Multinucleate

Transcription

[music playing] - I'M REALLY HAPPY AGAIN HERE TO WELCOME ALL OF YOU TO THIS INSTALLMENT OF THE 75TH ANNIVERSARY CELEBRATION OF NASA AMES RESEARCH CENTER AND THE DIRECTOR'S COLLOQUIUM SUMMER SERIES. THE--NOW, THIS IS PARTICULARLY, AS A LOT OF YOU KNOW, IS FOCUSED ON, YOU KNOW, OUR STUDENTS THAT ARE HERE DURING THE SUMMER, BUT IT'S ALSO FOCUSED ON THE REST OF US WHO, YOU KNOW, LIKE ME, I'M A BUREAUCRAT. I DON'T REALLY GET A CHANCE TO HEAR COOL STUFF. SO I'M LOOKING FORWARD TO THIS. TODAY, WE HAVE DR. JOSH ALWOOD. HE'S A RESEARCH SCIENTIST IN THE SPACE BIOSCIENCES DIVISION HERE AT NASA AMES RESEARCH CENTER. AND AS I'LL TELL YOU IN A MOMENT, YOU KNOW, I'M KIND OF ENVIOUS, BECAUSE HE HAS A BACKGROUND KIND OF SIMILAR TO MINE. HE STUDIED PHYSICS AND ASTRONOMY AND, YOU KNOW, THEN WENT AND DID SOME ENGINEERING STUFF AND--AND HE SORT OF TRANSITIONED TO, YOU KNOW, BIOLOGY, WHICH I THINK IS REALLY IMPORTANT. WHEREAS I'M TOO OLD TO UNDERSTAND ALL THE BIOLOGY STUFF. SOMEBODY TRIED TO TELL ME ABOUT CELLS, AND SAID, YOU KNOW--YOU KNOW, THE ONLY CELLS I KNOW IS WHEN I WENT AND VISITED SAN QUENTIN. [laughter] BUT, YOU KNOW, JUST TO KIND OF REVIEW A LITTLE BIT, THE MISSION OF THE BIOSCIENCES RESEARCH BRANCH IS TO ADVANCE SPACE EXPLORATION BY NEW SCIENTIFIC DISCOVERIES IN--IN TECHNOLOGICAL DEVELOPMENTS IN BIOLOGY. AND THIS--THIS PARTICULAR RESEARCH IS GOING TO REVEAL REALLY IMPORTANT CLUES ABOUT WHAT CAUSES OSTEOPOROSIS AND OTHER BONE DISORDERS. WHEN YOU GET MY AGE, IT'S REALLY INTERESTING TO HEAR ABOUT THOSE. AND HIS PRIMARY FOCUS IS UNDER-- EXAMINING HOW SPACEFLIGHT AND MECHANICAL LOADING TRIGGERS COMPLEX CHANGES IN ORGANISMS, PARTICULARLY THE MAMMALIAN SKELETON. HE RECEIVED HIS PhD FROM STANFORD UNIVERSITY-- IT'S A JUNIOR COLLEGE UP THE ROAD HERE, FOR THOSE THAT DON'T KNOW-- [laughter] IN AERONAUTICS AND ASTRONAUTICS. AND HIS BACHELOR OF SCIENCE DEGREE FROM THE UNIVERSITY OF FLORIDA IN PHYSICS AND ASTRONOMY. YOU KNOW, ANOTHER, YOU KNOW, SEMI-WELL-KNOWN PLACE. HE COULDN'T GET INTO MICHIGAN. [laughter] BUT I--ALL-- ALL KIDDING ASIDE. JOSH IS ONE OF OUR MOST DISTINGUISHED RESEARCHERS. HE RECENTLY COMPLETED HIS NASA POSTDOCTORAL PROGRAM HERE AT AMES. BUT ON APRIL OF THIS YEAR, AND I AM REALLY PROUD OF JOSH AND I THINK THAT THE WHOLE CENTER SHOULD BE, HE WAS HONORED AT THE WHITE HOUSE-- SOME OF YOU MIGHT HAVE HEARD OF THAT-- BY PRESIDENT OBAMA--SOME OF YOU MIGHT HAVE HEARD OF HIM-- AND HE WAS NAMED ONE-- HE WAS ONE OF THE FIVE NASA RESEARCHERS THAT WAS A RECIPIENT OF THE 2012 PRESIDENTIAL EARLY CAREER AWARD FOR SCIENTISTS AND ENGINEERS. SO JOSH IS GONNA TALK TODAY ABOUT "TO THE BONE: SPACEFLIGHT AND THE SKELETAL SYSTEM." I ALSO NOTE, YOU KNOW-- YOU KNOW, SINCE I WORE KIND OF AN INTERESTING OUTFIT, THAT JOSH HAS TODAY, TOO, 'CAUSE YOU USUALLY DON'T SEE HIM IN A SUIT. SO PLEASE JOIN ME IN WELCOMING DR. JOSH ALWOOD. [applause] - THANK YOU, PETE. WELL, THANK YOU FOR THE INTRODUCTION, PETE. AND THANK YOU FOR INVITING ME TO PARTICIPATE IN THIS COLLOQUIUM SERIES THIS SUMMER. AND AS YOU CAN TELL BY THE PROPS ON THE STAGE AND THE MUSIC, THE--THE PERSIAN RUG, WE'RE GONNA HAVE A LITTLE BIT OF FUN TODAY. AND I WAS CHALLENGED TO WEAR A COSTUME, AND I DIDN'T--I WOULDN'T HAVE COUNTED THIS AS A COSTUME, BUT I GUARANTEE ONE COSTUME DURING THE PRESENTATION TODAY. SO KEEP YOUR EYES OPEN. SO, AS PETE SAID, I'M A NEWLY HIRED SCIENTIST HERE AT NASA AMES IN SPACE BIOLOGY. IN TODAY'S TALK, I'D LIKE TO BROADLY COVER THE BODY OF KNOWLEDGE IN SKELETAL BIOLOGY AND BIOMECHANICS DURING SPACEFLIGHT. AND I AM TO CONVEY THE RISKS OF BONE LOSS DURING THE SPACE MISSIONS AND THAT RESEARCH-- FUNDAMENTAL RESEARCH IN THIS AREA IS AN IMPORTANT COMPONENT OF ANY SPACE PROGRAM FOR TWO REASONS-- THE FIRST BEING TO UNCOVER BASIC BIOLOGICAL MECHANISMS THAT IMPROVE OUR UNDERSTANDING OF THESE CONDITIONS, AS WELL AS TO TEST PROTECTIVE TREATMENTS, REFERRED TO IN THE TALK AS COUNTERMEASURES, THAT ENABLE HUMAN EXPLORATION OF SPACE. AND THIS IS A PROCESS OF TRANSLATING BASIC SCIENCE RESULTS INTO--INTO PRACTICE AND INTO SOLUTIONS. AND THIS IS NICELY ENCAPSULATED BY THE AMES LOGO, ACTUALLY-- DISCOVERY LEADING TO INNOVATIONS LEADING TO SOLUTIONS. AND YOU CAN SEE THE LITTLE CELL-- THE FLUORESCENT GREEN HERE ARE CELLS, AND SO THAT REALLY ILLUSTRATES THE PROCESS WE'LL BE TAKING WITH THIS TRANSLATIONAL PIPELINE. AND WHEN I WAS AT THE WHITE HOUSE, PRESIDENT OBAMA ACTUALLY IS VERY IN TUNE WITH TRANSLATIONAL RESEARCH. HE ACTUALLY EMPHASIZED THAT IT'S REALLY IMPORTANT FOR BASIC SCIENTISTS TO TRANSLATE THEIR WORK TO HELP HUMAN PROBLEMS. SO IF I HAD TO SUMMARIZE MY TALK IN ONE SLIDE, SPACEFLIGHT IS BAD FOR THE BONE THOROGOOD ALMOST GOT IT RIGHT. AND SO SPACEFLIGHT IS--PRESENTS UNIQUE BIOLOGICAL CHALLENGES TO THE SURVIVAL AND EQUILIBRIUM OF LIVING SYSTEMS. AND TWO NOTABLE ASPECTS OF THE ENVIRONMENT ARE WEIGHTLESSNESS ASSOCIATED WITH MICROGRAVITY AS WELL AS IONIZING RADIATION EXPOSURE FROM SOLAR PARTICLE EVENTS, WHICH ARE MAINLY PROTONS AND GALACTIC COSMIC RAYS, WHICH ARE VERY HIGH ENERGY AND VERY HARD TO SHIELD AND CAN-- AND DO GREAT DAMAGE IN BIOLOGICAL ORGANISMS. IT'S WIDELY KNOWN THAT WEIGHTLESSNESS INDUCES BONE LOSS, BUT LESS WELL-KNOWN ARE THE EFFECTS OF SPACE RADIATION. AND THIS WILL BECOME VERY IMPORTANT ONCE WE VENTURE OUTSIDE OF THE EARTH'S MAGNETIC FIELDS, WHICH ARE CURRENTLY PROTECTING US FROM SOME OF THESE HIGH-ENERGY COSMIC RAYS. AND SO THIS KIND OF ILLUSTRATES THAT TRANSLATIONAL PIPELINE. WHY DO WE STUDY BONE LOSS? WELL, THERE'S THE BASIC HYPOTHESIS-DRIVEN SCIENCE AND DISCOVERY OF NEW KNOWLEDGE BUT ALSO TRYING TO ENABLE LONGER DURATION MISSIONS THAT ARE FARTHER AWAY FROM OUR HOME HERE ON EARTH. AT THE SAME TIME, WE ALSO WANT TO HELP PEOPLE ON EARTH IN TERMS OF UNDERSTANDING OSTEOPOROSIS BETTER, UNDERSTANDING WHAT IS-- WHAT ARE THE MECHANISMS OF AGING, WHAT ARE THE NEGATIVE EFFECTS OF BED REST, SEDENTARY LIFESTYLES, RADIATION ON-- FROM OCCUPATIONAL EXPOSURE AND RADIO THERAPY, AND THINKING BIG, OPENING UP NEW POSSIBILITIES FOR HUMANITY'S ROLE IN SPACE. BEFORE I DELVE INTO SCIENCE, I'D LIKE TO SHARE WHERE MY INTEREST ORIGINATED FROM AND THE PATH I TOOK TO BECOME A SCIENTIST. AND AS YOU HEARD IN THE INTRODUCTION, MY BACKGROUND IS SOMEWHAT STAGGERED. BUT LOOKING BACK, I WAS PURSUING AN INTEREST THAT RESIDED IN THE NEXUS OF THREE SEEMINGLY SEPARATE AREAS, AND I'VE KIND OF GENERALIZED THESE ELEMENTS AS FORCE, LIFE, AND SPACE. AND SO I THINK IT STARTED WITH SCIENTIFIC CURIOSITY, ASKING QUESTIONS, SEEKING UNDERSTANDING, AND THEN WITH-- WITH MY RESEARCH, LEARNING HOW TO FORM A HYPOTHESIS AND--AND ANSWER THAT HYPOTHESIS. I GREW UP IN FLORIDA AND WAS REALLY ABLE TO SEE FIRSTHAND THE SPACE SHUTTLE LAUNCHES. AND SO THIS IS A PICTURE I TOOK IN HIGH SCHOOL, AND THIS REALLY CAPTIVATED MY IMAGINATION AND PROPELLED ME INTO STUDYING PHYSICS AND, LATER, STRUCTURAL ENGINEERING. AND SO IF ANY OF YOU RECOGNIZE THE LAST FORMULA THERE, YOU CAN GO AHEAD AND HEAD TO THE RECEPTION, 'CAUSE YOU'LL--YOU UNDERSTAND THE TALK ALREADY. AND SO I THINK I WAS-- FROM MY CHILDHOOD, WHEN I WAS ABOUT MAYBE HALF THE SIZE THAT I CURRENTLY AM, I WAS FASCINATED WITH BONE AS A LIVING STRUCTURE-- AND I'LL KIND OF EXPLAIN WHAT A LIVING STRUCTURE IS IN A COUPLE SLIDES-- BUT I REALLY IMMERSED INTO SKELETAL BIOLOGY RESEARCH AND--AND SO THE THING THAT TIES THIS ALL TOGETHER IS THE EFFECTS OF SPACEFLIGHT ON THE HUMAN BODY AND ON THE SKELETON. I'VE ALSO--I ALSO SOON IMMERSED IN-- FOLLOWING HIGH SCHOOL, IMMERSED IN SCIENTIFIC RESEARCH. AND WAS A PARTICIPANT IN A NUMBER OF PROGRAMS, EDUCATIONAL PROGRAMS. AND I WANT TO EMPHASIZE TO THE STUDENTS IN THE AUDIENCE, YOU ALREADY KNOW THIS, BUT GET INVOLVED, BROADEN YOUR INTERESTS, AND--AND REALLY DEVELOP YOUR--YOUR EXPERTISE AND INTERESTS. AND THOSE ON THE WEB, HERE ARE SOME PROGRAMS THAT NASA PROVIDES. SO MOVING NOW TO THE SCIENCE. I'LL START AT THE STRUCTURAL LEVEL. SO THINKING ABOUT BONES AS LIVING STRUCTURES, AND SO WHAT I HAVE HERE IS A RAT SKELETON AND A HUMAN SKELETON, JUST TO COMPARE AND CONTRAST THE DIFFERENT MORPHOLOGIES AND SIZES AND THAT RESEARCH WITH SOME OF THESE MODEL ORGANISMS CAN COMPLEMENT OUR KNOWLEDGE OF BONE LOSS IN ASTRONAUTS. AND THEN I'LL PROGRESSIVELY GO TO SMALLER AND SMALLER LINK SCALES SO THEN WORKING AT THE CELLULAR LEVEL AS WELL AS THE MOLECULAR LEVEL. SO IN ADDITION TO SKELETAL EFFECTS, GENERALLY SPACEFLIGHT IS BAD FOR THE ENTIRE BODY. AMONG A NUMBER OF RESPONSES IN THE BODY, THERE'S FLUID REDISTRIBUTION TO THE TORSO, THERE ARE VISUAL CHANGES, AMONG OTHERS. AND WE--YOU KNOW, THIS UNDERSCORES THAT WE'VE EVOLVED AT 1G. IT'S BEEN CONSTANT. AND WE INTIMATELY DEPEND ON GRAVITY FOR--FOR SKELETAL HOMEOSTASIS AND HOMEOSTASIS IN THE BODY. IT'S AN INTERESTING FACT THAT BREAKING DOWN THE BONE MAY INCREASE-- LEAD TO INCREASED RISK OF KIDNEY STONES AS THE CALCIUM IS EXCRETED IN THE URINE. AND THIS--THIS HAS BECOME A PROBLEM IN THE PLUMBING ON ISS. SO THIS IS--YOU KNOW, SPACEFLIGHT IS BAD AND THE LOSS OF SKELETAL MINERAL IS BAD FOR THE ISS HARDWARE AS WELL. THIS IS A URINE PROCESSING ASSEMBLY THAT RECYCLES URINE INTO DRINKING WATER. AND--AND THIS WAS ACTUALLY CLOGGED BY ELEVATED CALCIUM CONCENTRATIONS, IN PART DUE TO THE HEIGHTENED BONE LOSS IN ASTRONAUTS. GETTING BACK TO THE SKELETON AS A LIVING STRUCTURE. THIS IS--THIS IS ONE REASON WHY BONE REALLY FASCINATES ME. WHAT DOES A LIVING STRUCTURE MEAN? WELL, CONTRAST BONE TO A BRIDGE MADE OF CONCRETE AND STEEL. THEY BOTH CARRY THE EFFECTIVE LOAD, AND-- HOWEVER, THE SKELETON ACTIVELY SENSES AND ADAPTS TO THE DEMANDS OF ITS MECHANICAL ENVIRONMENT-- LIKE MUSCULAR FORCES, GROUND REACTION FORCES-- BY DISTRIBUTING MINERAL-- MINERALIZED TISSUE WHERE IT'S MOST NEEDED AND REMOVING IT WHERE IT'S NOT. AND SO OVER--THIS IS-- THIS LINE OF THINKING EXTENDS BACK OVER 100 YEARS WITH AN ORTHOPEDIST NAMED JULIUS WOLFF WHERE HE PROPOSED THESE IDEAS AFTER OBSERVING THE ORGANIZATION OF THE FEMORAL HEAD. AND SO THAT'S SHOWN IN CROSS SECTION HERE. SO THIS IS THE HIP JOINT KIND OF IN-- THIS IS THE PROXIMAL-- PROXIMAL FEMUR IN A LONGITUDINAL CROSS SECTION. NOW, WHAT YOU SEE WHEN YOU CRACK OPEN A FEMUR IS YOU SEE KIND OF THIS HOLLOW TUBULAR STRUCTURE IN THE MIDSHAFT, WHICH IS THE REALLY, REALLY DENSE CORTICAL BONE. AS YOU GET UP TO THE JOINT, THE HIP JOINT, YOU SEE THIS VERY-- HIGHLY STRIATED AND HIGHLY POROUS CANCELLOUS OR TRABECULAR BONE. AND WHAT WOLFF RECOGNIZED IS THAT LIKE A CANTILEVERED BEAM AND BENDING, THE FEMUR HAS COMPRESSIVE STRUTS. IT HAS TENSILE STRUTS, AND THAT THESE ARE UNIQUE LOAD PATHS THAT TRANSFER FORCE INTO THE CORTICAL BONE. IT'S IMPORTANT TO NOTE THAT LOCATIONS OF FRACTURE IN OSTEOPOROTIC PATIENTS, AS WELL AS POTENTIALLY IN ASTRONAUTS, OCCURS IN THESE HIGHLY POROUS CANCELLOUS REGIONS. SO IF YOU DISTURB THE--THE TISSUE THERE, IT'S VERY FRAGILE TISSUE AND THAT CAN LEAD TO A HEIGHTENED PROPENSITY FOR FRACTURE. ZOOMING IN NOW TO THE CELLULAR LEVEL, THERE ARE THREE CELL TYPES THAT I'LL TALK ABOUT TODAY. THE FIRST IS THE OSTEOBLAST THESE ARE BONE-FORMING CELLS THAT RESIDE AT THE SURFACE OF THE BONE. OCCASIONALLY, SOME OF THESE OSTEOBLAST CELLS BECOME TRAPPED IN THEIR OWN MATRIX IN MINERALIZED TISSUE AND BECOME EMBEDDED INTO CAVE-LIKE LACUNAE, AND THESE ARE DEEMED OSTEOCYTES. THERE'S A THIRD TYPE OF CELL CALLED OSTEOCLASTS, AND THESE ARE GIANT MULTINUCLEATED CELLS THAT ATTACH TO THE BONE AND DISSOLVE AWAY THIS MATRIX AND MINERAL. AND COORDINATED--COORDINATED ACTIVITY OF THESE CELLS IS CALLED BONE REMODELING AND ALLOW SHAPING OF THE BONE, AND IT'S A REMARKABLY DYNAMIC PROCESS. FOR EXAMPLE, THE SKELETON COMPLETELY REMODELS ITSELF ABOUT ONCE EVERY DECADE. LOOKING AT THE ULTRASTRUCTURE OF THE OSTEOCYTE, WHICH IS IN THE LOWER RIGHT HERE, WHAT YOU CAN SEE IS A WATERMELON-SHAPED CELL BODY AND PROCESSES THAT EXTEND OUT INTO THE MINERALIZED TISSUE. SO THESE CELLS FORM NETWORKS WITH OTHER OSTEOCYTES, AND THESE CELLS ARE THOUGHT TO SENSE THE MECHANICAL ENVIRONMENT IN TERMS OF MECHANICAL STRAIN, FLUID SHEAR STRESS, ACCELERATION. AND THESE CELLS ARE THOUGHT TO DIRECT BONE REMODELING. SO WE HAVE A SPECIAL PERFORMANCE NOW. BIOLOGY'S AN INHERENTLY COLLABORATIVE FIELD. AND SO TO ILLUSTRATE THIS PROCESS OF BONE REMODELING, WE HAVE AN ACTOR WHO'S-- ANN-SOFIE-- WHO'S AN ASTRONAUT. AND WE'RE GONNA DEMONSTRATE THE PROCESS OF BONE REMODELING. SO PLEASE WELCOME THE BONE AND SIGNALING LAB ACTING TROUPE. [cheers and applause] SO FIRST, WE'LL COVER BONE RESORPTION. SO OSTEOCYTES, WHICH-- [Pac-Man music] AH, WE HAVE A--WE HAVE A SIGNAL BEING SENT. [laughs] SO OSTEOCYTES, WHICH ARE THE CELLS THAT RESIDE WITHIN THE BONE, THEY SEND A MOLECULAR SIGNAL TO THE MARROW AND TO OSTEOCLAST PRECURSORS. THESE CELLS THEN HOME TO THE BONE SURFACE, ATTACH, AND DEPOSIT ACID AND ACTIVELY DEGRADE AWAY THE MATRIX AND THE MINERALIZED TISSUE. BY THAT MECHANISM, WE GET CHANGES IN STRUCTURAL VOLUME. NEXT, THE OTHER COMPONENT OF BONE REMODELING IS BONE FORMATION. SO AGAIN, WE HAVE A UNIQUE MOLECULAR SIGNAL SENT TO THE OSTEOBLAST PROGENITOR, WHICH THEN COMES TO THE BONES SURFACE AND CREATES NEW MATRIX AND NEW MINERAL. AND BY THAT--BY THIS PROCESS, THE COORDINATED ACT-- ACTIVITY OF THESE CELLS, WE HAVE FRESH NEW BONE AND SKELETAL HOMEOSTASIS. AND IN ASTRONAUTS, WE SEE THAT THESE PROCESSES GO AWRY. SO WITH THAT, PLEASE-- PLEASE THANK ANN-SOFIE AS THE ASTRONAUT. [applause] MOHIT, BETSABEL, AND REBECCA. [chuckles] I DEFINITELY OWE YOU ALL SOME BEERS AFTER THIS. [laughs] SO BUILDING ON THIS IDEA OF BONE IS A LIVING STRUCTURE AND THE PROCESS OF BONE REMODELING, IT'S NOT TOO FAR A LEAP TO STATE THAT BONE REMODELING IS A FUNCTION OF THE MECHANICAL LOADING ENVIRONMENT. AND SO IN MORE SPECIFICITY THE MECHANICAL STRAIN EXPERIENCED BY THE DEFORMATION OF THE BONE, FLUID SHEAR STRESS AS IT PASSES OVER THE SURFACE OF THE BONE, HYDROSTATIC PRESSURE, AND ALSO GRAVITY IN TERMS OF GRAVITATIONAL ACCELERATION. THESE ELEVATIONS IN MECHANICAL LOADING, WHEN THEY'RE ELEVATED, CAUSE, FOR EXAMPLE, DURING EXERCISE, CAUSE CHANGES IN BONE VOLUME. AND THIS IS THE DOMAIN OF THE OSTEOBLASTS. IN THE-- IN THE OPPOSITE DIRECTION, IN MICROGRAVITY, WEIGHTLESSNESS, AND BED REST, THIS IS IN THE DOMAIN OF THE OSTEOCLAST CELLS, AND SO WE SEE NEGATIVE CHANGES IN BONE VOLUME. TO ILLUSTRATE THESE IDEAS IN MORE DEPTH, WE'LL LOOK AT THE RIGHT AND LEFT ARM OF A TENNIS PLAYER AS A MODEL OF ELEVATED MECHANICAL LOADING. SO LOOKING AT THIS X-RAY, WHAT WE SEE IS THAT ELITE TENNIS PLAYERS WHO HAVE PLAYED THEIR WHOLE LIFE WITH HITTING--HITTING THE TENNIS BALL WITH ONE HAND, THEY HAVE--THEY SHOW, YOU KNOW, IMMEDIATE DIFFERENCES IN THE MINERAL DENSITY AND ALSO THE GEOMETRY OF--OF THEIR ARMS. AND SO THAT MANIFESTS IN BONE MINERAL CONTENT AS WELL AS DIAMETER AND THICKNESS OF THE BONE. AND UNDOUBTEDLY THESE GEOMETRIC AND MATERIAL CHANGES CAN IMPROVE STRENGTH AS WELL. IN CONTRAST, ASTRONAUTS EXPERIENCE WEIGHTLESSNESS DURING MICROGRAVITY. THIS DOESN'T MEAN INACTIVITY JUST DIFFERENT LOADING PROFILE THAN WHAT'S EXPERIENCED ON EARTH. AND SO WHAT THIS HISTOGRAM SHOWS IS THE NUMBER OF LOADING OCCURRENCES VERSUS THE--EACH PEAK FORCE OF EACH OCCURRENCE. AND SO IN BLACK, YOU SEE NORMAL ACTIVITY LIKE WALKING AND RUNNING ON 1G HERE ON EARTH. AND IN GRAY, YOU SEE THE INTERNATIONAL SPACE STATION. SO RUNNING ON THE COLD, BARE TREADMILL, FOR EXAMPLE, THAT GETS A PEAK FORCE OF ABOUT 1.4 ON ISS, 1.4 TIMES BODY WEIGHT. WHEREAS ON EARTH, IT'S ABOUT 2.5. AND SO THIS IS--SUNI WILLIAMS, WHEN SHE RAN THE BOSTON MARATHON IN SPACE, SHE--SHE SAID THAT SHE WAS GETTING ABOUT 75 TO 85% OF HER BODY WEIGHT LOADING ON THE-- ON THE TREADMILL. APPARENTLY IT WASN'T DESIGNED TO DO MARATHONS IN SPACE, AND SO IT WAS VERY UNCOMFORTABLE TO RUN 26.2 MILES. INTERESTING NOTE, WHEN SHE RETURNED THE YEAR AFTER AND SHE RAN THE BOSTON MARATHON, SHE SHAVED ABOUT HALF AN HOUR OFF OF HER TIME. SO, YOU KNOW, YOU CAN IMMEDIATELY SEE THAT THE HIGH FORCE EXERCISE STIMULATION IS MISSING ON ISS. AND THIS WAS A GAP IN THE--IN THE CADRE OF EXERCISE EQUIPMENT FOR SOME TIME. AND THOUGH THIS HAS SINCE BEEN RECTIFIED, AND I'LL SHARE THOSE RESULTS WITH YOU IN A MOMENT. SO WHAT HAVE WE LEARNED FROM THE--FROM THE PAST DECADES OF RESEARCH INTO THIS AREA? SO THIS IS REALLY THE KEY DATA FROM ASTRONAUTS THAT CHARACTERIZE THE PROBLEM, AND THIS IS GENERATED THROUGH DEXA SCANS AND MORE RECENTLY THROUGH CT SCANS. SO--SO RIGHT HERE, IT'S SHOWN-- THIS IS DATA FROM MIR, AND SO WHAT YOU SEE IS THAT IN LONG-DURATION MISSIONS BONE LOSS MANIFESTS, AND IT APPEARS AT A RATE OF ABOUT 1% LOSS OF BONE MINERAL DENSITY PER MONTH. THIS OCCURS IN THE WEIGHT-BEARING BONES, LIKE THE SPINE, THE FEMORAL NECK, THE TIBIA. BUT IT DOESN'T MANIFEST IN THE UPPER EXTREMITIES, LIKE THE HUMERUS. SO THESE WEIGHT-BEARING BONES ARE REALLY-- THEY NEED THIS MECHANICAL FORCE TO SURVIVE AND TO MAINTAIN HOMEOSTASIS. IN MORE DEPTH, THE SKELETAL TURNOVER IS MORE PRONOUNCED IN THE CANCELLOUS TISSUE. AND ONCE THE ASTRONAUTS RETURN TO EARTH, IT TAKES A LONG TIME TO RECOVER. AND IN FACT, IT MAY NOT EVER RECOVER AFTER--AFTER ONE YEAR EARTHBOUND. AND AS A RESULT OF CANCELLOUS DEFICITS, THERE'S AN EXPANSION OF THE CORTICAL BONE THAT--THAT TAKES PLACE IN ASTRONAUTS AFTER THEY'VE RETURNED TO NORMAL LOADING. SO, YOU KNOW, TAKEN TOGETHER, I THINK THIS REALLY IS A CONCERN IN TERMS OF ASTRONAUT FRACTURE RISK. IN FACT, WE CAN QUANTIFY THIS RISK IN MORE DETAIL WITH COMPUTER MODELING. SO FROM THE IN VIVO CT SCANS FROM THE ASTRONAUT BONES, ONE CAN GENERATE STRUCTURAL ANALYSES-- IN THIS CASE, FINITE ELEMENTS-- AND INVESTIGATE THE DISTRIBUTION OF STRESS WITHIN BONES. AND SO THIS IS THE CONCENTRATION OF FORCE WITHIN AN AREA. THIS EXEMPLARY FIGURE SHOWS HIGH STRESS IN THE FEMORAL HEAD, WITH RED BEING HIGH SHEAR STRESS AND BLUE BEING LOW. AND SO THIS TYPE OF ANALYSIS WAS PERFORMED BEFORE AND AFTER FLIGHT ON ASTRONAUTS. AND SO THE DATA IS HERE ON THE LEFT WITH A STANCE LOADING CONFIGURATION AND A FALL LOADING CONFIGURATION. AND SO EACH LINE HERE IS AN INDEPENDENT ASTRONAUT BEFORE AND AFTER FLIGHT. AND SO ACROSS THE BOARD, YOU CAN SEE THERE'S A LARGE MAJORITY OF NEGATIVE SLOPES IN EACH LOADING CONFIGURATION. AND WITH THE STANCE CONFIGURATION, THERE'S ABOUT A 2.5% DECREMENT PER MONTH IN--IN THE BONE STRENGTH NORMALIZED PER BODY WEIGHT. AND THESE DATA SUGGEST THAT THE FORCES ARE CONCENTRATING WITHIN THE ASTRONAUT BONES AND SUGGEST ASTRONAUT BONES HAVE REDUCED STRENGTH. AND NOW, TRANSITIONING TO MODEL ORGANISMS THAT HAVE BEEN FLOWN INTO SPACE AS WELL AS GROUND-BASED MODELS THAT INCORPORATE MODEL ORGANISMS AND--AND HUMAN MODELS OF WEIGHTLESSNESS. IT'S--THESE TYPES OF ANALYSES COMPLEMENT THOSE PRIMARY DATA SETS THAT WE JUST WENT OVER FROM THE ASTRONAUTS. AND SO WE CAN COMPARE THE DATA THAT WE JUST REVIEWED AND ALSO EXTEND OUR UNDERSTANDING AND LOOK AT MORE FUNDAMENTAL BIOLOGY MECHANISMS, LOOK AT THE CELLULAR AND MOLECULAR CHANGES THAT THE ANIMALS OR THE HUMANS ARE EXPERIENCING. AND SO IN 1978, IT WAS OBSERVED WITH ANIMALS FLOWN IN SPACE THAT THERE WAS DECREASED MINERALIZATION BY OSTEOBLAST CELLS. MORE RECENTLY, THERE'S--IN A SIMULATION OF WEIGHTLESSNESS, SHOWN HERE-- THIS IS CALLED THE HINDLIMB UNLOADING MODEL OF--USED FOR RODENTS TO SIMULATE WEIGHTLESSNESS ON THE TIBIA AND FEMUR. THEY--THESE RESEARCHERS IDENTIFIED ELEVATED OSTEOCLAST ACTIVITY, AND THIS IS MOST LIKELY RESPONSIBLE FOR BONE LOSS OBSERVED IN SIMULATED WEIGHTLESSNESS. AND THERE'S--THIS DATA WAS ALSO CONFIRMED IN HUMANS WHO WERE UNDERGOING BED REST. SO 12 WEEKS OF BED REST LISTED ELEVATIONS IN OSTEOCLAST ACTIVITY AND DECREASES IN OSTEOBLAST ACTIVITY. SO THESE--THINKING BACK TO THE BONE REMODELING, THESE ARE ALL REALLY NEGATIVE FOR-- FOR SKELETAL STRUCTURE AND-- AND THIS PROVIDES CELLULAR MECHANISMS THAT UNDERLIE THOSE VOLUMETRIC CHANGES. WITH ANIMALS FLOWN IN SPACE, WE CAN OBSERVE THE SKELETON WITH GREATER RESOLUTION. AND SO WHAT'S SHOWN HERE ARE THE PELVIC ISCHIA OF GROUND CONTROL ON THE LEFT AND 15 DAYS OF SPACEFLIGHT ON THE RIGHT. THESE WERE IMAGED WITH MICRO-CT BY COLLEAGUES IN THE BONE AND SIGNALING LAB HERE AT AMES. AND WHAT THESE SHOW IS THAT BONE LOSS OCCURRED IN THE PELVIC AREA THROUGH THINNING OF THE CORTICAL BONE. AND IN OTHER--IN THE FEMUR, IT ACTUALLY SHOWED THINNING OF BOTH THE CORTEX AS WELL AS THE TRABECULAR STRUTS. AND WHAT-- SO THIS IS A TRABECULAR STRUT ON THE RIGHT. AND SO BASICALLY JUST A RADIAL DECREASE IN--IN THAT STRUCTURE. AND THEN IN COMPLEMENTARY GROUND-BASED MODELS THIS SHOWS PROGRESSIVE THINNING AND EVENTUALLY REMOVAL OF THESE TRABECULAE WITH--WITH LONGER DURATION SPACEFLIGHT. SO IT'S THE PROGRESSION OVER THE COURSE OF A COUPLE MONTHS, OR WEEKS TO MONTHS, THAT THE SURFACE MEDIATED RESORPTION STARTS TO REMOVE AWAY THESE TRABECULAR STRUTS. AND ONCE THEY'RE REMOVED, THEY CANNOT BE CREATED DE NOVO. SO THAT'S--THIS UNDERSCORES KIND OF A STRUCTURAL MECHANISM UNDERLYING THESE REALLY PERSISTENT DEFICITS IN THE ASTRONAUT CANCELLOUS TISSUE AND WHY THE CORTICAL BONE SEEMS TO COMPENSATE WITH AN EXPANSION. ADDITIONALLY, BONES FROM SPACEFLIGHT ANIMALS AND GROUND-BASED MODELS HAVE CONFIRMED THAT MECHANICAL PROPERTIES AND BONE STRENGTH ARE REDUCED FOLLOWING WEIGHTLESSNESS. WITHIN THESE SAME MICE WE ASKED, HOW ARE THE OSTEOCYTES RESPONDING? WE ANALYZED THE SPACE-FLOWN BONES AT SLAC NATIONAL LAB WITH A 30 NANOMETER X-RAY TRANSITION MICROSCOPE-- TRANSMISSION MICROSCOPE. AND SO THESE IMAGES ARE PICTURED HERE. THE GROUND CONTROL ON THE LEFT AND THE SPACE-FLOWN ANIMALS ON THE RIGHT. AND WE ASKED WHETHER THE LOCAL TISSUE DENSITY WAS ALTERED DURING SPACEFLIGHT, AND WHETHER THE OSTEOCYTES SHOWED ANY MORPHOLOGICAL CHANGES, AND THE RESULTS WERE SURPRISING. WE DID NOT SEE ANY TISSUE LEVEL DENSITY CHANGES, BUT WE DID SEE THE LACUNAE-- THESE ARE THE APARTMENTS OF THE OSTEOCYTES-- THESE WERE BECOMING LARGER IN TERMS OF THEIR AREA AND PERIMETER. AND THESE DATA SUGGEST AN ADDITIONAL METHOD OF BONE REMODELING IN ADDITION TO THE SURFACE MEDIATED OSTEOCLAST RESORPTION. NAMELY, THESE BONES ARE REMODELING FROM THE INSIDE OUT. AND COLLEAGUES IN THE BONE AND SIGNALING LAB CONFIRMED THIS REMODELING PHENOTYPE WITH PROTEIN MARKERS OF MATRIX AND MINERAL REMODELING WITHIN THE OSTEOCYTE LACUNAE. SO STEPPING BACK TO ASTRONAUTS AND INTRODUCING THE IDEA OF EXERCISE AS A COUNTERMEASURE, RECALL THAT THE LACK OF HIGH-FORCE EXERCISES COULD BE A CRITICAL WEAKNESS OF UNDERLYING THE BONE LOSS THAT WE TALKED ABOUT EARLIER. AND THIS RELATIVELY NEW DEVICE, THE ADVANCED RESISTIVE EXERCISE DEVICE PICTURED HERE, HAS BECOME THE FIRST EFFECTIVE COUNTERMEASURE AT PREVENTING BONE LOSS EXPERIENCED BY ASTRONAUTS. SO WITH THIS DEVICE, THEY CAN GET ABOUT 500 POUNDS OF FORCE IN A SQUAT EXERCISE. THEY CAN DO HEEL RAISES AND REALLY REINTRODUCE THIS--THIS HIGH-FORCE EXERCISE ONTO THE WEIGHT-BEARING BONES. AND WHAT THE DATA SUGGESTS ARE IN THE SPINE AND THE FEMUR AND THE PELVIS, THAT THIS IS PREVENTING THAT--THE BONE LOSS THAT WE TALKED ABOUT EARLIER. HOWEVER, WE'RE NOT OUT OF THE WOODS YET. WHEN YOU LOOK AT THE BLOOD AND THE URINE, THE SKELETON IS IN A HIGH-TURNOVER STATE. SO WHAT THAT MEANS IS FORMATION IS HIGH, WHICH IS A GOOD THING, BUT RESORPTION IS STILL HIGH. SO THE OSTEOCLASTS ARE STILL IN AN ACTIVE STATE. SO I DON'T THINK WE'VE FULLY SOLVED THE PROBLEM, AND WE DON'T KNOW AT WHAT QUALITY THE BONE IS THAT FORMS UNDER THIS HIGH-TURNOVER STATE. NONETHELESS, THIS IS THE FIRST EFFECTIVE COUNTERMEASURE THAT--THAT--TO PREVENT BONE LOSS IN SPACE. LESS WELL-KNOWN ARE THE EFFECTS OF SPACE RADIATION ON THE BODY AND ON THE SKELETON, AND AS THE EARTH MAGNETIC FIELD IS CURRENTLY SHIELDING MOST OF THE CHARGED PARTICLE FLUX. THE RAD DOSIMETER, WHICH SHOWED-- WHICH TOOK DATA ON THE CRUISE PHASE TO MARS WITH THE "CURIOSITY" ROVER HAS MEASURED THE DOSE RATES OF THE GALACTIC COSMIC RADIATION, WHICH IS THIS LOW CHRONIC EXPOSURE THAT ASTRONAUTS WOULD BE EXPERIENCING, AS WELL AS SOLAR PARTICLE EVENTS-- THESE LITTLE SPIKES IN THE DOSE RATE VERSUS TIME CHART HERE. AND THE GCR PARTICLES ARE REALLY THE ONES OF CONCERN. THE--THEY'RE REALLY HARD TO SHIELD, AND THEY CAN DO REALLY INTENSE DAMAGE. AND THAT'S SHOWN HERE IN A PROTEIN--IN GREEN HERE, THAT LABELS ACTIVE DNA DAMAGE REPAIR OCCURRING. AND SO AT DOSES HERE THAT ARE ACHIEVABLE DURING A MARS-- A ROUND-TRIP MARS MISSION, YOU CAN SEE THAT THESE TYPES OF EXPOSURES ARE ELICITING DNA DAMAGE AND IN ADDITION, THEY CAN ELICIT FREE RADICAL STRESS TO ORGANISMS. AND SO DURING MY POSTDOCTORAL FELLOWSHIP, WE AIMED TO BETTER QUANTIFY THE EFFECTS OF SPACE RADIATION ON THE SKELETAL TISSUE. AND SO TO SIMULATE SPACE RADIATION, IONS AND ENERGIES, WE WENT TO THE NASA SPACE RADIATION LAB AT BROOKHAVEN NATIONAL LAB IN LONG ISLAND WERE WE USED A GAMMA RADIATION SOURCE. AND WE FOUND THAT RADIATION EXPOSURE CAUSES RAPID AND IRREVERSIBLE BONE LOSS. AND THINKING OF THE CANCELLOUS TISSUE, THIS WAS AFFECTED BY REMOVAL OF THE CANCELLOUS STRUTS. SO THIS IS A SIMILAR PROGRESSIVE BONE LOSS BUT IT--AS SIMULATED WEIGHTLESSNESS OR SPACEFLIGHT, BUT IT JUST HAPPENS MUCH, MUCH MORE RAPIDLY. AND SO THIS IS ATTRIBUTED TO THE OSTEOCLAST CELLS. THEY'RE MORE IN NUMBER. THEY'RE GREATER IN SIZE. AND THIS PERSISTED UNTIL--UNTIL AGE-RELATED BONE LOSS OVERTOOK THAT STRUCTURAL DECREMENT. SO WHAT'S SHOWN HERE IN BLACK IS-- CHARACTERIZES AGE-RELATED BONE LOSS OVER-- IN A MOUSE OVER A PERIOD OF ABOUT FOUR MONTHS. AND YOU CAN SEE THE REMOVAL OF TRABECULAR STRUTS REDUCING THIS PARAMETER CALLED TRABECULAR NUMBER, AND THEN THAT--THIS TISSUE NEVER RECOVERS. IT JUST GETS OVERTAKEN BY AGE-RELATED BONE LOSS. FURTHER, WE-- WE PERFORMED FINE ELEMENT MODELING ON THE VERTEBRA FROM SPECIMENS THAT HAD BEEN IRRADIATED AND EXPERIENCED THIS TYPE OF REMOVAL OF TRABECULAR STRUTS. AND WHAT WE SAW WAS THAT THE STRESS IN THESE BONES CONCENTRATES WITHIN THE REMAINING TISSUE ON THE CANCELLOUS BONE. ALSO, BECAUSE OF THE REMOVAL OF THESE LOAD PATHS, THERE'S MORE STRESS ON THE SURROUNDING CORTICAL SHELL. SO THIS IS--THIS IS-- THIS IS A REAL RISK FOR ASTRONAUT BONE STRENGTH ONCE THEY REACH THIS RADIATION DOSE. I'D LIKE TO KIND OF TAPER DOWN THE TALK AT THE MOLECULAR LEVEL AND THIS IS THE REALM OF PROTEINS, RECEPTORS, AND LIGANDS. THESE ARE CELL MACHINERY THAT ENGAGE WITH CELLS-- ALLOW THEM TO ENGAGE WITH THE ENVIRONMENT IN TRANSDUCED MECHANICAL SIGNALS AND ALSO TO COMMUNICATE WITH NEIGHBORING CELLS. SO WE DEMONSTRATED EARLIER THAT OSTEOCYTES CONTROL BONE REMODELING HOWEVER, THE SIGNALING MOLECULES THAT ELICIT THESE-- THIS CONTROL HAVE BEEN FAIRLY RECENTLY DISCOVERED IN THE PAST 15 YEARS OR SO. AND SO WE ASKED-- WELL, THE FIELD ASKED, HOW DO THESE MOLECULES CHANGE DURING SIMULATED SPACEFLIGHT? AND SO THERE ARE THREE KEY SIGNALING MOLECULES THAT I'LL TALK ABOUT TODAY. THE FIRST IS SCLEROSTIN. THIS IS A UNIQUE PROTEIN THAT OSTEOCYTES PRODUCE AND SECRETE INTO THE EXTRA CELLULAR SPACE. AND THIS SCLEROSTIN INHIBITS BONE FORMATION, AND SO THUS, IT ESTABLISHES NEGATIVE FEEDBACK WITHIN THIS OSTEOBLAST LINEAGE, WHERE HIGHER SCLEROSTIN LEVELS CAUSE LESS BONE FORMATION. THE NEXT MOLECULAR SIGNAL IS RANK LIGAND. AND THIS IS A LIGAND NOT UNIQUE TO OSTEOCYTES, HOWEVER THIS IS AN IMPORTANT FACTOR FOR DRIVING OSTEOCLAST FORMATION AND INITIATING THE PROCESS OF BONE RESORPTION. THERE'S A THIRD PLAYER NAMED OSTEOPROTEGERIN, WHICH IS OPG, SECRETED BY OSTEOCYTES AND OTHER CELLS THAT INHIBITS THIS RANK LIGAND MOLECULE. AND SO THIS STARTS TO-- IF THESE ARE IMPLICATED IN SPACEFLIGHT-INDUCED BONE LOSS, THEN THESE PROTEINS BECOME TRANSLATIONAL TARGETS FOR OUR COUNTERMEASURE DEVELOPMENT. NOW, RECALL THAT BONE FORMATION IS LOW IN SPACEFLIGHT. AND SIMULATIONS OF MICROGRAVITY HAVE SHOWN THAT SCLEROSTIN LEVELS ARE HIGH IN BED REST AND IN HINDLIMB UNLOADING MODELS. OPPOSITELY, PHYSIOLOGIC LOADING, LIKE EXERCISE OR PRESCRIBED MECHANICAL FORCE, DECREASE THESE SCLEROSTIN LEVELS AND NEGATIVELY REGULATE BONE FORMATION. SO TAKEN TOGETHER, INHIBITING SCLEROSTIN SHOULD RESTORE BONE FORMATION IN ASTRONAUTS. AND THIS IDEA WAS SHOWN TO BE CORRECT IN A SIMULATION OF WEIGHTLESSNESS. AND SO WHAT THEY DID WAS HINDLIMB UNLOAD ANIMALS AND TREAT THEM WITH AN ANTIBODY FOR THIS SCLEROSTIN MOLECULE, NEUTRALIZING THE ACTIVITY OF THAT MOLECULE. AND THIS WAS SHOWN TO STIMULATE BONE FORMATION IN THE CANCELLOUS TISSUE AND THE CORTICAL TISSUE AND PREVENT THE NEGATIVE CONSEQUENCES OF CONCENTRATING STRESS, SHOWN HERE IN RED, THAT WEIGHTLESSNESS AFFECTS. FURTHER, THIS ANTIBODY WAS TESTED ON STS-135, AND RESULTS ARE STILL FORTHCOMING. THIS MOLECULE-- THIS ANTIBODY TREATMENT IS CURRENTLY UNDERGOING CLINICAL TRIALS FOR OSTEOPOROSIS TREATMENT. SO THIS IS ONE LEVER OF MOLECULAR CONTROL OF BONE FORMATION THAT COULD HELP ASTRONAUTS PROTECT THEIR SKELETAL STRUCTURE. MOVING TO BONE RESORPTION, RECALL THAT IT'S HIGH IN SPACEFLIGHT. AND IN SIMULATIONS OF WEIGHTLESSNESS, IT'S BEEN SHOWN THAT RANK LIGAND EXPRESSION IS ELEVATED. ADDITIONALLY, AFTER HIGH DOSES OF RADIATION, RANK LIGAND IS ALSO ELEVATED, AS IS BONE RESORPTION. AND WE'RE ACTIVELY INVESTIGATING WHETHER RANK LIGAND PLAYS A ROLE IN THE RESPONSE TO SPACE RADIATION EXPOSURE. SO THIS INFORMATION SUGGESTS RANK LIGAND IS DRIVING OSTEOCLAST FORMATION AND BONE FORMATION IN ASTRONAUTS, AND RESEARCHERS HAVE ASKED, WHAT ROLE DO OSTEOCYTES PLAY IN CREATING RANK LIGAND? AND ADDITIONALLY, BECAUSE RANK LIGAND IS A KEY PLAYER, THAT INHIBITOR OF RANK LIGAND, OPG, COULD BE A TRANSLATIONAL-- A COUNTERMEASURE FOR ASTRONAUTS. SO TO IDENTIFY THE CELLULAR SOURCE OF THIS RANK LIGAND, A GROUP OUT OF LITTLE ROCK CREATED A TRANSGENIC MOUSE MODEL THAT DELETED THE RANK LIGAND GENE UNIQUELY IN OSTEOCYTE CELLS. AND THIS IS THE DMP1-CRE PROMOTER HERE ON THE RIGHT. SO WHAT THEIR EXPERIMENT SHOWS IS THAT, AS EXPECTED, THE SIMULATED WEIGHTLESSNESS CAUSES BONE LOSS, HOWEVER, IN THE DELETED-- THE OSTEOCYTE-SPECIFIC DELETION ANIMALS WERE NOT LOSING BONE. AND SO THIS IS SAYING THAT, ONE, THAT THE OSTEOCYTES ARE PRODUCING THE RANK LIGAND, AND THAT THIS IS THE RESPONSIBLE MECHANISM FOR WEIGHTLESSNESS-INDUCED BONE LOSS. LOOKING NEXT AT OPG AND A FAMILY OF MOLECULES CALLED ANTIRESORPTIVES, IT'S BEEN--LONG BEEN KNOWN THAT BISPHOSPHONATES ARE AN FDA APPROVED DRUG FOR OSTEOPOROSIS, AND THEY PREVENT OSTEOCLAST ATTACHMENT AND PREVENT OSTEOCLAST SURVIVAL. AND THEY HAVE BEEN TESTED IN ASTRONAUTS, AND THIS IS SHOWN TO PREVENT THE SPACEFLIGHT-INDUCED BONE LOSS. SO THIS IS THE SECOND COUNTERMEASURE THAT IS IN OUR TOOLBOX TO PREVENT THESE NEGATIVE CHANGES IN THE SKELETON. IN MICE, THIS FAMILY OF DRUGS, BISPHOSPHONATES, ALSO PREVENTED RADIATION-INDUCED BONE LOSS. AND LOOKING AT OPG, BASICALLY INHIBITING THAT RANK LIGAND MOLECULE, THIS--IN MICE, THIS WAS SHOWN IN STS-108, THAT IT PREVENTED SPACEFLIGHT-INDUCED BONE LOSS. SO THIS IS ALL FINE AND GOOD, BUT THERE'S STILL A NEGATIVE SIDE EFFECT OF PROLONGED USE OF SOME OF THESE ANTIRESORPTIVES. AND THIS HAS SHOWN UP IN OSTEOPOROTIC PATIENTS. THERE'S UNCOUPLING OF BONE REMODELING, WHICH YOU ALL UNDERSTAND NOW, BUT THERE'S ALSO OSTEONECROSIS OF THE JAW AND FEMORAL FRACTURES THAT ARE ATYPICAL EMERGED WITH PROLONGED USE. SO I THINK THESE ANTIRESORPTIVES ARE GOOD FOR THE SHORT DURATION, BUT NOT--THEY'RE NOT A PERMANENT SOLUTION. SO IN SUMMARY, WE'VE REALLY JUST SCRATCHED THE SURFACE TODAY, BUT THESE ARE BY NO MEANS THE ONLY SIGNALING MOLECULES OF RELEVANCE. BUT I HOPE THAT I'VE SUCCEEDED IN COMMUNICATING THE VALUE AND IMPORTANCE OF SPACE BIOLOGY AND STUDYING BONE LOSS IN ASTRONAUTS. I THINK WE'VE ILLUSTRATED THIS PROCESS OF DISCOVERY AND BRINGING SOLUTIONS TO THE ASTRONAUT. SO I'D LIKE TO CLOSE WITH JUST A SNAPSHOT OF WHERE WE'RE GOING. AND THIS IS A SLIDE THAT JEFF SMITH PROVIDED ME. THIS IS A--IT'S A PLOT OF DISTANCE THAT WE'VE TRAVELED FROM EARTH VERSUS THE MISSION DURATION. AND WHAT YOU SEE IS-- THIS L-SHAPE IN THE LOWER LEFT, THIS IS WHERE WE'VE BEEN SO FAR, AND THIS BIG ELLIPSE IS WHERE WE WANNA GO. AND I THINK-- I THINK WE CAN USE MODEL ORGANISMS AND A BASIC BIOLOGY APPROACH TO REALLY HELP ENABLE REACHING OUT AND EXTENDING DURATION AND EXTENDING DISTANCE FROM--FROM EARTH. SO WITH THAT, I THANK YOU FOR YOUR ATTENTION AND YOUR ATTENDANCE TODAY AND OPEN IT UP FOR QUESTIONS. [applause] - HI. I HAVE A QUESTION IN REGARDS TO THE AGE OF THE SUBJECTS THAT YOU WERE LOOKING AT. ARE THESE ALL YOUNG MICE OR OLDER MICE OR HAVE YOU STUDIED DIFFERENT AGE GROUPS? - THERE HAVE BEEN-- I THINK THE ORIGINAL STUDIES WERE WITH GROWING RATS. BUT THESE--I THINK THOSE ARE VERY KEENLY TUNED TO THE MECHANICAL ENVIRONMENT AND THOSE--THOSE SHOWED THE FIRST NEGATIVE CHANGES IN THE OSTEOBLAST. HOWEVER, WITH ADULT ANIMALS, I THINK YOU SEE SOMETHING MAYBE NOT AS DRAMATIC BUT SOMETHING IN THE SAME DIRECTION. OH, AND ALSO THE HUMAN BONE BIOPSY ALSO ACTUALLY SHOWED-- THESE WERE ADULT HUMANS, AND THAT SHOWED NEGATIVE OSTEOBLAST CHANGES AS WELL. - FIRST, THANKS FOR PUTTING AN O'NEILL CYLINDER ON YOUR SLIDES. THAT WAS NICE. I HAVE A QUESTION ABOUT CALCULATING THE-- THE BIOLOGICAL EFFECTIVENESS FOR GCR. - MM-HMM. - I THINK, ALTHOUGH I MIGHT BE WRONG, THAT ALMOST ALL THE DATA IS FROM A FAIRLY SHORT DURATION AND A LITTLE HIGHER DOSES BUT YOU NEED TO UNDERSTAND WHAT LOW DOSES OVER LONG PERIODS OF TIME, AND HOW-- IS THAT CONVERSION MADE IN SOME AD HOC WAY, OR IS THERE SOMETHING REALLY SOLID THAT DOES IT? - THAT'S--THAT'S A TOUGH QUESTION. I THINK--I THINK IT'S ON A TISSUE BY TISSUE BASIS. AND SO--AND IT DEPENDS ON WHAT YOU'RE MEASURING. ARE YOU GONNA MEASURE CELL DEATH? ARE YOU GONNA MEASURE FREE RADICAL GENERATION OR DNA DAMAGE? AND SO I THINK EACH OF THOSE-- WHATEVER YOU MEASURE IS GONNA HAVE A DIFFERENT RELATIVE BIOLOGICAL EFFECTIVENESS. I THINK MOST OF THE NUMBERS USED RIGHT NOW ARE FROM CELL DEATH OR EFFECTIVE CELL KILLING. - IS THAT HOW IT'S DONE FOR BONE? - MM-HMM. - HI, JOSH. ON ONE OF YOUR SLIDES, YOU SHOWED THE SPACEFLIGHT DATA FROM ASTRONAUTS, THAT THEY LOSE ABOUT 1% PER MONTH FOR THEIR WEIGHT-BEARING BONES BUT NOT FOR THE BONES OF THE UPPER EXTREMITIES. I'M CURIOUS WHAT YOU KNOW ABOUT THE MECHANISMS BY WHICH, YOU KNOW, YOUR ARM BONES ARE ABLE TO MAINTAIN HOMEOSTASIS, YOU KNOW, REGARDLESS OF GRAVITY LOAD, AND IF THAT CAN OFFER ANY INSIGHTS TO, YOU KNOW, HOW YOU CAN MANAGE BONE REMODELING IN MICROGRAVITY. I GUESS THE LAST PART IS, IS THAT PATTERN ALSO REFLECTED IN NORMAL OSTEOPOROTIC DISEASE PROCESSES FOR PATIENTS ON EARTH? - SO THE FIRST PART OF THE QUESTION, WE--I'VE NEVER LOOKED AT THAT, SO THAT'S A GOOD QUESTION. I WOULD PREDICT THAT IT UTILIZES SOME OF THE SAME MOLECULES TO REGULATE BONE TURNOVER, AND SO WE SAW WITH THIS USE IN THE BED REST, THE SCLEROSTIN WAS UP. AND SO I THINK THERE ARE A COUPLE INTERPRETATIONS. PERHAPS THE BONE IS AT A LOWER RATE OF TURNOVER TO BEGIN WITH, AND SO ANY CHANGE WOULD TAKE LONGER TO MANIFEST. OR THE SCLEROSTIN LEVEL VARIES BY TISSUE. AND MAYBE THAT HELPS EXPLAIN WHY THERE'S NOT A PHENOTYPE IN THE UPPER EXTREMITY. AND THE SECOND QUESTION, CAN YOU REPEAT? - WELL, COULD THAT-- IS THAT ALSO THE CASE FOR OSTEOPOROSIS ON EARTH? IS THERE A PATTERN BETWEEN LOAD-BEARING AND UNLOAD-BEARING BONES? - I THINK OSTEOPOROSIS ON EARTH, THERE'S A COUPLE DIFFERENT FORMS OF THE DISEASE. AND HORMONES PLAY AN IMPORTANT ROLE IN POSTMENOPAUSAL OSTEOPOROSIS. AND SO I THINK THERE ARE OTHER PLAYERS, BUT I THINK RANK LIGAND, SCLEROSTIN PROBABLY PLAY A ROLE. - HI. I WANT TO TOUCH ON A COUPLE DEEPER TOPICS THAT WE MAY HAVE TO HAVE BEERS ABOUT. BUT, UM... SO FIRST, COUNTER TO A LOT OF INTUITION, EVERYTHING I UNDERSTAND ABOUT BONE DEVELOPMENT IS THAT, FOR INSTANCE, COMPRESSION-- COMPRESSIVE PRESSURE ON A BONE CAUSES THAT BONE TO DEGRADE AND DISAPPEAR, VERSUS TENSION ON A BONE WILL CAUSE IT TO GROW, LIKE A BONE SPUR. SO THIS TIES IN TO SORT OF A DEEPER STORY OF, FOR INSTANCE, WHEN WE THINK OF "WEIGHT-BEARING" SKELETON, IT'S NOT ACTUALLY BECAUSE THE SKELETON IS BEING COMPRESSED BY THE WEIGHT OF THE BODY, IT'S BECAUSE IT'S EXPERIENCING GREATER TENSILE LOADS FROM THE MUSCLES SURROUNDING THEM. AND, UM... PART OF A SORT OF TENSION NETWORK APPROACH TO UNDERSTANDING THE BODY. IT'S A VERY DIFFERENT APPROACH THAN SORT OF COMMON SENSE, BUT THERE'S A LOT OF EVIDENCE BACKING IT. AND SO THAT WOULD FIT IN TO THIS IDEA THAT WHILE-- WHEN IN SPACEFLIGHT YOU ARE USING YOUR ARMS A LOT. YOU STILL NEED TO USE MUSCULAR ACTIVITY TO MOVE THE MASS AND INERTIA OF OBJECTS AROUND, AND ASTRONAUTS PUSH THEMSELVES AROUND A LOT WITH THEIR ARMS. SO THOSE MUSCLES ARE ACTIVE, THEREFORE THOSE BONES ARE GETTING LOTS OF LOAD AND SO THEY DON'T DEGRADE. WHEREAS THE LEGS AND OTHER PARTS OF THE BODY WHICH ARE ACCUSTOMED TO DEALING WITH GRAVITY AREN'T, THEREFORE THEY ARE NOT EXPERIENCING THAT SAME LEVEL OF TENSION. SO IT'S REALLY THE TENSION OF THE MUSCLES THAT'S THE ISSUE, NOT THE WEIGHT-BEARING, PER SE. - YEAH. I THINK-- YOU KNOW, A STATIC COMPRESSION CAN CERTAINLY BE DAMAGING INTO SKELETAL TISSUE, BUT YOU KNOW, INTERMITTENT COMPRESSION IS REALLY POSITIVE FOR SKELETAL GROWTH. SO I THINK--YOU KNOW, I THINK THE SKELETON IS SENSITIVE TO DIFFERENT TYPES OF FORCE. IT'S SENSITIVE TO TENSION, SHEAR, INTERMITTENT COMPRESSION. SO I THINK ALL THESE THINGS WOULD FEED INTO A PRETTY UNIQUE MODEL. BUT CERTAINLY, YOU'RE REMOVING THIS CONSTANT COMPRESSION OF WEIGHT-BEARING, SO I THINK THAT'S-- THAT'S A GOOD POINT. - AND HAVE PEOPLE LOOKED AT THE IDEA OF CONTINUOUS RESISTIVE DEVICES? FOR INSTANCE, I'VE BEEN TALKING WITH SOME FOLKS ABOUT, FOR INSTANCE, MAKING INFLATABLE EXOSKELETONS THAT ASTRONAUTS COULD WEAR ON A DAILY BASIS THAT WOULD RESIST ALL ACTIVITY AND ALL DIRECTIONS AND THEREFORE APPLY CONTINUAL LOADING? - YEAH, I THINK IT'S AN INTERESTING IDEA. THE KEY THING FROM THE HISTOGRAM CHART IS THAT YOU'D REALLY NEED TO GET UP TO THAT TWO AND THREE BODY WEIGHT HIGH-FORCE EXERCISE. AND SO IF YOU COULD HAVE A DEVICE THAT'S ABLE TO GET THAT FORCE REGIMEN, THEN YOU'RE GONNA BE SOME REALLY POTENT STIMULATION FOR BONE. - OKAY. - QUITE A FEW IMPLANT MANUFACTURERS ARE SUFFERING FROM THE SAME KIND OF PROBLEMS AS THE--YOU DESCRIBE THE BONE WE SAW. SO FOR EXAMPLE, IF WE INSTALL A FULLY NEW HIP FOR A PATIENT, THE LOWER PARTS OF THE-- OF THE FEMUR BONE ARE GOING TO START DEGRADING. HAVE YOU HAD ANY COLLABORATION WITH IMPLANT MANUFACTURERS OR HOSPITALS REGARDS OF THIS? - WE HAVE NOT. WE HAVE NOT. I MEAN, IT'S AN ACTIVE AREA OF RESEARCH IN THE FIELD, BUT WE'VE NOT DONE ANY DIRECT RESEARCH. - SO IF YOU COULD PLEASE JOIN ME IN THANKING JOSH ALWOOD. [applause] [musical tones] [electronic sounds of data]