDERSTANDING OF -- WE
HAD THIS NEW TYPE OF SYNERGY
BETWEEN SORT OF A METABOLIC
SYMBIOSIS BETWEEN THESE TWO
DIFFERENT TYPES OF PRO PROKARYOTS,
THAT'S GIVEN RISE TO THIS NEW
FORM, THIS EUKARYOTIC CELL.
HOW DOES IT GET A BIG GENOME AND
HOW DOES IT BECOME
MORPHOLOGICALLY COMPLEX?
WELL, THE BIGGER GENOME CAN
EASILY BE SORT OF IMAGINED BY
BASICALLY BEING POWERED BY ALL
OF THESE MITOCHONDRIAL ATP POWER
UNITS.
A LOT OF THE MITOCHONDRIAL
GENOME, A LOT OF THE ALPHA
PROTEOGENOME THAT WAS ORIGINALLY
FOUND IN THESE ENDOSYMBIANTS
HAVE NOW MOVED INTO THE NUCLEUS.
THIS GENOME BECAME EVEN LARGER
BECAUSE IT BASICALLY IS THE HOME
TO ALL OF THE ARCHAEA BASED
GENES.
SO BASICALLY IT'S NOT HARD TO
IMAGINE THANK YOU YOU HOW YOU COULD CREAT E A
BIGGER GENOME POWERED BY
MULTIPLE -- TO OPERATE IN THAT
REGIME.
BUT WHAT'S NOT SO CLEAR IS THE
EMERGENCE OF THE MORPHOLOGICAL
COMPLEXITY OF ALL OF THESE
MEMBRANES AND COMPARTMENTS
INSIDE THE EUKARYOTIC CELL, AND
THAT'S WHAT I WANT TO TALK ABOUT
FOR THE NEXT FIVE MINUTES OR 10
MINUTES OF THIS TALK.
BASICALLY WHAT I'M GOING TO
PROPOSE IS THAT THE PATTERNING
OF LIPIDS ARE PLAYING A VERY
CRITICAL ROLE IN THIS TYPE OF
COMPARTMENTALIZATION, AND
BASICALLY THE EMERGENCE OF THIS
INTERNAL COMPLEXITY INSIDE THESE
EUKARYOTIC CELLS WAS ENABLED BY
THE PRESENCE OR THE EMERGENCE OF
PARTICULAR TYPES OF EUKARYOTIC
LIQUIDS.
SO EUKARYOTES HAVE A COMBINATION
OF GLIS ROW PHOSPHOLIPIDS,
SPHINGOLIPIDS AND CHOLESTEROL,
WHICH NEITHER BACTERIA HAVE.
IN PARTICULAR -- DO NOT -- IT'S
THE PRESENCE OF THAT CLES TROT
WHICH IS GIVING RISE TO A VERY
INTERESTING CHARACTERISTIC OF
MEMBRANES, WHICH IS THEIR
ABILITY TO PARTITION INTO
REGIONS WHERE THE STERILE CAN
ORDER THE SPHIGOLIPIDS THAT CAN
ORDER A THICKER BIOLAYER INTO
WHICH THEY PREFERENTIALLY SORT.
NOW THERE'S A LOT OF INTEREST IN
THE EVOLUTION OF STEROLS IN
EUKARYOTES, BUT REALLY IT TOOK
OFF VERY EARLY IN THE EVOLUTION
OF EUKARYOTES, THIS STEROL, AND
MODERN DAY EUKARYOTES THAT CAN'T
MAKE STEROLS WILL BRING IN
STEROLS FROM OTHER SOURCES.
SO STEROLS ARE ABSOLUTELY A
FUNDAMENTAL PART OF EUKARYOTIC
MEMBRANES.
SO I MENTIONED HOW THESE STEROLS
OR CHOLESTEROL CAN ORDER THESE
MEMBRANES.
BASICALLY PHOSPHOLIPIDS ARE
HIGHLY DISORDERED, THEY'RE
FLOPPY, MAKES THE MEMBRANES THAT
CONTAIN JUST PURE PHOSPHOLIPIDS
ARE LEAKY AND HIGHLY DISORDERED.
AS SOON AS YOU START ADDING
SINGLE LIPIDS AND CHOLESTEROL,
ESPECIALLY THE CHOLESTEROL, YOU
CAN BEGIN OARING THESE ORDERING MEMBRANES .
YOU CAN SEE THIS SPARE MEANTLY
BY JUST TAKING THESE THREE
CLASSES OF LIPIDS, PUTTING THEM
IN A VIAL, SHAKING THE FILE UP
AND YOU'LL SEE, IF YOU CREATE
RES VEST CREATE
VESICLES, YOU SEE THEY SEPARATE
INTO ORDERED AND DISORDERED
DOMAINS, WHERE THE DISORDERED
DOMAINS WILL BE PRIMARILY
PHOSPHOLIPIDS AND THE ORDERED
DOMAINS WILL BE PRIMARILY SINGLE
LIPIDS IN CHOLESTEROL.
IT TURNS OUT WE CAN SEE THIS
EVEN IN BIOLOGICAL MEMBRANES, IN
CELLS.
YOU CAN HYPOTONICLY SWELL OUT A
VESICLE FROM YOUR CELL, AND IF
YOU LOIR THE TERRITORY USING
LIPPED PROBES OF THAT BLEB INTO
A DISOR'DED AND ORDERED DOMAINS.
WE'VE RECENTLY INTRODUCED
FLUORESCENT PROTEINS THAT HAVE
BEEN PROPOSED TO TARGET TO ORDER
VERSUS DISORDERED DOMAINS ON TO
THE PLASMA MEMBRANE OF CELLS.
IF WE BLEB OUT SOME OF THAT
PLASMA MEMBRANE AND LOWER OUR
TEMPERATURE TO DRY PHASE
SEPARATION, YOU CAN SEE SEPARATE
TYPES OF PROTEINS, THEY PHASE
PARTITION INTO DIFFERENT DOMAINS
IN THESE PLASMA MEMBRANE
VESICLES.
THIS IS EXTREMELY INTERESTING
AND EXCITING BECAUSE WHAT THIS
IS SAYING IS THAT THE PRESENCE
OF THESE LIPIDS ALLOWS FOR VERY
COMPLEX SORTING OF PROTEINS ON
BIOLOGICAL MEMBRANES IN
EUKARYOTIC CELLS.
IT'S NOT CLEAR THAT THIS IS
POSSIBLE TO THIS EXTENT, IN THE
PROKARYOTIC KINGDOM.
NOW, I WANT TO JUST SHARE WITH
YOU SOME REAL BIOLOGY THAT WE
THINK UNDERLIES, THAT
REQUIRES/INVOLVES THIS PHASED
PORE
PARTITIONS.
THIS IS A YEAST VACUOLE FROM A
YEAST THAT IS WELL-FED, AND YOU
CAN SEE THAT WHEN WE INTRODUCE A
MARKER, IN THIS CASE,
GFP-PHO8 WHICH LIKES BEING IN A
LIQUID DISORDERED MEMBRANE, AS
SOON AS WE STARVE THIS YEAST
CELL, WE CAN SEE THE VACUOLE
PHASED POSITION INTO THIS SOCCER
BALL-LIKE PATTERN WHERE THE
DISORDERED MEMBRANE IS NOW
SEPARATED FROM THESE BLACK AREAS
HERE, WHERE THE MEMBRANE IS
ENRICHED IN STEROLS AND SINGLE
LIPIDS.
THIS IS JUST SHOWING, THIS IS A
FREEZE FRACTURE OF THAT VACUOLE
FROM THAT STAR STARVED YEAST CELL.
THIS IS WHAT'S HAPPENING IN THAT
VACUOLE.
THIS IS A REAL CELL WHERE WE'RE
LOOKING AT THIS.
NOW ONE OF THE THINGS THAT WE'VE
DONE IN TERMS OF TRYING TO
ANALYZE HOW THIS PHASED
PARTITIONING OCCURS AND WHAT ITS
PURPOSE IS, IS SHOWN HERE
BASICALLY WHEN THE CELL IS
STARVED OF GLUCOSE, AUTOPHAGY IS
INITIATED AND THAT BRINGS
MEMBRANES FROM THE ENDO CYTIC --
TO THE VACUOLE.
STEROL ABUNDANCE IN THAT VACUOLE
START DRIVING PHASED
PARTITIONING ON THAT VK YOU'LL,
AND THAT, THEN, LEADS TO THE
ABILITY OF THE VACUOLE TO START
MAKING CONTACT WITH PARTICULAR
ORGANELLES, IN PARTICULAR, THE
ENDO PLASMIC RETICULUM, WHICH
ITSELF CAN MAKE CONTACT WITH THE
MITOCHONDRIA.
AND BASICALLY WHAT WE'RE
PROPOSING IS THAT THIS ENABLES A
LIPID PIPELINE TO FLOW INTO THE
MITOCHONDRIA UNDER STARVATION
CONDITIONS.
BECAUSE WHAT WE FIND IN THESE
YEAST CELLS IS THAT WHEN THEY
UNDERGO STARVATION, THEY ARE
VERY HAPPY, THEY CAN SURVIVE 50
DAYS UNDER ACUTE GLUCOSE
RESTRICTION, AND WHAT HAPPENS IS
THE MITOCHONDRIA ACTUALLY
PROLIFERATE DRAMATICALLY AS YOU
CAN SEE UNDER THESE CONDITIONS.
CELL RESPIRATION IS BOOSTED AS
YOU CAN SEE IN THIS MAP.
WE LOOK AT OXYGEN CONSUMPTION
UNDER THIS ACUTE GLUCOSE
STARVATION OF REGIME, IN
CONTRAST TO CELLS WHERE WE HAVE
NOT INITIATED THIS TYPE RESPONSE
IN TERMS OF PHASED PARTITIONING
AND THE ABILITY OF THESE
ORGANELLES TO BEGIN TO
COMMUNICATE WITH EACH OTHER.
SO BASICALLY THIS IS JUST AN
EXAMPLE WHERE WE SEE THAT THE
CELL IN ADAPTING ITS PATHWAYS
FOR DEALING WITH DIFFERENT TYPES
OF NUTRIENT STRESSES,
MITOCHONDRIA IS PLAYING A KEY
ROLE.
THERE ARE PATHWAYS THAT ARE
ENGAGED TO SPECIFICALLY FEED
FATTY ACIDS INTO THAT
MITOCHONDRIA, AND ALSO ENABLE
THAT MITOCHONDRIA TO GROW ITS
MEMBRANES IN ORDER TO GIVE THE
CELL ATP UNDER THESE
NUTRIENT-RESTRICT RESTRICTED REGIMES.
SO BASICALLY WHAT I'D LIKE TO
PROPOSE IS THAT THE APPEARANCE
OF CHOLESTEROL IN SINGLE LIPIDS
IN MEMBRANES COULD BE WHAT MIGHT
BE CALLED AN EVENT HORIZON FOR
EUKARYOTIC CELL EVOLUTION.
AND IT'S ENABLING BECAUSE IT'S
ALLOWING MEMBRANE
COMPARTMENTIZATION AND
TRAFFICKING.
BASICALLY IT'S ONLY BY BEING
ABLE TO PARTITION THESE
MEMBRANES THAT YOU CAN GET
PREFERENTIAL SORTING OF
PROTEINS.
NOW THE SUPPORT FOR THIS IS THAT
WE KNOW THAT BACTERIAL
MEMBRANES, IT'S ONLY BACTERIAL
MEMBRANES THAT HAVE STEROL LN
LIKE LIPIDS, ARCHAEA DON'T HAVE
ANY HINT OF THAT.
NEITHER BACTERIA OR ARCHAEA HAVE
TRUE STEROLS IN THEIR MEMBRANES,
AND BASICALLY WE KNOW
MITOCHONDRIA ARE COLLABORATING
WITH OTHER ORGANELLES IN
CHOLESTEROL BIOSYNTHESIS AND
THAT THE CHOLESTEROL AND THE
SINGLE LIPIDS ARE CREATING THESE AND
LIPID GRADIENTS.
SO SOME MEMBRANE-SPECIFIC
SPECULATION, MY THINKING IS THAT
BASICALLY WITH THE ABILITY TO
PHASE PARTITION MEMBRANES, THE
PRIMITIVE GTPASE IS ANOTHER
PROTEIN INCLUDING ESCORTS WOULD
THEN BE ABLE TO RAPIDLY EVOLVE.
SO A LOT OF THE ATP -- THE
GTPASES THAT ARE SHAPING AND
DRIVING POLYMERIZATION OF
VARIOUS CYTOSKELETAL COMPONENTS,
THEY BASICALLY ARE VERY MUCH
COUPLED TO BEING ABLE TO
ASSOCIATE WITH MEMBRANES, AND
THIS PHASED PARTITIONING MAY BE
A VERY IMPORTANT PART OF THAT
PROCESS.
I'D SAY IT'S ALSO POSSIBLE THIS
LED TO THE SPECIALIZED -- WE
KNOW MEMBRANES LIKE THE GOLGI
APPARATUS CAN COMBINE -- AND
CREATE TUBULIN ASTERS.
WITHIN THE CYTOPLASM OF A
EUKARYOTIC CELL IS VERY MUCH
DEPENDENT ON SPECIALIZATION OF
MEMBRANES THAT WILL EITHER
SEQUESTER OR ACCUMULATE
DIFFERENT TYPES OF LIPIDS THAT
RECRUIT KNEW CLEE ATORES FOR
CYTOSKELETON.
SO WE THINK THIS MAY HELP
EXPLAIN WHY PROKARYOTS NEVER
DEVELOPED MORE COMPLEX
CYTOSKELETONS, THEY HAD NEITHER
THE SPECIALIZED MEMBRANES NOR
THE KNEW CLEE ATORES TO DO THIS.
SO MY LAST QUESTION IS, WELL,
HOW CAN WE ADDRESS THESE ISSUES?
HOW CAN ANY OF WHAT I'VE TALKED
ABOUT TODAY BE PROVED OR IN ANY
WAY SUPPORTED.
BASICALLY I THINK WE'RE GOING TO
HAVE TO ADDRESS THIS IN I A LOT
OF DIFFERENT WAYS.
ONE IS, WE NEED NEW TOOLS TO
VISUALIZE, PROBE AND MEASURE
LIPIDS AND PROTEINS WITHIN THE
CELL.
WE NEED TO REALLY LOOK AT THIS
PHASED PARTITIONS AND SEE
EXACTLY WHAT IT'S DOING.
WE NEED HIGHER RESOLUTION TO
EXAMINE PROTEIN DISTRIBUTIONS IN
RELATION TO LIPIDS WITHIN
ORGANELLES, AND FINALLY
MATHEMATICAL MODELING WOULD BE
INCREDIBLY VALUABLE TO ASSESS
THE DYNAMICS OF THE SYSTEM, AND
START LEADING TO OTHER TYPES OF
HYPOTHESES FOR TESTING SOME OF
THESE QUESTIONS.
SO WITH THAT, I WANT TO THANK
YOU, AND I WILL NOW STOP SHARING
AND WE CAN BE OPEN FOR
QUESTIONS.
>> THANK YOU VERY MUCH,
JENNIFER.
NICK, WE DO HAVE A SERIES OF
QUESTIONS AND I HOPE BOTH OF YOU
ARE THINKING OF QUESTIONS YOU
WOULD LIKE TO ADDRESS TO EACH
OTHER.
ONE QUESTION THAT'S BEEN ASKED,
NICK, IS COULD LIFE PERHAPS HAVE
STARTED A FEW TIMES, MORE THAN
ONE, ABIOGENESIS?
IS THERE -- BACTERIA, ARCHAEA,
AND THE EUKARYOTES MAY HAVE
ARISEN SEVERAL TIMES OR HAVE
ARISEN FROM --
>> I MEAN, THEY MAY HAVE DONE --
THERE'S NO EVIDENCE TO SUPPORT
THAT.
I MEAN, PLAINLY LIFE SHARES A
COMMON ANCESTOR BECAUSE THE
GENETIC CODE REALLY IS THE
SINGLE STRONGEST PIECE OF
EVIDENCE THAT SUGGESTS THAT ALL
LIFE IS DERIVED FROM THE SAME
SOURCE.
NOW RIGHT AT THE END OF MY TALK,
I SUGGESTED THAT THERE ARE
BIOPHYSICAL REASONS FOR THE
CODE, I DON'T THINK THAT WOULD
EXPLAIN THE WHOLE CODE AND I
WOULD BE ABSOLUTELY AMAZED IF WE
FOUND BACTERIA ON MARS OR
SOMEWHERE LIKE THAT AND THEY HAD
EXACTLY THE SAME CODE, WE
CONCLUDED THEY DIDN'T COME FROM
EARTH OR VICE VERSA.
IT WOULD BE SHOCKING IF YOU LIKE
CHEMICAL DETERMINE NISM CAN TAKE
US RIGHT UP TO THE CODE ITSELF.
ALL THE WAY.
IT'S POSSIBLE IT CAN, THOUGH WE
DON'T KNOW ENOUGH YET, BUT I
WILL BE SURPRISED.
NOW THAT DOESN'T MEAN TO SAY
THAT THERE WEREN'T MULTIPLE
ORIGINS OF LIFE AND THAT IT
SIMPLY DISAPPEARED AND THERE'S
NO EVIDENCE FOR IT, AND WHAT
WOULD YOU SEE IN A FOSSIL RECORD
YOU'D SAY SMEARS THAT LOOK A BIT
LIKE BACTERIA IN THE ROCKS AND
YOU'D NEVER KNOW WHAT THEY WERE.
BUT ALL THAT REALLY MEANS IS
THEY DIDN'T SURVIVE.
I THINK IN THE CASE OF BACTERIA
AND ARCHAEA, THERE'S ALMOST A
MORE DIFFICULT QUESTION ABOUT IF
THEY SHARED A COMMON ANCESTOR
AND EMERGED SEPARATELY FROM
EVENTS, WHY DID IT HAPPEN TWICE,
WHY DID THEY NOT DIVERGE AT ALL?
AND I THINK I HAVE SOME THOUGHTS
ON THAT, BUT THEY'RE NOT
TERRIBLY WELL THOUGHT THROUGH
BUT IT'S REALLY TO DO WITH THE
ORIGIN OF PUP PING. OF PUMPING.
AS SOON AS YOU CAN PUMP, YOU
HAVE A TREMENDOUS ADVANTAGE OVER
CELLS THAT DON'T PUMP.
THAT'S THE LAST STEP IF YOU LIKE
OF BECOMING A FREE, INDIVIDUAL
CELL, IS YOU CAN NOW LEAVE A
VENT AND YOU CAN LIVE SOMEWHERE
ELSE.
SO AS SOON AS CELLS HAD LEFT,
THEN I THINK DARWIN WAS RIGHT.
BASICALLY HE SAID ONCE LIFE
APPEARED, IT'S GOING TO EAT
EVERYTHING ELSE.
IT'S GOING TO BE REALLY
DIFFICULT FOR KIND OF A
PREBIOTIC SYSTEM IN A
HYDROTHERMAL VENT TO GET A FOOT
IN WHEN THERE'S ALREADY CELLS
OUT THERE, THEY'RE SO MUCH
BETTER AT WHAT THEY DO.
JENNIFER, DO YOU HAVE THOUGHTS
ON THAT?
>> DIDN'T DARWIN SAY THAT HE
THOUGHT THAT LIFE EVOLVED IN A
NICE CALM LITTLE POND, A WORM
POND?
WORM
POND?
>> YES, HE DID.
I THINK HE WAS MI STAY MISTAKEN ON THAT
ONE PERSONALLY, WITH YOU MOST OF
THE CHEMISTS FOND OF PROTEIN
CHEMISTRY ARE FOND OF DARWIN,
THE GREAT GOD GOD DARWIN, THEY
QUIETLY FORGET ABOUT SOME OF THE
GENETICS, DARWIN WAS A GENIUS
BUT HE WASN'T RIGHT ABOUT
EVERYTHING.
>> I WAS JUST GOING TO ASK NICK
A QUESTION, THOUGH IT MAY TAKE
US INTO A DIFFERENT WORLD, BUT
ONE OF THE THINGS THAT WAS
EXCITING ABOUT YOUR REACTOR THAT
YOU GENERATED IS THAT IT ABLE TO
REMOVE CO2.
BASICALLY IT'S PUMPING CO2 OUT
OF A SYSTEM.
HAVE YOU THOUGHT ABOUT USING
THAT AT ALL FOR SORT OF SCALING
UP FOR GLOBAL WARMING PURPOSES?
>> ABSOLUTELY.
I MEAN, FIRST OF ALL WE HAVE TO
MAKE IT WORK.
RIGHT NOW IT WORKS A LITTLE BIT
BUT NOT VERY WELL.
BUT IT BASICALLY -- I THINK ONE
OF THE REASONS WHY THESE IDEAS
ON CO2 AND HYDROGEN ARE COMING
MORE INTO VOGUE THAN THEY WERE
10 YEARS AGO, 20 YEARS AGO, WHEN
ALL THE CHEMISTRY WAS CYANIDE
CHEMISTRY, NOW THERE'S MORE
INTEREST IN CAN WE MAKE CO2
REACT WITH HYDROGEN, AND IT'S
REALLY ABOUT GLOBAL WARMING AND
ENERGY SECURITY.
BECAUSE IF WE CAN STRIP CO2 FROM
THE ATMOSPHERE, SPLIT WATER,
TAKE THE HYDROGEN, MAKE
HYDROCARBONS AND EFFECTIVELY
HAVE A CARBON NEUTRAL ECONOMY
WHERE WE DOCHT DON'T HAVE TO CHANGE SO
MUCH, THAT'S AN IDEAL SOLUTION,
AND THAT'S WHAT THEY DO, THAT'S
HOW THEY GROW.
THERE HAS TO BE A SIMPLE WAY OF
DOING IT.
>> -- ATMOSPHERE TOO, YEAH.
AMAZING.
>> NICK, YOU TOUCHED ON SEVERAL
QUESTIONS.
WOULD YOU ELABORATE AS TO HOW AN
EARLY MEMBRANE DEVELOPED PUMPING
ACTIVITY TO MAINTAIN INTERNAL
AND EXTERNAL MILIEUS?
>> IN A HYDROTHERMAL SYSTEM,
WE'VE GOT CONTINUOUS FLOW, SO I
SUPPOSE THE KEY THING ABOUT
THESE IDEAS IS THAT PUMPING IS A
LATE STEP.
AND WHAT THAT MEANS IS WITHOUT
PUMPS, PROTONS HAVE TO COME --
IF YOU'VE GOT A MODERN MEMBRANE
WHICH IS EFFECTIVELY CLOSE TO
BEING PROTON-TIGHT, A COUPLE
MEMBRANE WE WOULD SEE THAT
MEMBRANE HAVE, BACTERIA OR
ARCHAEA HAVE, THAT'S THE LAST
THING, YOU HAVE A TURBINE, ECH
OR ANY PIECE OF MOLECULAR
MACHINERY, PROTON COMES IN AND
THERE'S NO PUMP TO GET IT OUT
AGAIN, THEN YOU JUST COLLAPSED
THE DRIVING FORCE.
SO WHAT YOU ACTUALLY NEED IS A
LEAKY MEMBRANE, LEAKY TO PROTONS
SPECIFICALLY, SO THEY CAN COME
IN AND THEN THEY'RE SWEPT AWAY
BY THE FLOW OF ALKALINE FLUIDS,
THEY REACT WITH THE HYDROXIDE
IONS.
SO IT CAN ONLY WORK IF THEY
DON'T HAVE A MODERN PHOSPHOLIPID
MEMBRANE THAT LOOKS LIKE -- THEY
HAVE TO BE MORE OR LESS LEAKY TO
THE OUTSIDE WORLD FOR THESE
IDEAS TO WORK AT ALL.
SO THAT WOULD BE MY EXPLANATION
FOR WHY BACTERIA AND ARCHAEA
HAVE QUITE DIFFERENT MEMBRANES.
THEY AROSE AT THE SAME TIME AS
PUMPING, SO HOW DID PUMPING
BEGIN?
I THINK WE ARE DEALING THEN IN
THE WORLD OF GENES.
WE'RE DEALING WITH PROTEINS
WHICH ARE ENCODED BY GENES WHICH
ARE CAPABLE OF -- WE'RE DEALING
WITH MOLECULAR MACHINES.
SO I PERSONALLY DOUBT THAT THERE
WERE SOPHISTICATED PUMPS BEFORE
GENES. THERE ARE WAYS OF DOING
IT.
QUINONES, FOR EXAMPLE, CAN PICK
UP PROTONS AND CARRY THEM ACROSS
THE MEMBRANE.
AND IT WOULD DEPEND WHERE THEY
GO, THEY CAN SHUTTLE BACKWARDS
AND FORWARDS DEPENDING ON THE
REDOX DIFFERENCE AND THE PH
DIFFERENCE.
SO IT'S POSSIBLE TO HAVE PUMPING
IN THE ABSENCE OF COMPLEX
PROTEINS, BUT IF YOU'VE GOT A
SYSTEM WHERE EFFECTIVELY YOU
DON'T NEED IT BECAUSE THE VENT
IS DOING ALL THE WORK, THE VENT
IS KEEPING THE GRADIENTS THERE,
THEN I KIND OF DON'T NEED PUMPS
UNTIL THE END WHERE CELLS
EFFECTIVELY NEED TO LEAVE OR ARE
CUT OFF FROM -- THERE WILL BE A
SELECTIVE ADVANTAGE IF YOU ARE
IN THE CORNER OF A VENT WHERE
THERE'S NOT THAT MUCH FLOW AND
YOU FIGURED OUT A LITTLE BIT HOW
TO PUMP YOUR OWN PROTONS OUT,
YOU WILL THRIVE IN THAT REGION
WHEREAS OTHER CELLS WOULDN'T.
SO IT'S EASY TO IMAGINE
SELECTIVE ADVANTAGES, IT'S
REALLY DIFFICULT TO PROVE ANY OF
THIS STUFF.
WE'RE KIND OF STUCK WITH THE
CENTRAL QUESTIONS THAT WE CAN
ACTUALLY TEST.
>> SO COULD YOU HAVE AN
EXCHANGER WITHOUT HAVING A
PROTEIN?
IS THAT WHAT YOU'RE SAYING?
>> YES, YOU CAN HAVE AN
EXCHANGER WITHOUT HAVING A
PROTEIN SO LONG AS IT'S A SEMI
OPEN SYSTEM.
STUFF HAS TO COME IN AND LEAVE
AGAIN.
IN OTHER WORDS, I MEAN, FROM AN
ORIGIN OF LIFE POINT OF VIEW, IT
ACTUALLY VERY GOOD.
THE LAST THING YOU REALLY WANT
TO HAVE IS TO SAY RIGHT, I NEED
A REALLY SOPHISTICATED
MEMBRANE -- WHAT I'M ACTUALLY
SAYING IS WE NEED A CRAFTY
MEMBRANE, WE DON'T NEED ANY
MOLECULAR MACHINES, WE JUST NEED
CONTINUOUS FLOW AND A
HYDROTHERMAL VENT AND THAT'S
POWERED IN THE END BY GRAVITY.
SO WE NEED BAD SYSTEMS OR WE
NEED TO SEE WAYS OF HOW THEY
WILL GET BETTER, WHY THEY WILL
GET BETTER AND THOSE STEPS, ALL
OF THIS -- AS SOON AS WE'VE GOT
GENES, WHEN I FINISH MY TALK,
WITH THE BEGINNINGS OF RANDOM
RNAs BUT NON-RANDOM TEMPLATING
OF PEPTIDES, THEN WE HAVE
NATURAL SELECTION AS WE KNOW IT,
AND SO LONG AS YOU HAVE THE
POWER TO KEEP GENERATING THESE
THINGS, SO LONG AS YOU CAN BEGIN
TO COPY THEM, THEN EVERYTHING
CHANGES.
THAT'S WHEN LIFE BECOMES LIVING,
TO MY MIND.
BEFORE THAT IS PREBITE IK
CHEMISTRY.
>> IT BECOMES AN RNA WORLD FROM
THE BEGINNING AT THAT POINT.
>> BUT IT'S AN RNA WORLD INSIDE
GROWING PROTO CELLS CAPABLE OF
DOING ALL THE METABOLIC
CHEMISTRY THAT OTHER CELLS CAN
DO.
THAT
>> -- HYDROTHERMAL VENT.
WHY ARE THEY ALKALINE AND NOT
NEUTRAL OR ACYTIC?
>> WELL, IT'S BASICALLY A
REACTION BETWEEN THE ROCK AND
THE WATER BETWEEN OLIVENE WHICH
IS RICH IN THER ACYAIN, SOME OF
THOSE HOE DROX I'D IONS ARE SIM
SPLI BEING RELEASED INTO
SOLUTION.
SO AND THAT'S WHERE THE HYDROGEN
IS COMING FROM, THE ELECTRONS
ARE COMING FROM THE ION AS IT'S
BEING OXIDIZED AND THE WATER IS
BEING SPLIT INTO HYDROXIDE IONS
AND HYDROGEN IN EFFECT.
SO THAT'S WHY IT'S ALKALINE.
AND IT HAPPENS ON ANY WET ROCKY
PLANET, THEY'RE ALWAYS ALKALINE.
IT'S THE ONLY SYSTEM THAT WE
KNOW OF, REALLY, THAT GENERATES
ALKALINE FLUIDS.
>> SO DO YOU THINK THERE ARE
SIMILAR VENTS ON OTHER BODIES IN
THE HEAVENS?
>> I THINK ALL OF THEM PROBABLY.
I WOULD SAY ANY WET ROCKY PLANET
WILL HAVE THESE VENT SYSTEMS ON,
AND THAT'S ONE OF THE PLEASURES
OF THESE IDEAS, IS THAT IT MAKES
LIFE COMPLETELY UBIQUITOUS.
EXCEPT THEN AS JENNIFER WAS
SAYING, WE HAVE THIS 2 BILLION
YEAR GAP BEFORE WE SEE COMPLEX
LIFE, SO IF WE FIND LIFE
SOMEWHERE ELSE IN THE UNIVERSE,
THE CHANCES ARE, IT'S GOING TO
BE BACTERIA, AND MOST PEOPLE
WON'T BE VERY EXCITED ABOUT IT,
YOU NEED THE KIND OF PROCESSES
THAT JENNIFER WAS TALKING ABOUT
TO GO FROM BACTERIA OR ARCHAEA
TO COMPLEXITY.
CAN I ASK YOU A QUESTION,
JENNIFER, BECAUSE I'M CURIOUS TO
KNOW HOW WHAT'S THE ENERGY COSTS
OF HAVING THESE PHASED
TRANSITIONS IN MEMBRANES AND
BEING ABLE TO -- ALL THIS
DYNAMISM YOU'RE TALKING ABOUT,
IS IT TREMENDOUSLY COSTLY?
>> THE PHASED TRANSITIONS
REQUIRE NO ENERGY.
YOU DON'T HAVE AN ENERGY INPUT
FROM AN EXOGENOUS SOURCE.
>> YOU NEED TO MAKE THE
MEMBRANES THEMSELVES --
>> THE MEMBRANES THEMSELVES WILL
SPONTANEOUSLY MOVE -- PREFER
BEING IN, YOU KNOW, A -- COME
TOGETHER IF THERE'S CHOLESTEROL
AND SPHINGOLIPIDS, FOR INSTANCE.
AND THE IDEA IS THE INTRODUCTION
OF THE PROTEINS INTO THESE
BILAYERS WILL -- PROTEINS WILL
PREFER BEING IN THE THICKER
BILAYER FROM THE SINGLE LIPIDS
AND THE CHOLESTEROL OR THE
STIFFER VERSUS MORE FLUID LIPID
ENVIRONMENT, AND THAT'S HOW YOU
BEGIN TO SORT PROTEINS IN A
BILAYER.
ONCE YOU START SORTING PROTEINS
IN A BILAYER, YOU CAN START
DOING VERY INTERESTING SORT OF
FURTHER RECRUITMENTS OF THINGS
IN THE CYTOPLASM TO BUILD
CYTOSKELETON, TO CREATE A
VESICLE THAT CAN MOVE FROM ONE
PLACE TO ANOTHER.
I SEE IT AS -- ONCE YOU REALIZE
THAT THE COMPLEXITY OF THESE
LIPIDS IS NOT PRESENT IN THESE
ARCHAEA AND BACTERIA, YOU START
TO UNDERSTAND WHY THEY CAN'T DO
INTERCELLULAR --
>> IF THEY WERE PRESENT IN
BACTERIA AND ARCHAEA, DO YOU
THINK THAT THAT WOULD ALLOW
BACTERIA AND ARCHAEA TO BECOME
LARGER OR ARE THEY STILL
EFFECTIVELY STYMIED BY THE ISSUE
WITH MITOCHONDRIA AND THE
ENERGETICS OF IT, AND SO BECAUSE
EUKARYOTES CAN BECOME LARGER,
THEY NOW NEED MORE MEMBRANES IN
EFFECT, AND THEN CAN DO MORE
SOPHISTICATED THINGS WITH THEM?
SO I'M WOULD WONDERING IF YOU'RE
SEEING THE CHEMISTRY OF THE
SINGLE LIPIDS BEYOND BACTERIA OR
THEY HAD NO NEED FOR IT BECAUSE
THEY NEVER COULD EXPAND --
>> I THINK THEY HAD NO NEED FOR
IT, BECAUSE I LIKE THE ARGUMENT
THAT YOU MAKE IN TERMS OF THE
GENES THAT ARE CODING FOR THESE
ELECTRON TRANSPORT COMPONENTS
NEED TO BE -- THEY NEED TO BE --
THEY'VE GOT TO BE COUPLED TO THE
EXPRESSION OF THE PROTEINS.
THAT JUST DOESN'T -- I MEAN,
BECAUSE BACTERIA AND ARCHAEA
BOTH HAVE THOSE ELECTRON
TRANSPORT SYSTEM ON THEIR OUTER
MEMBRANES, THEY'RE BEHOLDEN TO A
SMALL SIZE.
BUT THE EUKARYOTE DOESN'T HAVE
THAT ON ITS PLASMA MEMBRANE.
IT GOT ENERGY PACKETS FOR DOING
ALL THAT.
WHICH IS JUST AN AMAZING, COOL
WAY TO DEAL WITH THE PROBLEM.
>> SO IN TERMS OF WHERE ALL
THESE MEMBRANE SYSTEMS CAME
FROM, ORIGINALLY, THERE'S SOME
LOVELY IDEAS ABOUT THE OUTER
MEMBRANE VESICLES, BUDDING FROM
BACTERIA AND ARCHAEA AS WELL IS
QUITE A COMMON PROCESS.
BUT IF YOU'RE DOING THAT INSIDE
A PROKARYOTIC CELL THEN YOU'RE
EFFECTIVELY PRODUCING AT LEAST
BAD MEMBRANE SYSTEMS, YOU'RE
PRODUCING VESICLES INSIDE CELLS
THAT ARE GOING TO FUSE WITH EACH
OTHER, ARE GOING TO DO THINGS.
IS PART OF THE PROBLEM HOW DO
YOU STOP IT BECOMING A HORRIBLE
MESS?
>> YEAH.
YOU'VE GOT TO SHIFT OVER, THE
ARCHAEA LIPID, BASE KRI BASICALLY YOU GOT
RID OF IT SO ALL THE
PHOSPHOLIPIDS ARE ESTER LINKED
SO THAT'S ONE SYSTEM.
AND THAT'S A HUGE ARGUMENT
AGAINST THE CLASSIC MODEL, YOU
KNOW, THE STEP WISE MODEL FOR
THE ORIGIN OF EU EUKARYOTES, IT'S
GOING TO HAVE THE ARCHAEA LIPIDS
THAT ARE MAKING ALL OF THOSE
INTERNAL MEMBRANES, AND --
>> YES.
>> NONE OF THE MODERN-DAY
EUKARYOTES HAVE THE ETHER LINKED
LIPIDS.
>> I THINK THERE ARE SOME ETHER
LINKED LIPIDS IN EU CARE YOTS,
AREN'T THERE, I THINK,
OCCASIONALLY, BUT THEY TEND TO
BE --
>> THEY'RE VERY RARE.
>> RIGHT.
THEY'RE PART OF A PATHWAY IN
CERTAIN TYPES OF BIG LIPIDS,
MYELIN, FOR INSTANCE.
BUT I WANTED TO ASK YOU ABOUT IF
YOU WERE GOING TO LOOK FOR A
SIGNATURE FOR LIFE ON ANOTHER
PLANET, NOW WE HAVE THE BIG WEB
TELESCOPE, WHAT IS THAT YOU
WOULD LOOK FOR?
I MEAN, I AGREE THE
EUKARYOTIC -- GETTING TO A
EUKARYOTIC STATE IS GOING TO
TAKE SOME TIME.
THERE'S A LOT OF ISSUES THAT ARE
INVOLVED, BUT IT SEEMS LIKE LIFE
COMES PRETTY QUICK IN TERMS OF
PROKARYOTIC METABOLIC --
>> SEEMS THAT WAY TO ME, YES.
I THINK I WOULD OFFER -- YOU CAN
GET SOME LEVEL OF -- FROM
MINERAL CATALYSIS OR VARIOUS
PROCESSES, BUT AS SOON AS YOU'VE
GOTTEN
GOT ENZYMES, EU MORE OR LESS OWE
OBLIGED -- WHEN WE TALK ABOUT
KIE RALLITY -- IT WAS ONE OR THE
OTHER.
BUT THE LIPIDS ARE REALLY
INTERESTING HERE, BECAUSE THE
PHOSPHATE HEAD GROUPS ARE THE
OPPOSITE AND OPPOSING CHIRALITY
IN THE ARCHAEA.
SO THE THREE LARGE GROUPS OF
MOLECULES THAT HAVE THIS
CHIRALITY, TWO OF THEM ARE
UNIVERSAL BETWEEN BACTERIA AND
ARCHAEA, ONE OF THEM IS
SHOWING -- WHICH TO MY MIND,
IT'S ABOUT ENZYMES, NOT ABOUT
SOME STRANGE PHYSICAL PROCESS,
IT'S JUST ABOUT ARE YOU
APPROACHING IT FROM ABOVE OR
BELOW AS AN ENZYME, AND THEN
YOU'LL GET THE OPPOSITE
CHIRALITY.
SO I THINK OF CHIRALITY AS A
PRODUCT OF BIOLOGY, AND THAT
MEANS THAT IF WE SEE IN ANY
PLANETARY ATMOSPHERE VERY STRONG
CHIRALITY, THEN THAT WOULD BE A
SIGN OF LIFE.
WOULD WE BE LOOKING FOR NIDH OR
ATP, I CAN'T IMAGINE THAT WE
WOULD BE.
AND IF YOU'RE LOOKING FOR THINGS
LIKE ACETATE OR PYRUVATE, THEN
THAT'S SOMETHING THAT A
HYDROTHERMAL SYSTEM CAN PRODUCE
ANYWAY, SO IT'S REALLY HARD TO
KNOW WHERE YOU DRAW THE LINE,
AND I THINK CHIRALITY IS WHERE I
WOULD DRAW IT.
>> DO YOU KNOW WHETHER ANYBODY
HAS DONE ANY CHIRALITY
MEASUREMENTS IN THESE METEORITES
THAT HAVE COME FROM MARS OR --
>> YOU KNOW, I DON'T.
I ASSUME THEY HAVE.
I'D BE AMAZED IF THEY HADN'T.
IT'S NOT SOMETHING THAT I FOLLOW
VERY CLOSELY.
I'M SURE IF THEY FOUND THEY
REALLY CHIRAL, I'M GUESSING NOT.
>> LET ME POSE A QUESTION THAT
EITHER OF YOU MAY ANSWER.
THIS IS FROM PATTI.
IT SAYS SOME BACTERIA THAT HAVE
AN OBLIGATORY COEXISTENCE WITH
THE EUKARYOTE ACIDIC HOST HAVE
SMALL GENOMES, MINIMA LIST
METABOLISMS, SCAVAGED FATTY
ACIDS FROM THE HOSTS AND HAVE
MEMBRANES THAT CONTAIN EUKARYOTE
ACYTIC LIPIDS, WOULD YOU EXPECT
THEM TO HAVE A MORE COMPLEX
CYTOSKELETAL STRUCTURE?
>> INTERESTING QUESTION.
JENNIFER, DO YOU WANT TO HAVE A
GO FIRST?
>> WELL, IF THEY HAVE A SMALL
GENOME, PROBABLY NOT.
I'D LIKE TO KNOW MORE ABOUT THAT
BACTERIA IN TERMS OF -- WHEN YOU
SAY IT HAS EUKARYOTIC LIPIDS,
DOES IT HAVE STEROLS?
I WOULD ARGUE THAT IF IT'S
NOT -- BASED ON THE PROPOSAL
THAT I MADE, WHICH THERE'S NO
EVIDENCE FOR, BUT IT JUST THE
WAY I LIKE TO THINK ABOUT IT, IF
THAT BACTERIA DOESN'T HAVE THESE
COMPLEX LIPIDS THAT CAN PHASE
PARTITION, YOU'RE TO THE GOING
TO GET ANY COMPLICATED
CYTOSKELETON THAT'S GOING TO
COUPLE TO THAT MEMBRANE AND
DRIVE --
>> THE QUESTION IS IF IT'S
STEALING ITS LIPIDS FROM THE
EUKARYOTIC HOST CELL, THEN
EFFECTIVELY IT'S GOT STOLEN
COMPLEX LIPIDS, WOULD IT THEN --
>> NO, THAT'S A GOOD POINT.
THAT'S A VERY GOOD POINT.
YEAH.
I THINK THE ENERGETIC
CONSTRAINTS WOULD BE THE PROBLEM
FOR IT THERE, IT EFFECTIVELY
WOULD HAVE THE POTENTIAL TO DO
THESE SOPHISTICATED THINGS WITH
THESE LIPIDS, BUT I'VE THOUGHT
FOR QUITE A LONG TIME ABOUT WHY
YOU COULDN'T JUST USE A
BACTERIAL PLASMID, FOR EXAMPLE.
INSTEAD OF -- SO I WOULD SEE
MITOCHONDRIAL DNA MORE OR LESS
LIKE PLASMID SITTING INSIDE THE
MITOCHONDRIA.
TAKE OUT THE MITOCHONDRIAL DNA
AND STICK IT NEXT TO THE PLASMA
MEMBRANE AND THEN SCALE UP A
BACTERIAL CELL TO A EUKARYOTIC
SIZE AND LET'S PUT TENS OF
THOUSANDS OF COPIES OF THIS
GENOME RIGHT NEXT TO THE
MEMBRANE, WHY IS IT NOT GOING TO
WORK?
BECAUSE WE NEVER SEE THAT,
REALLY.
>> RIGHT, RIGHT.
>> I THINK ONE OF THE REASONS IT
DOESN'T WORK IS THAT THIS KIND
OF -- THERE'S VERY LITTLE
ADVANTAGE FOR BACTERIUM SIMPLY
BEING BIGGER FOR ITS OWN SAKE.
IT JUST TAKES LONGER TO
REPLICATE ITSELF THEN.
SO IF YOU THINK, WELL, OKAY, IF
YOU MAKE YOURSELF TWEIST AS BIG
AND YOU'RE A STREAMLINE SHAPE
AND SO ON, THEN YOU CAN MAKE
TWICE AS MUCH ATP, SO YOU HAVE
AN ADVANTAGE, YOU'VE GOT MORE
ATP, BUT YOU'VE TAKEN TWICE AS
LONG TO REPLICATE YOURSELF AND
SO YOU'RE GOING TO LOSE OUT TO
SMALLER BACTERIA, SO THE
SELECTION PRESSURE ON BACTERIA
IS PRETTY MUCH ALWAYS GOING TO
BE -- TO REMAIN SMALL.
BUT THE OTHER REASON I DON'T
THINK IT'S GOING TO WORK IS THAT
IF YOU'VE GOT HUNDREDS OF COPIES
OF A GENOME AND THEY'RE ALL
KRNTING TO A COMBINED PHENOTYPE,
WHICH IS LET'S SAY THE MEMBRANE
POTENTIAL ON THE PLASMA
MEMBRANE, EVEN IF IT'S
INVAGINATED, THEN SELECTION
CAN'T SEE MUTATIONS IN ANY ONE
OF THOSE GENOMES PAUSE THREAR
ALL BECAUSE THEY'RE
ALL CONTRIBUTING TO A COMMON
PHENOTYPE.
YOU DON'T CHANGE THE MEMBRANE
POTENTIAL MUCH SO YOU'RE GOING
TO ACCUMULATE MUTATIONS UNTIL
YOU HAVE A MU MUTATIONAL MELT DOWN.
IF YOU HAVE A SICKLE MY TOE CON
MITOCHONDRIA, WHY DO WE HAVE
INFUSION INTO WHOLE NETWORKS
WHICH YOU SHOW SEW AMAZINGLY AND
BEAUTIFULLY BUT YOU HAVE KIND OF
A LAMINATED NETWORK OF ALL THESE
MITOCHONDRIA, BUT IF YOU BLOCK
THEM -- EVERYTHING DEGENERATES
AFTER SOME TIME.
SO WHY IS MITOCHONDRIAL FISSION
SO IMPORTANT.
WHAT YOU HAVE THEN IS A GENOTYPE
PHENOTYPE RELATIONSHIP.
WE HAVE A -- IF YOU'VE GOT
MUTATIONS IN THAT GENOME, THEN
IT'S NOT GOING TO BE ABLE TO
MAINTAIN A GOOD MEMBRANE
POTENTIAL AND IT CAN BE TARGETED
BY AUTOPHAGY AND BROKEN DOWN AND
SO BY FISSIONING, YOU
RE-ESTABLISH A CAUSAL
RELATIONSHIP BETWEEN THE
PHENOTYPE AND GENOTYPE, YOU CAN
VECT THINGS
SELECT THINGS AND DISPOSE OF THE
JUNK.
WHEREAS IF YOU HAVE A KIND OF
COMMON PHENOTYPE, THEN YOU CAN
NEVER DO THAT.
SO I THINK THERE'S SEVERAL
REASONS WHY BACTERIA DON'T WANT
TO GET THAT BIG.
>> THERE'S A LOT OF REASONS WHY
YOU WANT TO USE SMALL UNITS FOR
THAT TYPE OF MITOCHONDRIAL
EVOLUTION.
I MEAN, THE MITOCHONDRIAL -- I
MEAN, WE USE MITOCHONDRIAL DNA
TO TRACK HUMAN EVOLUTION.
HUMAN MIGRATION.
AND IT BECAUSE OF THIS RAPID
ABILITY TO MUTATE, AND ON A MUCH
RAPID SCALE THAN WE SEE IN THE
NUCLEUS.
>> AND THE SELECTION AS WELL IN
THE GERMLINE, IN THE FEMALE
GERMLINE, YOU HAVE THIS
COMBINATION OF FAST RATES OF
MUTATION COMBINED WITH SELECTION
FOR THE ONES THAT WORK, SO
YOU'RE NOT PRODUCING MANY
CHILDREN WITH MITOCHONDRIAL
DISEASES.
IT HAPPENS, BUT GIVEN THAT IT'S
MUTATING AT 10 TIMES FASTER THAN
THE RATE OF THE -- GENES,
MITOCHONDRIAL DISEASES ARE
AMAZINGLY RARE.
>> SO JENNIFER, WE HAVE AN
INTERESTING QUESTION ABOUT
PLASMALOGENS, WHICH IN
EUKARYOTIC CELLS HAVE BOTH AN
ESTER AND ETHER LINKAGE.
SO JOSHUA WOULD LIKE TO KNOW, DO
YOU HAVE ANY IDEAS AS TO THE
EMERGENCE OR THE IMPORTANCE OF
PLASMALOGENS IN EUKARYOTIC
CELLS?
>>
>> I KNOW PROXOSOMES ARE DEALING
WITH THEM, AND SOME OF THESE
PLASMOLOGENS ARE INVOLVED IN
MYELINATION OF NERVES.
IT MIGHT -- I MEAN, THESE F
ETHER LIPIDS COULD BE VERY --
YOU KNOW, MAKE THE MEMBRANE MORE
RESISTANT TO BEING PERMEABLE.
I DON'T KNOW.
BUT IT'S VERY, VERY INTERESTING.
YEAH.
>> WHAT DO YOU THINK, NICK?
>> I DON'T HAVE AN OPINION ON
THAT.
I THINK I'M OUT OF MY --
>> [INAUDIBLE]
>> IT'S CONNECTED TO WHAT?
SORRY?
>> MYELINATION, NERVE
MYELINATION.
>> RIGHT.
OKAY.
>> SO WE HAVE A FUNDAMENTAL
QUESTION FOR BOTH OF YOU.
COULD EACH OF YOU PLEASE DEFINE
LIFE?
>> WELL, I STARTED OUT BY
REFUSING TO DEFINE LIFE, AND I
ACTUALLY THINK IT'S THE WRONG
QUESTION.
BECAUSE LIFE IS A PROCESS.
IT'S SOMETHING HAPPENING OVER
TIME.
AND SO IS A VIRUS ALIVE?
MOST BIOLOGISTS WOULD ARGUE
ABOUT WHETHER A VIRUS IS ALIVE
OR NOT BECAUSE IT DOESN'T HAVE
ITS OWN METABOLISM.
I BASICALLY SEE A VIRUS AS BEING
ALIVE BECAUSE THEY'RE NASTY
BASTARDS AND THEY TAKE OVER THE
METABOLISM OF THE CELLS THAT
THEY LIVE IN IN VERY
SOPHISTICATED WAYS.
THEY EVOLVE, THEY CHANGE, THEY
MUTATE, THEY DO EVERYTHING TO DO
WITH LIFE APART FROM METABOLISM,
AND THEY DON'T NEED THAT.
BUT THEN WE ARE FAR MORE
PARASITIC ON OUR ENVIRONMENT
THAN PLANTS ARE.
WE NEED TO EAT OTHER THINGS.
SO IN SOME SENSE, LIKE A VIRUS,
WE ARE ALSO PARASITIC ON THE
ENVIRONMENT, AND THEN YOU THINK
WELL, PLANTS ARE AS WELL IN THE
SENSE THAT THEY STILL REQUIRE
CO2 TO FIX IN WATER, THEY'RE NOT
GOING TO GROW IN A DESERT OR IN
THE DARK, SO THEY REQUIRE THINGS
FROM THE ENVIRONMENT TO ENABLE
THEM TO GROW.
AND BY THAT DEFINITION, IT'S NOT
A DEFINITION, BY THAT WAY OF
SEEING IT, THE VIRUS JUST
REQUIRES MORE THINGS FROM ITS
ENVIRONMENT TO BE ABLE TO GROW.
SO YOU COULD THEN THINK OF LIFE
AS BEING PARASITIC UPON AN
ENVIRONMENT, AND BY THAT, THEN
WHAT ABOUT RETRO ELEMENTS?
ARE THEY ALIVE?
BY THAT, THEY TAKE EVEN MORE
FROM THEIR ENVIRONMENT THAN A
VIRUS DOES.
AND IT'S IMPOSSIBLE TO KNOW
WHERE TO DRAW THE LINE.
THERE ISN'T A LINE.
THERE'S JUST SIMPLY DIFFERENT
FORMS OF PARASITISM ON AN
ENVIRONMENT, AND IT'S AMAZING IF
YOU SEE THE WORLD THAT WAY, JUST
HOW BEAUTIFUL IT ALL TURNS OUT
TO BE.
>> WHAT DO THE -- I'M STRUGGLING
FOR THE WORD.
I COME UP WITH OFFICIALS BUT --
WHAT IS THIS SORT OF
ORGANIZATIONAL DEFINITION OF
LIFE THESE DAYS?
>> I IGNORE IT DELIBERATELY, SO
I DON'T KNOW.
>> OKAY.
WE HAVE AN INTERESTING QUESTION.
IF THE PROTON -- THE MODE OF
FORCE IS ONLY ABOUT 200 MILL
200 MILLIVOLTS, THAT ISN'T A
LOT.
>> WELL, IT IS A LOT IF YOU
THINK ABOUT THE FIELD STRENGTH,
BECAUSE WE'RE DEALING WITH A
MEMBRANE WHICH IS 5,
6-NANOMETERS THICK, AND SO THE
FIELD STRENGTH IS IN THE RANGE
OF 30 MILLION VOLTS PER METER.
WHICH IS EQUIVALENT TO A BOLT OF
LIGHTNING.
IT REALLY IS.
NOW THERE'S ANOTHER INTERESTING
THING, I'LL BE INTERESTED TO
KNOW WHAT YOU THINK ABOUT THIS,
JENNIFER, THERE'S A DIRTY SECRET
SECRET, WHICH IS THAT IT'S VERY,
VERY DIFFICULT TO MEASURE THE
MEMBRANE POTENTIAL.
IT'S USUALLY DONE WITH
FLUORESCENT DYES, SO THE
MITOCHONDRIAL MATRIX OR THE
INSIDE OF SOLID BACTERIA IS
RELATIVELY NEGATIVELY CHARGED,
SO THESE CAT IRONS WILL
ACCUMULATE IN THERE AND THEY
SHOULD CROSS THE MEMBRANE
BECAUSE THEARL -- IT ALL MAKES
SENSE BUT THEY INTERACT WITH
PROTEINS IN WAYS THAT ARE
DIFFICULT TO QUANTIFY, AND THE
STRUCTURE OF MITOCHONDRIA HAS
BECOME MUCH MORE INTERESTING
REALLY.
WE USED TO THINK, I USED TO
THINK OF THE CHRISTY STRUCTURES
BASICALLY OPEN AND CONTINUOUS
WITH THE INTERMEMBRANE SPACE,
BUT THEY'RE NOT.
THE ONE COMPLEX CLOSES THE
CHRISTY, THEY'RE VERY NARROW,
THEY'RE VERY CONFINED SPACES,
NOT MUCH WATER IN THERE, AND
THERE'S NOT CONTINUOUS WITH THE
INTERMEMBRANE SPACE.
SO THAT'S HOW THE LIPOPHILIC CAT
IONS CAN GET IN, THEY'RE NEVER
CROSSING SOMETHING WITH REALLY
STRONG POSITIVE CHARGE AS THEY
WOULD IF THEY CROSSED THE
CHRISTY.
BUT WHEN PEOPLE HAVE TRIED TO
TAKE MEASUREMENTS OF THE ACTUAL
MEMBRANE -- USING ELECTRODES,
THEY TEND TO MEASURE 10,
20 MILLIVOLTS VERY, VERY LOW.
NOW, THERE ARE STILL PEOPLE OUT
THERE INCLUDING SOME VERY GOOD
SIGN TIES THAT HAVE CHALLENGED
THE HYPOTHESIS ON THAT BASIS,
YOU MEASURE IT USING THE KIND OF
NEUROLOGICAL TOOLS THAT PEOPLE
USE FOR LOOKING AT NEURONS, AND
INSTEAD OF 200 MILL VOLTS, MILLIVOLTS, YO U
GET 10, 20 MILLIVOLTS.
WHAT WHAT THEY'RE MEASURING IS THE
DIFFERENCE BETWEEN THE CYTOSOL
AND THE MATRIX, NOND THE MATRIX
AND THE CHRISTY SPACE.
SO THEN THE QUESTION IS, AND
THIS IS MY QUESTION TO YOU,
JENNIFER, BECAUSE I DON'T KNOW
HOW YOU DO IT, HOW CAN WE
MEASURE -- IT'S HARD TO THINK OF
ANY OTHER WAY THAN USING DYES,
THAT'S GOING TO ACCUMULATE IN
THE CHRISTY SPACE AND TELL US
WHAT THE MEMBRANE POTENTIAL IS
BETWEEN THE CHRISTY AND THE
MATRIX.
NOW, THE OLD MEASUREMENTS THAT
PETER MITCHELL AND JENNIFER
MOYLE USED TO DO LOOKING AT
CHANGES IN PH, THEY ESTIMATED
THE MEMBRANE POTENTIAL TO BE IN
THE RANGE OF 230 MILLIVOLTS.
AND THAT CLIMBED DOWN AND
CLIMBED DOWN AND IT'S CALIBRATED
NOW USING THE CATIONS AND YOU
WON'T READ VERY OFTEN OF A
MEMBRANE POTENTIAL OF ABOUT
118 MILLIVOLTS.
BUT I DON'T KNOW WHAT IT'S BEING
CALIBRATED WITH.
PEOPLE TRY IN BACTERIA BY THE
ROTATION SPEED OF THE BACTERIAL
FLAGELLUM AND IT DOESN'T
CORRELATE VERY WELL AT ALL, SO I
DON'T THINK WE HAVE A VERY
RELIABLE WAY OF CALIBRATING WHAT
THE ACTUAL MEMBRANE POTENTIAL OF
THE CHRISTY IS, USING THE
LIPPHILIC CATIRONS BECAUSE WE
DON'T HAVE ANY WAY OF GETTING --
MAYBE WE CAN DO IT BY EM
TOMOGRAPHY AND DOING THE
MEASUREMENTS WITH THE MATRIX
VALUES AND THEN CALCULATE THE
VOLUME AND CALCULATE IT THAT
WAY.
THAT MIGHT TELL US.
BUT THIS IS A QUESTION FOR YOU
AS A CELL BIOLOGIST WHO KNOWS
ALL ABOUT WAYS OF MEASURING
THESE THINGS, BECAUSE I'M AT A
BIT OF A LOSS, BUT I THINK WE'RE
ON THE POINT OF SOMETHING REALLY
FUNDAMENTAL HERE.
>> THAT'S REALLY COOL.
I MEAN, SO WE DO FOCUS ION BEAM
SCANNING MICROSCOPY AND RECENTLY
HAVE BEEN PRODUCING THESE DYES,
THESE MEMBRANE POTENTIAL DYES
INTO MITOCHONDRIA, AND YOU CAN
THEN DO CORRELATIVE IMAGING, YOU
CAN CORRELATE -- BASICALLY HIGH
PRESSURE FREEZING OF THE CELL
THAT'S JUST HAD THE DYE ADDED,
SO ITS CELLS FOE 16.
FROZEN.
TURNS OUT THE DYE IS FLUORESCENT
AND YOU CAN REALLY LOOK AT IT
RELATIVE TO THE REST OF THE
MITOCHONDRIA.
SO IT COULD BE THAT THAT SYSTEM
COULD BE USED.
WE HAVEN'T BEEN THINKING ABOUT
IT FROM THE PERSPECTIVE OF
TRYING TO GET A MORE ACCURATE
MEASUREMENT OF THE MEMBRANE
POTENTIAL, BUT MAYBE WE SHOULD
TALK TO YOU MORE ABOUT IT.
I'LL SEND YOU AN IMAGE OF WHAT
THIS LOOKS LIKE.
WHAT'S INTERESTING IS WE SEE
VARIABILITY OF THAT MEMBRANE
POTENTIAL DYE ACROSS THAT
MITOCHONDRIA.
>> BETWEEN CHRISTY AS WELL, I
UNDERSTAND.
>> YEAH.
MM-HMM.
YEAH.
>> JENNIFER, EXCUSE ME, BUT I
WAS REMINDED THAT YOU DIDN'T
HAVE AN OPPORTUNITY TO PROVIDE
YOUR DEFINITION OF LIFE.
>> WELL, I MEAN, I THINK I WILL
AGREE WITH NICK.
I'VE BEEN IN MANY CONVERSATIONS,
DEBATES, ARGUMENTS ABOUT THE
DEFINITION OF LIFE, AND I THINK
IT'S -- BASICALLY IT'S A
PROCESS, IT'S AN ENERGY FLUX.
THAT'S THE TYPICAL DEFINITIONS,
WHEN PEOPLE TALK ABOUT
SELF-REPLICATING CONTAINING DNA,
A MEMBRANE.
>> IT'S KIND OF MORE OF A
DESCRIPTION THAN A DEFINITION,
THOUGH, ISN'T IT?
>> EXACTLY.
I THINK WHAT LIFE IS IS
BASICALLY BEING ABLE TO TAKE --
HARVEST ENERGY TO DRIVE
PROCESSES.
IN A WAY THAT'S WAY OUT OF
EQUILIBRIUM.
BUT I REALIZE THAT THAT ALLOWS
YOU TO EXTEND THE DEFINITION TO
SOMETHING BIGGER POTENTIALLY
THAN CELLS.
AND IS THE WHOLE EARTH A LIVING
THING.
YOU KNOW.
THIS WHOLE IDEA THAT EARTH IS --
IT'S A SYSTEM.
IT A LIVING SYSTEM, IT'S NOT --
>> IT HAS A STRUCTURE VERY
SIMILAR TO A CELL IN THE SENSORY
DUED, RELATIVELY ALKALINE --
ASIC DICK
ACYTIC AND OXIDIZED ON THE
OUTSIDE.
CELLS MIMIC THE STRUCTURE OF THE
EARTH.
THERE IS A DEFINITION OF LIFE, A
WORKING DEFINITION OF LIFE THAT
MASSA HAVE.
I PROBABLY CAN'T GET THIS QUITE
RIGHT, BUT IT'S SOMETHING LIKE A
SELF SUSTAINED DAR DARWINIAN
EVOLUTION, SOMETHING ALONG THOSE
LINES.
I REBEL AGAINST SELF SUSTAINED
BECAUSE IT DENIGRATES THE
ENVIRONMENT TO THE POINT OF
NON-EXISTENCE.
I KNOW WHAT THEY MEAN, BUT IT
CERTAINLY DOESN'T EMPHASIZE AN
ENVIRONMENTAL DISEQUILIBRIUM
DRIVING EVERYTHING.
PEOPLE CAN POKE FUN, BY THAT
DEFINITION ONLY A PAIR OF
RABBITS IS ALIVE, A SINGLE
RABBIT -- COPY ITSELF.
SO ALL OF THESE DEFINITIONS HAVE
HOLES IN THEM, ALMOST RISIBLE
HOLE, AND YOU'RE LEFT WITH THIS
FEELING, ARE WE ACTUALLY
LEARNING ANYTHING FROM MAKING
FUN AT OTHER PEOPLE'S
DEFINITIONS?
I THINK THERE'S A PROBLEM WITH
DEFINITIONS ALL TOGETHER WHEN IT
COMES TO LIFE JUST BECAUSE IT'S
A CONTINUUM.
>> WELL, ON THAT SOBER NOTE, I
HAVE TO NOTE THAT WE HAVE
REACHED THE LIMIT OF OUR TIME.
>> OH, MY GOSH.
THAT WAS FAST.
>> HOWEVER, ON BEHALF OF THE
MANY, MANY, MANY PEOPLE WHO
WATCHED AND PARTICIPATE IN THIS,
I JUST WANT TO BE THE SPOKESMAN
TO THANK YOU BOTH FOR INFORMING,
EXCITING AND CERTAINLY
STIMULATING THE HELL OUT OF OUR
THINKING, AND IT MAKES ME REAL
REALIZE THAT THERE ARE PROBABLY
AT LEAST FIVE OTHER SUBJECTS
RELATED TO THE COMBINED
INTERESTS OF YOU TWO THAT MAYBE
WE CAN APPROACH ON ANOTHER
OCCASION.
SO THANK YOU VERY, VERY MUCH FOR
TAKING PART OF THIS, AND WE
GRATEFULLY APPRECIATE IT.
I'M SOOR OH, BUT ALL GOOD THINGS
HAVE TO SORRY, BUT ALL GOOD THINGS
MUST COME TO AN END.
>> THANK YOU VERY MUCH.