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Welcome to the Clinical
Center Grand Rounds,

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a weekly series of educational
lectures for physicians and

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health care professionals
broadcast from the Clinical

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Center at the National
Institutes of Health in

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Bethesda, MD.

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The NIH Clinical Center is the
world's largest hospital totally

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dedicated to investigational
research and leads the global

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effort in training today's
investigators and discovering

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tomorrow's cures.

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Learn more by visiting us online
at http://clinicalcenter.nih.gov

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TODAY, OUR SPEAKER IS

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DR. ARE--ADMINISTRATIVEIEL

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LEVINE, STADTMAN INVESTIGATOR

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AND CHIEF OF THE PLASTICITY UNIT

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OF THE NEUROLOGICAL DISORDERS

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AND STROKE.

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DR. LEVINE COMPLETED HER Ph.D.

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IN 2008 WHERE HERE THESIS WAS ON

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THE ROLE OF TGF BETA SIGNALING

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DURING EMBRYONIC DEVELOPMENT.

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SHE THEN EARNED HER MEDICAL

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DEGREE FROM THE UNIVERSITY OF

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CORNELL IN 2009.

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DR. LEVINE JOINED THE FAULKFLER

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INSTITUTES WHERE SHE WORKED ON

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NEURONS THAT ENCODE MOTOR

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SYNERGY, NERVE PROGRAMS FOR

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SIMPLE MOVEMENT WERE THOUGHT TO

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UNDERLIE A WIDE VARIETY OF

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COMMON BEHAVIORS.

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IN 2015, DR. LEVINE JOINED THE

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DISORDERS AND STROKES AS EARL

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STADTMAN INVESTIGATOR AND NOW

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LEADS THE PLASTICITY UNIT,

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DR. LEVINE'S GROUP HAS AUTHORED

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NUMEROUS PAPERS AND A RESEARCH

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THAT SEEKS TO IDENTIFY AND

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UNDERSTAND THE CELL TYPES OF THE

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SPINAL CORD, HOW TO CONTRIBUTE

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TO BEHAVIOR AND HOW WE MAY USE

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THIS KNOWLEDGE TO HELP PATIENTS

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WITH SPINAL CORD DISEASE AND

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INJURY.

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SHE IS A NATIONALLY AND

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INTERNATIONALLY RECOGNIZED

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EXPERT IN NEURAL REGENERATION

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AND REPAIR.

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DR. LEVINE IS A RECIPIENT OF THE

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NINDS DIRECTOR OF WORK FOR

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MENTORSHIP AND A MEMBER OF THE

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SOCIETY OF NEURAL SCIENCE AND

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SOCIETY FOR NEURAL CONTROL

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MOVEMENT AND REVIEW OF NUMEROUS

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JOURNALS AND SCIENCE.

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HER TALK TODAY IS ENTITLED WHAT

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HUMAN MOTOR NEURONS ARE MADE OF.

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PLEASE WELCOME OUR SPEAKER

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DR. ARIEL LEVINE.

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>>THANK YOU VERY MUCH FOR
THAT

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INTRODUCTION AND IT'S REALLY A

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PLEASURE TO BE HERE.

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I DON'T ALWAYS GET TO SHARE MY

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WORK WITH SUCH A BROAD AUDIENCE

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INCLUDING CLINICIANS AND THAT'S

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REALLY BEEN A MOTIVATING

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INTEREST FOR US IN TERMS OF

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FIGURING OUT HOW BASIC BIOLOGY

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OF THE SPINAL CORD WORKS AND HOW

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WE CAN MAKE THIS KNOWLEDGE

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ACCESSIBLE AND HELPFUL TO

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CLINICAL BIOLOGIST AND CLINICAL

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SCIENTISTS.

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SO I'M EXCIDED FOR THIS

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OPPORTUNITY TODAY TO TELL YOU

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ABOUT OUR WORK ON WHAT HUMAN

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MOTONEURONS ARE MADE OF.

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FIRST I WILL BEGIN BY SAYING I

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HAVE NO FINANCIAL DISCLOSURES TO

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REPORT, NO COMPETING INTERESTS

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AND I WON'T BE MAKING ANY

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STATEMENTS ABOUT KNOWA APPROVED

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OR OFFLABEL DRUGS IN MY TALK.

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AND I HOPE THAT THERE ARE MANY

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THINGS YOU WILL LEARN FROM THE

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TALK TODAY IN PARTICULAR,

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THOUGH, I THINK THERE ARE 2

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SPECIFIC THINGS WE SHOULD

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DEFINITELY BE ABLE TO GET OUT OF

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IT.

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I HOPE YOU WILL LEARN ABOUT

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EMERGING TECHNOLOGIES FOR

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PROFILING GENE EXPRESSION IN

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HUMAN ISSUE, SO I'M IN

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PARTICULAR GOING TO TALK TO YOU

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ABOUT HUMAN MOTONEURONS AND

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SPINAL CORD BUT I LOT OF THESE

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ARE AT THE BLOODING EDGE OF

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HUMAN TISSUE IN GENERAL AND CAN

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BE BROADLY APPLIED AND I ALSO

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HOPE YOU'RE LEARN ABOUT THE

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MOLECULAR SIGNATURES OF HUMAN

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MOTOR NEURONS AND COME TO SEE

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FROM OUR PERSPECTIVE WHY WE

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THINK THAT JUST UNDERSTANDING

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THIS BASIC INFORMATION WILL HAVE

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IMPORTANT INSIGHTS FOR DISEASE.

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SO IN MY LAB, WE KIND OF STUDIED

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THE MIND BODY PROBLEM.

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BASICALLY WE'RE REALLY

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INTERESTED IN HOW THE CENTRAL

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AND PERIPHERAL NERVOUS SYSTEMS

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ARE ABLE TO ACCOMPLISH BEHAVIOR,

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AND THE MAIN WAY THAT WE THINK

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ABOUT THAT IS HOW THEY'RE

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CONNECTED TO THE BODY.

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AND THE ANSWER IS REALLY THROUGH

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THE SPINAL CORD.

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SO THE SPINAL CORD IS THE LINK

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BETWEEN YOUR BRAIN AND YOUR

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BODY, BOTH FOR WHAT WE CALL

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DESENSING CONTROL IN TERMS OF

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MOTOR CONTROL, AUTONOMIC CONTROL

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AND BASICALLY ALL OF THE BODY

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CONTROL THAT'S NOT IN YOUR HEAD.

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AND ALSO FOR ASCENDING CONTROL,

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SO ALL THE INFORMATION YOU

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PERCEIVE FROM OUR BODY NEEDS TO

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GET BACK UP TO THE BRAIN FROM

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THE SPINAL CORD.

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SO ALL OF THESE PATHWAYS COMING

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UP AND DOWN, WE ACTUALLY THINK

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THAT THE SPINAL CORD IS NOT JUST

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A PASSIVE RELAY BUT WE'RE REALLY

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INTERESTED IN THE COMPUTATIONS

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AND THE BIOLOGY OF THIS TISSUE

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ITSELF.

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SO IF WE LOOK AT A SECTION OF

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THE SPINAL CORD, SO WE THINK

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ABOUT INSIDE THE VERTEBRAL

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COLUMN GOING UP AND DOWN YOUR

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BACK AND WE TAKE A THIN SLICE

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THIS, IS WHAT THE SPINAL CORD

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LOOKS LIKE IN HUMANS, AND THIS

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DARK TISSUE ON THE OUTSIDE ARE

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ALL OF THE PATHWAYS THAT LINK

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THE BRAIN AND THE SPINAL CORD

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RUNNING UP AND DOWN, AND THEN

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THIS WHITE AREA HERE HAD IS

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ACTUALLY CALLED THE GRAY MATTER

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OF THE SPINAL CORD, THAT'S WHERE

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ALL THE CELLS ARE, THE CELLS

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THAT RECEIVE THIS INFORMATION,

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THAT INTEGRATE IT, THE COMPUTE

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IT, AND THEN ACTUALLY ALLOW US

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TO MOVE TO BREATHE, TO CONTROL

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OUR BODIES.

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AND MY LAB IS REALLY INTERESTED

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IN HOW THAT ALL HAPPENED AND WE

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THINK IN GENERAL OF THE SPINAL

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CORD AS A PIECE OF TISSUE, LIKE

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ALL BIOLOGY, COMPRISED OF A

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COMMUNITY OF CELL TYPES, SO IF

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WE LOOK AT THIS PIECE OF TISSUE

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RIGHT HERE, IT'S JUST KIND OF

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BLACK AND WHITE AND OF COURSE

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THAT'S NOT HOW, AS BIOLOGISTS WE

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HOPE TO PEER AT IT, BUT RATHER

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IT HAS BLOOD VESSEL CELLS AND

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GLUE MARIOUSA SUPPORT CELLS, ALL

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DIFFERENT KINDS OF NEURONS, MENG

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ENETHAT ENCASE THE SYSTEM AND

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HERE I'M SHOWING THE CORE TYPES

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IN A DIFFERENT COLOR.

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JUST TO GIVE THE SENSE THAT LIKE

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THIS FOR INSTANCE AN ON/OFF

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SWITCH, THIS OR RELAY, IT'S A

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COMPLEX OF TISSUE AND BIOLOGY IN

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THE CONTEXT OF DISEASE, INJURY,

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ALL THESE CELL TYPES

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INDIVIDUALLY ARE RESPONDING AND

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AS A COMMUNITY ARE RESPONDING.

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AND THAT WHEN WE THINK ABOUT

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SPINAL CORD BIOLOGY, AND THE

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BASIC OR INJURY OR DISEASE

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CONTEXT, WE NEED TO HAVE THIS

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GLOBAL POINT OF VIEW.

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SO IN MY LAB, WE'RE REALLY

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INTERESTED IN CELL TYPES, THE

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PARTICULARS OF THAT COMMUNITY,

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THE COMMUNITY MEMBERS, SHALL WE

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SAY.

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AND I WANT TO START BY JUST

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JUSTIFYING THAT KIND OF PRIORITY

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AND ASKING DO CELL TYPES MATTER

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AND WHY DO CELL TYPES MATTER,

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AND SO IN PARTICULAR, I'M GOING

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TO BEGIN BY DISCUSSING NEURONS,

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ALTHOUGH IN MY LAB WE'RE

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INTERESTED IN ALL CELL TYPES AND

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I WANTED TO TAKE THIS EXAMPLE OF

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A RANDOM GENERIC NEURON, COULD

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WE JUST KIND OF GET THEM TO THE

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RIGHT PLACE AND DEVELOPMENT AND

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HOPE THAT RANDOM GENERIC NEURONS

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COULD GET ALL THE JOB DONE, AND

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I WOULD SUGGEST THE ANSWER IS

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NO, FOR 2 REASONS,OT BASIC SIDE

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HERE ON THE LEFT SIDE OF MY

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SCREEN, I'M SHOWING 2 DIFFERENT

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HIGHLY RELATED CELL TYPES,

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THEY'RE BOTH LOCATED IN THE IN

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MIDDLE AREA OF THE SPINAL CORD

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AND YOU CAN SEE THE CELL BODIES

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HERE, THEY'RE BOTH INHIBITORY,

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YOU WOULD THINK FOR ALL THE

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WORLD THAT BASICALLY LIKE WHAT'S

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REALLY THE BIG DIFFERENCE THERE.

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BUT IF WE LOOK AT WHERE THEY

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SEND THEIR TARGET, THE SCWR IS

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QUITE DIFFERENT, SO 1 STAYS IN

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THE DORSAL AREA OF THE SPOONAL

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CORD WHICH IS PRIMARILY FOCUSED

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ON SENSORY RECEIVING SENSORY

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INFORMATION, AND PROCESSING AND

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INTEGRATING IT.

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AND THE OTHER SENDS ALL OF ITS

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SIGNALS OUT TO THE HORN WHERE

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MOTOR IS THE THEME OF THE DAY.

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SO I THINK THAT WHEN WE--IT'S

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LESS OF A SURPRISE, WHEN WE

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PERTUSH THESE CELL TYPES AND WE

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LOOK AT BEHAVIOR IN MICE, WE SEE

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REALLY DIFFERENT PHENOTYPES

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ACTUALLY SO IN THIS CASE, WHEN

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WE PERTURB THESE CELLS, ANIMAL

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CANS CARRY OUT A NORMAL BEHAVIOR

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AND THEN THEY CAN'T STOP IT.

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SOY, WE REALLY THINK ABOUT THESE

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CELL TYPES AS CONVEYING A LOT OF

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UNIQUE AND IMPORTANT

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INFORMATION.

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THEY HAVE DIFFERENT LOCATIONS,

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DIFFERENT MORPHOLOGY, DIFFERENT

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CONNECTIVITY AND ULTIMATELY IN A

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NEURAL NETWORK, DIFFERENT

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FUNCTIONS.

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BUT IT'S NOT JUST ABOUT KIND OF

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HOW DID THEY GET THEIR JOB DONE

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IN A NETWORK, I THINK WE NEED TO

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CONSIDER THE CONTEXT OF HUMAN

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DISEASE AND INJURY, AND THAT'S

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WHAT I'M SHOWING ON MY RIGHT

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SIDE OF THE SLIDE AND THESE ARE

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JUST AS IMPORTANT IN THAT

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INDIVIDUAL CELL TYPE VS

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DIFFERENT PROPENSITIES FOR

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DIFFERENT FEATURES OF BIOLOGY,

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00:08:23,960 --> 00:08:26,080
FOR INSTANCE SOME OF THEM

259
00:08:26,080 --> 00:08:27,240
PROLIFERATE, ARE THEY THEN TO

260
00:08:27,240 --> 00:08:28,160
GIVE RISE TO CANCER.

261
00:08:28,160 --> 00:08:30,560
SOME OF THEM ARE MORE LIKELY TO

262
00:08:30,560 --> 00:08:32,800
DEGENERATE, SO FOR INSTANCE IN A

263
00:08:32,800 --> 00:08:33,920
LOT OF THE NEURODEGENERATIVE

264
00:08:33,920 --> 00:08:35,280
DISEASES THAT WE ALL XAIR ABOUT,

265
00:08:35,280 --> 00:08:36,360
PARTICULAR CELL TYPES ARE DYING

266
00:08:36,360 --> 00:08:38,240
AND WE REALLY KNOW VERY LITTLE

267
00:08:38,240 --> 00:08:39,800
ABOUT WHAT IT IS ABOUT THOSE

268
00:08:39,800 --> 00:08:43,400
CELL TYPES, THAT'S CAUSING THAT

269
00:08:43,400 --> 00:08:44,080
VULNERABILITY, RELATEDLY, WHEN

270
00:08:44,080 --> 00:08:46,400
WE THINK ABOUT FOR INSTANCE

271
00:08:46,400 --> 00:08:48,480
SPINAL CORD INJURY, MOST CELL

272
00:08:48,480 --> 00:08:52,760
TYPES CAN'T REGENERATE BUT  A FW

273
00:08:52,760 --> 00:08:53,120
CAN.

274
00:08:53,120 --> 00:08:54,840
SO MY LAB IS INTERESTED IN

275
00:08:54,840 --> 00:08:55,520
UNDERSTANDING THE NITTY-GRITTY

276
00:08:55,520 --> 00:08:56,640
OF WHAT MAKES CELL TYPES

277
00:08:56,640 --> 00:08:57,560
DIFFERENT FROM EACH OTHER AND IF

278
00:08:57,560 --> 00:08:59,480
WE CAN UNDERSTAND THAT TO STUDY

279
00:08:59,480 --> 00:09:01,120
NEURAL NETWORKS AND ALSO TO

280
00:09:01,120 --> 00:09:03,000
STUDY BASIC BIOLOGY THAT WOULD

281
00:09:03,000 --> 00:09:07,000
SUPPORT DISEASE AND INJURY

282
00:09:07,000 --> 00:09:07,240
INSIGHTS.

283
00:09:07,240 --> 00:09:09,000
SO JUST TO BRING IT ALL

284
00:09:09,000 --> 00:09:10,600
TOGETHER, MY LAB STUDIES CELLS

285
00:09:10,600 --> 00:09:12,040
AND CIRCUITS OF THE SPINAL CORD,

286
00:09:12,040 --> 00:09:15,200
WHICH IS KIND OF OUR MIDLEVEL.

287
00:09:15,200 --> 00:09:17,320
WE'RE REALLY INTERESTED IN THE

288
00:09:17,320 --> 00:09:18,480
PARTICULAR GENE EXPRESSION

289
00:09:18,480 --> 00:09:20,080
PATTERN THAT CHARACTERIZE EACH

290
00:09:20,080 --> 00:09:22,960
CELL TYPE, THAT KIND OF GIVE IT

291
00:09:22,960 --> 00:09:23,800
THE MOLECULAR REPERTOIRE THAT IT

292
00:09:23,800 --> 00:09:25,480
WILL USE TO GET THE JOB DONE AND

293
00:09:25,480 --> 00:09:26,320
THEN ULTIMATELY WE WANT TO

294
00:09:26,320 --> 00:09:29,680
UNDERSTAND HOW ALL OF THOSE MORE

295
00:09:29,680 --> 00:09:30,840
MECHANISTIC LEVELS COME TOGETHER

296
00:09:30,840 --> 00:09:32,800
AND ENABLE NORMAL HEALTHY

297
00:09:32,800 --> 00:09:33,080
MOVEMENT.

298
00:09:33,080 --> 00:09:43,640
SO TODAY I'M GOING TO THANK YOU

299
00:09:45,960 --> 00:09:47,200
2 SECTIONS WHICH IS MOUSE WHERE

300
00:09:47,200 --> 00:09:48,280
WE HAVE GREATER RANGE OF

301
00:09:48,280 --> 00:09:49,880
TECHNIQUES AND A GREATER RANGE

302
00:09:49,880 --> 00:09:51,680
OF AVAILABLE TO STUDY MECHANISM

303
00:09:51,680 --> 00:09:54,200
AND THEN, A STORY ABOUT OUR NEW

304
00:09:54,200 --> 00:09:56,880
FINDINGS ON HUMAN SPOONAL CORD

305
00:09:56,880 --> 00:09:59,280
MOTOR NEURONS AND HOW THEY'RE

306
00:09:59,280 --> 00:10:01,160
DEFINED BY ALS RELATED GENES

307
00:10:01,160 --> 00:10:03,040
BECAUSE THAT'S THE 2 HALVES OF

308
00:10:03,040 --> 00:10:04,640
OUR LAB, BASIC WORK AND

309
00:10:04,640 --> 00:10:04,960
APPLICATION.

310
00:10:04,960 --> 00:10:07,240
SO WHEN I STARTED MY LAB, I

311
00:10:07,240 --> 00:10:09,240
THOUGHT, YOU KNOW WE KNOW ALL OF

312
00:10:09,240 --> 00:10:10,680
THE CELL TYPES, WE KNOW THERE

313
00:10:10,680 --> 00:10:13,280
ARE BLOOD VESSEL CELLS THERE AND

314
00:10:13,280 --> 00:10:14,200
OLIGIO DENDRITIC CELLROCYTES AND

315
00:10:14,200 --> 00:10:16,360
EACH OF THE MAIN KIND OF CLASSES

316
00:10:16,360 --> 00:10:18,040
AND IN FACT WE KNOW A LOT ABOUT

317
00:10:18,040 --> 00:10:19,320
THE DIFFERENT TYPES OF NEURONS

318
00:10:19,320 --> 00:10:21,880
AS WELL SO WHY IS THIS EVEN A

319
00:10:21,880 --> 00:10:24,240
QUESTION, WHY ARE WE REVISITING

320
00:10:24,240 --> 00:10:24,760
CELL TYPES IN 2022.

321
00:10:24,760 --> 00:10:26,280
AND I WOULD SAY IT'S PROBABLY

322
00:10:26,280 --> 00:10:30,320
FOR 2 MAIN REASONS.

323
00:10:30,320 --> 00:10:32,080
ONE IS, I THINK OUR VERY

324
00:10:32,080 --> 00:10:33,360
DEFINITIONS OF CELL TYPES ARE

325
00:10:33,360 --> 00:10:35,240
CHANGING WHRIL I LEARNED THEM IN

326
00:10:35,240 --> 00:10:38,160
THE TEXTBOOK AS A FIXED KIND OF

327
00:10:38,160 --> 00:10:39,400
IDENTITY WITH GIVEN FEATURE FOR

328
00:10:39,400 --> 00:10:40,520
EACH DIFFERENT WAY OF THINKING

329
00:10:40,520 --> 00:10:44,080
ABOUT A CELL TYPE, I THINK THAT

330
00:10:44,080 --> 00:10:48,160
THESE CATEGORIES ARE BLURRING

331
00:10:48,160 --> 00:10:50,720
NOW AND WE'RE REVISITING HOW

332
00:10:50,720 --> 00:10:52,240
FIXED AND DEFINED THE CELL TYPE

333
00:10:52,240 --> 00:10:53,640
IS, AND THE OTHER REASON IS FOR

334
00:10:53,640 --> 00:10:54,880
EVERY WAY OF THINKING ABOUT THE

335
00:10:54,880 --> 00:10:56,840
A CELL TYPE, THERE'S A TECHNIQUE

336
00:10:56,840 --> 00:10:58,880
THAT BROUGHT THAT PERSPECTIVE SO

337
00:10:58,880 --> 00:11:00,960
FOR INSTANCE WE CAN ASK HOW CAN

338
00:11:00,960 --> 00:11:02,080
WE CATEGORIZE ALL THE CELLS OF

339
00:11:02,080 --> 00:11:03,440
THE BODY BASED ON WHERE THEY

340
00:11:03,440 --> 00:11:04,880
COME FROM THE EMBRYO OR WHAT

341
00:11:04,880 --> 00:11:07,440
GENES THEY EXPRESS IN THE ADULT.

342
00:11:07,440 --> 00:11:09,360
OR FOR THE NEURONS WHAT THEY

343
00:11:09,360 --> 00:11:12,400
LOOK LIKE AND WHAT THEIR

344
00:11:12,400 --> 00:11:12,960
ELECTROPHYSIOLOGY IS.

345
00:11:12,960 --> 00:11:15,360
AND EACH OF THESE HAS BEEN

346
00:11:15,360 --> 00:11:15,920
INCREDIBLY RICH LITERATURES

347
00:11:15,920 --> 00:11:17,800
DEVELOPED IN THE SPINAL CORD.

348
00:11:17,800 --> 00:11:19,440
HOWEVER, THEY DON'T CLICK, THEY

349
00:11:19,440 --> 00:11:20,040
DON'T GO TOGETHER.

350
00:11:20,040 --> 00:11:22,680
THEY'RE EACH A COMPLETELY

351
00:11:22,680 --> 00:11:23,040
SEPARATE SCHEMA.

352
00:11:23,040 --> 00:11:24,240
SO I WAS REALLY INTERESTED IN

353
00:11:24,240 --> 00:11:26,960
COMING UP WITH A STRATEGY WHERE

354
00:11:26,960 --> 00:11:28,240
WE COULD JUST LITERALLY LET ME

355
00:11:28,240 --> 00:11:30,920
KNOW WHAT ARE THE CELL TYPES OF

356
00:11:30,920 --> 00:11:32,320
THIS SPINAL CORD, HOW DO THEY

357
00:11:32,320 --> 00:11:34,240
RELATE TO THESE DIFFERENT

358
00:11:34,240 --> 00:11:34,760
FEATURES, THESE DIFFERENT

359
00:11:34,760 --> 00:11:36,440
PERSPECTIVES ON CELL TYPE

360
00:11:36,440 --> 00:11:37,960
IDENTITY.

361
00:11:37,960 --> 00:11:38,720
DO THESE INDEED ALL COME

362
00:11:38,720 --> 00:11:39,920
TOGETHER OR NOT AND THEN OF

363
00:11:39,920 --> 00:11:41,040
COURSE, CAN WE USE THIS

364
00:11:41,040 --> 00:11:43,120
KNOWLEDGE, CAN WE THINK ABOUT

365
00:11:43,120 --> 00:11:45,160
HOW FOR INSTANCE THE PARTICULAR

366
00:11:45,160 --> 00:11:47,640
MOLECULAR MARKERS ARE GOING TO

367
00:11:47,640 --> 00:11:49,320
ENABLE, LET'S SAY IF YOU HAVE A

368
00:11:49,320 --> 00:11:52,600
CHANNEL, NOW YOU CAN HAVE

369
00:11:52,600 --> 00:11:53,960
CERTAIN DISEASE GENE, YOU MIGHT

370
00:11:53,960 --> 00:11:54,400
GET THE DISEASE.

371
00:11:54,400 --> 00:11:55,760
AND SO WE WERE REALLY INTERESTED

372
00:11:55,760 --> 00:11:57,320
IN KIND OF BRINGING THIS

373
00:11:57,320 --> 00:12:00,080
ALTOGETHER TO HAVE A COHERENT

374
00:12:00,080 --> 00:12:02,360
SET OF CELL TYPES IN THE SPINAL

375
00:12:02,360 --> 00:12:04,200
CORD AND BEDS THEIR MOLECULAR

376
00:12:04,200 --> 00:12:05,760
WEPPER TWOARS.

377
00:12:05,760 --> 00:12:07,440
WHEN I FIRST STARTED SINGLE CELL

378
00:12:07,440 --> 00:12:08,280
SEQUENCING WAS JUST KIND OF

379
00:12:08,280 --> 00:12:09,240
COMING UP AND I THOUGHT THIS IS

380
00:12:09,240 --> 00:12:10,320
GOING TO BE A GREAT WAY.

381
00:12:10,320 --> 00:12:13,120
AND I JUST WANT TO TAKE A FEW

382
00:12:13,120 --> 00:12:13,960
SLIDES AND PREVENTIVELY DESCRIBE

383
00:12:13,960 --> 00:12:15,720
THIS BECAUSE I THINK IT BECOMES

384
00:12:15,720 --> 00:12:17,200
SUCH A WORK HORSE AND NEW

385
00:12:17,200 --> 00:12:18,240
DIRECTION IN BIOLOGY THAT

386
00:12:18,240 --> 00:12:19,840
PROBABLY MANY OF YOU ARE

387
00:12:19,840 --> 00:12:21,560
FAMILIAR WITH IT ALREADY.

388
00:12:21,560 --> 00:12:24,120
SO BASICALLY THE IDEA IS YOU USE

389
00:12:24,120 --> 00:12:26,840
THE GENE EXPRESSION IN MANY,

390
00:12:26,840 --> 00:12:27,600
MANY DIFFERENT CELLS AND USE

391
00:12:27,600 --> 00:12:29,120
THAT TO KIND OF THINK ABOUT WHAT

392
00:12:29,120 --> 00:12:30,680
ARE THE PATTERNS THAT KEEP

393
00:12:30,680 --> 00:12:32,640
EMERGING, IS THERE A PATTERN OF

394
00:12:32,640 --> 00:12:33,360
GENE EXPRESSION THAT'S FOUND

395
00:12:33,360 --> 00:12:35,680
OVER AND OVER AND OVER, WELL,

396
00:12:35,680 --> 00:12:37,240
MAYBE THAT'S A TRANSCRIPTIONAL

397
00:12:37,240 --> 00:12:38,480
CELL TYPE AND THE WAY THAT WE DO

398
00:12:38,480 --> 00:12:41,200
THAT IS WE TAKE A COMPLEX PIECE

399
00:12:41,200 --> 00:12:43,400
OF TISSUE, WE DIVIDE IT INTO

400
00:12:43,400 --> 00:12:44,800
MANY INDIVIDUAL CELLS, WE

401
00:12:44,800 --> 00:12:45,760
SEPARATE THOSE CELLS, AND THERE

402
00:12:45,760 --> 00:12:48,160
ARE DIFFERENT WAYS TO DO IT,

403
00:12:48,160 --> 00:12:50,600
TEND TO USE MICROFLUIDICS AND

404
00:12:50,600 --> 00:12:52,480
THEN PUT A BAR CODEOT RNA FOR

405
00:12:52,480 --> 00:12:53,560
EACH 1.

406
00:12:53,560 --> 00:12:55,520
WHEN WE REVERSE TRANSCRIBE THAT

407
00:12:55,520 --> 00:12:57,600
RNA INTO CDNA, WE CAN THEN

408
00:12:57,600 --> 00:12:58,560
AMPLIFY IT AND SEQUENCE IT AND

409
00:12:58,560 --> 00:13:00,200
NOW WE CAN SEE ALL OF THE GENES

410
00:13:00,200 --> 00:13:02,600
FROM EACH CELL, AND THEN USE

411
00:13:02,600 --> 00:13:03,520
COMPUTATIONAL APPROACHES TO KIND

412
00:13:03,520 --> 00:13:07,080
OF CLUSTER THOSE INTO PATTERNS

413
00:13:07,080 --> 00:13:07,560
THAT TYPICALLY EMERGE.

414
00:13:07,560 --> 00:13:08,800
SO THIS WAS OUR GOAL AND WE

415
00:13:08,800 --> 00:13:09,720
THOUGHT THIS WOULD BE A GREAT

416
00:13:09,720 --> 00:13:11,120
WAY TO KIND OF THINK ABOUT THE

417
00:13:11,120 --> 00:13:13,600
GENES THAT WOULD SUPPORT ALL OF

418
00:13:13,600 --> 00:13:14,640
THESE DIFFERENT FEATURES OF HOW

419
00:13:14,640 --> 00:13:16,480
YOU CAN THINK ABOUT CELL TYPES

420
00:13:16,480 --> 00:13:18,720
AND ALSO GIVE US KIND OF A

421
00:13:18,720 --> 00:13:20,200
MASSIVE RESOURCE FOR THINKING

422
00:13:20,200 --> 00:13:21,600
ABOUT THE DIVERSITY, THE

423
00:13:21,600 --> 00:13:23,600
DIFFERENCE, THE KIND OF RAW

424
00:13:23,600 --> 00:13:24,560
MATERIAL OF NEURONAL DIVERSITY

425
00:13:24,560 --> 00:13:26,120
FOR INSTANCE THAT CHARACTERIZES

426
00:13:26,120 --> 00:13:27,320
EACH OF THE DIFFERENT CELL

427
00:13:27,320 --> 00:13:27,520
TYPES.

428
00:13:27,520 --> 00:13:29,200
HOWEVER WHEN YOU DO THIS ON

429
00:13:29,200 --> 00:13:30,200
ADULTS SPINAL CORD TISSUE, IT

430
00:13:30,200 --> 00:13:32,160
DOES NOT LIKE IT.

431
00:13:32,160 --> 00:13:34,080
AND THE REASON IS YOU BASICALLY

432
00:13:34,080 --> 00:13:37,520
TAKE THE TISSUE AND CHOP IT UP

433
00:13:37,520 --> 00:13:38,840
AND THIS IS INCREDIBLY

434
00:13:38,840 --> 00:13:40,920
DESTRUCTIVE, BOTH OF THESE ARE

435
00:13:40,920 --> 00:13:42,680
OFTEN VERY LARGE COMPLEX CELLS

436
00:13:42,680 --> 00:13:47,480
IN THE SPINAL CORD AND YOU'RE

437
00:13:47,480 --> 00:13:48,440
SHARING DIFFERENT BITS OFF OF

438
00:13:48,440 --> 00:13:49,280
THEM AND THAT'S SOMETHING THAT

439
00:13:49,280 --> 00:13:50,560
MAKES IT SO THAT THEY'RE

440
00:13:50,560 --> 00:13:52,200
STRESSED OR EVEN DIE AND AS A

441
00:13:52,200 --> 00:13:54,360
RESULT WE MAY NOT SEE THEM THEN

442
00:13:54,360 --> 00:13:55,640
IN OUR COMPUTATIONAL ANALYSIS

443
00:13:55,640 --> 00:13:57,360
BUT ALSO WE'RE TREATING THEM

444
00:13:57,360 --> 00:13:58,560
WITH ENZYMES THAT CLEAVE

445
00:13:58,560 --> 00:14:01,440
PROTEINS FOR LIKE AN HOUR AT

446
00:14:01,440 --> 00:14:02,680
37-DEGREES AND YOU'RE LITERALLY

447
00:14:02,680 --> 00:14:04,720
CHANGING THE SIGNALING AND THE

448
00:14:04,720 --> 00:14:06,240
CELL STATE ALL AT ONCE AND THEN

449
00:14:06,240 --> 00:14:08,720
ASKING WHAT IS THE RNA LOOK LOOK

450
00:14:08,720 --> 00:14:10,360
AND THAT SEEMED TO US LIKE IT

451
00:14:10,360 --> 00:14:14,040
WAS A NONSTARTER FOR STUDYING

452
00:14:14,040 --> 00:14:15,520
REAL ENDOGENOUS BIOLOGY, SO IN

453
00:14:15,520 --> 00:14:17,880
MY LAB WE WERE MONTHST THE FIRST

454
00:14:17,880 --> 00:14:19,280
TO TURN TO NUCLEI WHICH IS

455
00:14:19,280 --> 00:14:20,600
CURRENTLY LIKE A STANDARD

456
00:14:20,600 --> 00:14:23,520
APPROACH AND TO DEVELOP AND A

457
00:14:23,520 --> 00:14:25,520
PROTOCOL FOR MASSIVELY PARALLEL

458
00:14:25,520 --> 00:14:26,760
SINGLE NUCLEUS STUDIES, AND THE

459
00:14:26,760 --> 00:14:30,320
IDEA HERE IS THAT ONCE YOU SHARE

460
00:14:30,320 --> 00:14:32,360
THE TISSUE, AND ONLY HAVE NUCLEI

461
00:14:32,360 --> 00:14:33,960
THAT ARE NO LONGER ASSOCIATE

462
00:14:33,960 --> 00:14:36,040
WIDE THE WHOLE CELL BODY, THAT

463
00:14:36,040 --> 00:14:37,240
CELL MEMBRANE IS NO LONGER

464
00:14:37,240 --> 00:14:38,720
SIGNALING STRESS TO THE NUCLEUS,

465
00:14:38,720 --> 00:14:40,800
SO ACTUALLY IT'S KIND OF LIKE A

466
00:14:40,800 --> 00:14:41,640
HAPPY LITTLE NUCLEUS SITTING

467
00:14:41,640 --> 00:14:44,000
THERE, SINGING TO ITSELF, REALLY

468
00:14:44,000 --> 00:14:45,200
AWARE OF STRESS SIGNALS COMING

469
00:14:45,200 --> 00:14:46,800
IN BECAUSE IT HAS NO MEANS TO

470
00:14:46,800 --> 00:14:47,760
DETECT THEM.

471
00:14:47,760 --> 00:14:50,080
AND THEREFORE IT CAN STAY IN ITS

472
00:14:50,080 --> 00:14:51,280
ENDOGENOUS CONTEXT SO WHAT WE DO

473
00:14:51,280 --> 00:14:53,280
IS WE TAKE A COMPLEX PIECE OF

474
00:14:53,280 --> 00:14:57,600
TISSUE, WE DO A VERY RAPID LYSIS

475
00:14:57,600 --> 00:15:00,160
AND THEN WE HAVE COLD, CLEAN

476
00:15:00,160 --> 00:15:02,040
NUCLEI PREPARATION, WE THEN

477
00:15:02,040 --> 00:15:04,200
INCAPSULATE THESE CELL INTOS THE

478
00:15:04,200 --> 00:15:05,640
NUCLEI INTO DROPLETS OR USE

479
00:15:05,640 --> 00:15:10,160
ANOTHER MECHANISM AND PERFORM

480
00:15:10,160 --> 00:15:11,000
SEQUENCING AND ANALYSIS.

481
00:15:11,000 --> 00:15:12,920
SO THAT'S A PROTOCOL WE SHARE

482
00:15:12,920 --> 00:15:14,680
WIDELY IT'S USED BY MANY, MANY

483
00:15:14,680 --> 00:15:16,000
PEOPLE AND VARIANTS AND THEY'RE

484
00:15:16,000 --> 00:15:17,640
USED BY MANY, MANY PEOPLE AND

485
00:15:17,640 --> 00:15:20,240
ALLOWED US TO PERFORM THE FIRST

486
00:15:20,240 --> 00:15:21,640
SINGLE CELLAT LAS PINTAS TO

487
00:15:21,640 --> 00:15:24,240
CREATE THE FIRST SINGLE CELL

488
00:15:24,240 --> 00:15:25,640
ATLAS IN THE SPINAL CORD.

489
00:15:25,640 --> 00:15:26,880
SO WE DID IN THIS 2018 AND IT

490
00:15:26,880 --> 00:15:31,320
WAS WORK THAT WAS LED BY MURPHY

491
00:15:31,320 --> 00:15:33,920
IN MY LAB AND WE WERE FEELING

492
00:15:33,920 --> 00:15:34,840
PLEASED WITH OURSELVES, AND WE

493
00:15:34,840 --> 00:15:36,600
HAD A LOOK AT ALL THE CELL TYPES

494
00:15:36,600 --> 00:15:38,360
AND WE DID IN THIS THE ADULT AND

495
00:15:38,360 --> 00:15:48,800
PRETTY QUICKLY IN THE NEXT 2

496
00:15:52,240 --> 00:15:54,440
YEARS AFTER THAT CELLS AND

497
00:15:54,440 --> 00:15:55,240
NUCLEI, SORTING POPULATIONS

498
00:15:55,240 --> 00:15:56,040
VERSUS THE WHOLE TISSUE AND WE

499
00:15:56,040 --> 00:15:57,280
THOUGHT THIS IS GREAT.

500
00:15:57,280 --> 00:15:58,640
NOW A NUMBER OF LABS HAVE DONE

501
00:15:58,640 --> 00:16:01,680
THIS AND WE CAN USE THE FACT

502
00:16:01,680 --> 00:16:02,880
THAT IT'S BEEN DONE ALL OVER THE

503
00:16:02,880 --> 00:16:04,080
WORLD TO BRING THIS DATA

504
00:16:04,080 --> 00:16:06,840
TOGETHER AND ASK WHAT'S ROBUST,

505
00:16:06,840 --> 00:16:08,160
WHAT ARE THE REAL CELL TYPES OF

506
00:16:08,160 --> 00:16:09,720
THE SPINAL CORD AND WE WERE

507
00:16:09,720 --> 00:16:10,520
DISAPPOINTED TO SEE THAT

508
00:16:10,520 --> 00:16:12,760
ACTUALLY IT WAS A BIT OF A TOWER

509
00:16:12,760 --> 00:16:13,840
OF BABEL SITUATION, BASICALLY

510
00:16:13,840 --> 00:16:15,920
EACH OF THE STUDIES HAD

511
00:16:15,920 --> 00:16:16,840
COMPLETELY DIFFERENT CELL TYPES

512
00:16:16,840 --> 00:16:19,480
AND THIS WASN'T JUST A MATTER OF

513
00:16:19,480 --> 00:16:20,400
NOMENCLATURE, COMPUTATIONALLY IT

514
00:16:20,400 --> 00:16:21,120
WAS REALLY DIFFICULT TO LINE

515
00:16:21,120 --> 00:16:26,240
THEM UP WITH EACH OTHER.

516
00:16:26,240 --> 00:16:30,280
SO DANIEL RUSS AT NCI AND RYAN

517
00:16:30,280 --> 00:16:31,240
PATTERSON IN THE LAB

518
00:16:31,240 --> 00:16:33,240
COLLABORATED TO DO A

519
00:16:33,240 --> 00:16:33,920
COMPUTATIONAL ANALYSIS AND

520
00:16:33,920 --> 00:16:35,040
HARMONIZE AND BRING THESE

521
00:16:35,040 --> 00:16:36,200
RESOURCES TOGETHER AND WHAT THAT

522
00:16:36,200 --> 00:16:39,120
ALLOWED THEM TO DO WAS HAVE

523
00:16:39,120 --> 00:16:39,720
UNPRECEDENTED LEVEL OF

524
00:16:39,720 --> 00:16:40,800
RESOLUTION OF THE CELL TYPES OF

525
00:16:40,800 --> 00:16:42,960
THE SPINAL CORD AT LEAST IN

526
00:16:42,960 --> 00:16:44,360
MOUSE, AND THIS ALLOWED US TO

527
00:16:44,360 --> 00:16:46,800
SEE ALL DIFFERENT FLAVORS, SO WE

528
00:16:46,800 --> 00:16:48,880
WEREN'T JUST LOOKING AT ASTRO

529
00:16:48,880 --> 00:16:51,440
CITES ANYMORE BUT ALL FLAVORS OF

530
00:16:51,440 --> 00:16:52,800
ASTRO SIGHTS, WE WEREN'T JUST

531
00:16:52,800 --> 00:16:54,640
LOOKING AT VASCULAR CELLS BUT

532
00:16:54,640 --> 00:16:55,880
MULTIPLE FLAVORS OF VASCULAR

533
00:16:55,880 --> 00:16:57,440
CELLS AND I REALLY THINK THAT

534
00:16:57,440 --> 00:17:00,840
THE COMPLEXITY OF BIOLOGY

535
00:17:00,840 --> 00:17:01,840
RECITES AND UNDERSTANDING WHAT

536
00:17:01,840 --> 00:17:04,240
IS THE MOST REFINED LEVEL, AND

537
00:17:04,240 --> 00:17:05,760
THEN THE LEVEL AT WHICH WE NEED

538
00:17:05,760 --> 00:17:07,080
TO CARE ABOUT FUNCTION AND WE

539
00:17:07,080 --> 00:17:08,800
CAN REALLY ONLY MAKE THAT

540
00:17:08,800 --> 00:17:10,120
ASSESSMENT WHEN WE KNOW A LOT OF

541
00:17:10,120 --> 00:17:11,800
DETAIL AND WE CAN KIND OF THEN

542
00:17:11,800 --> 00:17:13,240
STEP BACK, WHEN WE NEED TO OR

543
00:17:13,240 --> 00:17:17,440
EMBRACE THE DETAIL WHEN WE NEED

544
00:17:17,440 --> 00:17:17,880
TO.

545
00:17:17,880 --> 00:17:24,760
SO FOR INSTANCE WE SAW

546
00:17:24,760 --> 00:17:25,760
OLIGOCELLS, DENDRITIC CELLROCYTE

547
00:17:25,760 --> 00:17:27,960
CELLS, YOU NAME IT AND WE DID A

548
00:17:27,960 --> 00:17:28,800
FOCUS ANALYSISOT NEURONS AND WE

549
00:17:28,800 --> 00:17:31,320
WERE ABLE TO SEPARATE THEM INTO

550
00:17:31,320 --> 00:17:33,640
APPROXIMATELY 70 CELL TYPES, AND

551
00:17:33,640 --> 00:17:35,240
SO, WHAT I WANT TO HIGHLIGHT

552
00:17:35,240 --> 00:17:36,600
HERE IS 2 THINGS.

553
00:17:36,600 --> 00:17:38,880
FIRST OF ALL, EACH DOT HERE

554
00:17:38,880 --> 00:17:42,280
REPRESENTS 1 CELL OR NUCLEUS,

555
00:17:42,280 --> 00:17:47,000
AND WE'RE REPRESENTING THEM IN A

556
00:17:47,000 --> 00:17:48,760
COMPUTATIONAL SPACE TO SHOW ALL

557
00:17:48,760 --> 00:17:50,280
THE VARIABILITY ATA A IN LECULAR

558
00:17:50,280 --> 00:17:51,840
LEVEL AND THE CELLS THAT HAVE

559
00:17:51,840 --> 00:17:52,880
SIMILAR PATTERNS THAT SHOW UP

560
00:17:52,880 --> 00:17:53,840
TOGETHER WILL BE CLOSE TOGETHER

561
00:17:53,840 --> 00:17:56,000
IN THAT SPACE AND CELLS THAT

562
00:17:56,000 --> 00:17:57,200
HAVE NOTHING REALLILY TO DO WITH

563
00:17:57,200 --> 00:17:59,200
EACH OTHER WILL BE FURTHER APART

564
00:17:59,200 --> 00:18:01,280
IN THAT SPACE AND SO, 1 THING

565
00:18:01,280 --> 00:18:04,320
THAT WE NOTICED VERY QUICKLY,

566
00:18:04,320 --> 00:18:06,680
WAS THAT EXCITATORY NEURONS HANG

567
00:18:06,680 --> 00:18:07,840
TOGETHER AND INHIBITORY NEURONS

568
00:18:07,840 --> 00:18:09,040
HANG TOGETHER AND THAT MAY NOT

569
00:18:09,040 --> 00:18:12,680
BE THE WORLD'S BIGGEST SURPRISE.

570
00:18:12,680 --> 00:18:14,320
BUT ACTUALLY THERE'S ANOTHER

571
00:18:14,320 --> 00:18:15,280
REALLY COOL THING HIDDEN HERE

572
00:18:15,280 --> 00:18:16,720
WHICH IS ALL OF THE CELLS THAT

573
00:18:16,720 --> 00:18:18,600
ARE ON THE OUTSIDE THAT ARE

574
00:18:18,600 --> 00:18:20,200
THESE DISCREET CLUSTERS ARE THE

575
00:18:20,200 --> 00:18:22,640
CELLS OF THE DORSAL HORN OF THE

576
00:18:22,640 --> 00:18:24,160
SPINAL CORD WHERE SENSORY

577
00:18:24,160 --> 00:18:26,040
PROCESSING IS A KEY FUNCTION.

578
00:18:26,040 --> 00:18:28,280
WHERE THE CELLS ARE INVOLVED IN

579
00:18:28,280 --> 00:18:30,160
MOTOR CONTROL ARE HERE,

580
00:18:30,160 --> 00:18:32,760
OVERLAPPING WITH EACH OTHER IN

581
00:18:32,760 --> 00:18:34,560
THESE CONTINUUM, AND SO BY

582
00:18:34,560 --> 00:18:36,600
HAVING THIS INCREDIBLY THOROUGH

583
00:18:36,600 --> 00:18:37,640
FRAMEWORK FOR LOOKINGA THE ALL

584
00:18:37,640 --> 00:18:38,880
OF THE DIFFERENT CELL TYPES, WE

585
00:18:38,880 --> 00:18:41,200
WERE ABLE TO SEE THIS GENERAL

586
00:18:41,200 --> 00:18:42,840
TREND OF HOW NOT JUST WHAT

587
00:18:42,840 --> 00:18:44,040
FUNCTION ARE YOU INVOLVED IN,

588
00:18:44,040 --> 00:18:46,000
ARE YOU SENSORY, ARE YOU MOTOR,

589
00:18:46,000 --> 00:18:47,640
BUT THAT THIS DISTINCTION EVEN

590
00:18:47,640 --> 00:18:49,240
COMES OUT IN YOUR MOLECULAR

591
00:18:49,240 --> 00:18:50,120
IDENTITY AS A CELL.

592
00:18:50,120 --> 00:18:52,800
HOW DIFFERENT ARE YOU FROM YOUR

593
00:18:52,800 --> 00:18:54,320
NEIGHBORS, ARE YOU DISCREET AND

594
00:18:54,320 --> 00:18:55,800
SPECIFIC OR DO YOU KIND OF HAVE

595
00:18:55,800 --> 00:18:57,960
LIKE A LITTLE BIT OF A MUSH,

596
00:18:57,960 --> 00:19:01,080
THERE'S OVERLAPPING AND SHARED

597
00:19:01,080 --> 00:19:01,520
RESPONSIBILITY TIME.

598
00:19:01,520 --> 00:19:02,880
SO WE THOUGHT THAT WAS SUPER

599
00:19:02,880 --> 00:19:03,800
INTERESTING AND THE OTHER THING

600
00:19:03,800 --> 00:19:05,400
THAT WE CAN SEE HERE WHICH I

601
00:19:05,400 --> 00:19:07,360
THINK SHOWS UP BETTER IF WE

602
00:19:07,360 --> 00:19:10,440
ROTATE THIS IN 3 DIMENSIONS, IS

603
00:19:10,440 --> 00:19:13,560
THAT SOME OF THESE LITTLE GROUPS

604
00:19:13,560 --> 00:19:16,080
ARE IN SLIGHTLY LARGER GROUPS,

605
00:19:16,080 --> 00:19:17,280
SO FOR INSTANCE THIS ORANGE

606
00:19:17,280 --> 00:19:18,240
GROUP HERE, WE CONSIDER THIS

607
00:19:18,240 --> 00:19:24,760
LIKE A FAMILY OF CELL TYPES.

608
00:19:24,760 --> 00:19:26,200
AND BY CONSIDERING THE 70

609
00:19:26,200 --> 00:19:27,320
REFINED POPULATIONS AND THESE

610
00:19:27,320 --> 00:19:28,600
LARGER FAMILIES, THERE ARE 2

611
00:19:28,600 --> 00:19:33,080
LEVELS WE CAN OPERATE AT FOR

612
00:19:33,080 --> 00:19:34,360
THINKING ABOUT DISEASE

613
00:19:34,360 --> 00:19:35,040
VULNERABILITY, ET CETERA.

614
00:19:35,040 --> 00:19:36,720
I WANT TO HIGHLIGHT 2 CELL TYPES

615
00:19:36,720 --> 00:19:38,760
HERE, 1 IS THE MOTOR NEURONS

616
00:19:38,760 --> 00:19:40,600
WHICH ARE LOCATED DOWN HERE, CAN

617
00:19:40,600 --> 00:19:42,640
YOU SEE THEY'RE VERY DIFFERENT

618
00:19:42,640 --> 00:19:44,160
FROM THE OTHER NEURONS OF THE

619
00:19:44,160 --> 00:19:46,280
SPINAL CORD WHICH WE ATTEMPT TO

620
00:19:46,280 --> 00:19:48,000
CALL INTERNEURONS AND ALSO

621
00:19:48,000 --> 00:19:50,760
THERE'S THIS VERY FUNKY

622
00:19:50,760 --> 00:19:51,480
INTERNEURONAL POPULATION THAT'S

623
00:19:51,480 --> 00:19:52,560
WAY UP HERE, OTHER THAN THAT THE

624
00:19:52,560 --> 00:19:55,480
REST OF THE NEURONS ARE

625
00:19:55,480 --> 00:19:56,120
DISTINGUISHABLE BUT RELATIVELY

626
00:19:56,120 --> 00:20:00,600
SIMILAR TO EACH OTHER.

627
00:20:00,600 --> 00:20:01,920
THOSE ARE DOTS ON A PAGE AND WE

628
00:20:01,920 --> 00:20:03,800
WANT TO MAKE SURE THAT THE CELL

629
00:20:03,800 --> 00:20:04,880
TYPES EXIST TRULY IN THE SPINAL

630
00:20:04,880 --> 00:20:06,160
CORD AND SO WHAT WE DID IS WE

631
00:20:06,160 --> 00:20:08,200
TOOK A LIST OF ALL OF THE MARKER

632
00:20:08,200 --> 00:20:10,280
GENES THAT WE DETECTED THAT WE

633
00:20:10,280 --> 00:20:11,800
PREDICT WOULD BE IN EACH CELL

634
00:20:11,800 --> 00:20:14,760
TYPE AND WE LOOKED FOR THEM BACK

635
00:20:14,760 --> 00:20:15,840
IN TISSUE.

636
00:20:15,840 --> 00:20:17,400
ANDEE WE ASKED DO THEY EXIST IN

637
00:20:17,400 --> 00:20:18,840
TISSUE, DO THEY EXIST IN THE

638
00:20:18,840 --> 00:20:20,800
PATTERNS WE EXPECTED AND

639
00:20:20,800 --> 00:20:23,840
PREDICTED, WHERE ARE THEY?

640
00:20:23,840 --> 00:20:26,000
SO AS I'VE BEEN HINTING AT A

641
00:20:26,000 --> 00:20:27,040
COURSE LEVEL ANATOMY DEFINES

642
00:20:27,040 --> 00:20:29,680
FUNCTION IN THE SPINAL CORD BUT

643
00:20:29,680 --> 00:20:30,800
AT REFINED LEVEL THAT'S THE

644
00:20:30,800 --> 00:20:31,040
CASE.

645
00:20:31,040 --> 00:20:32,560
SO DIFFERENT TYPES OF SENSORY

646
00:20:32,560 --> 00:20:33,520
NEURONS FOR INSTANCE FOR PAIN

647
00:20:33,520 --> 00:20:36,240
COME IN, AND THIS IS A VERY TOP

648
00:20:36,240 --> 00:20:36,640
LEVEL HERE.

649
00:20:36,640 --> 00:20:38,360
WHEREAS ONCE FOR DEEP TOUCH AND

650
00:20:38,360 --> 00:20:40,640
OTHER SENSORY MODALITIES ENTER

651
00:20:40,640 --> 00:20:42,440
MORE OVER HERE AND WE CAN REALLY

652
00:20:42,440 --> 00:20:43,640
SEE LIKE THE DIFFERENT CELL

653
00:20:43,640 --> 00:20:45,880
TYPES KIND OF LINING UP IN ORDER

654
00:20:45,880 --> 00:20:51,440
TO RECEIVE THOSE DIFFERENT KINDS

655
00:20:51,440 --> 00:20:51,760
OF SIGNALS.

656
00:20:51,760 --> 00:20:55,160
SO WE DID THIS FOR THE CELLS

657
00:20:55,160 --> 00:20:57,480
THEY ALL STRESS OX5 AND WE CAN

658
00:20:57,480 --> 00:20:58,680
DISTINGUISH WITHIN THE FACAS

659
00:20:58,680 --> 00:20:59,720
AMLY THE INDIVIDUAL MEMBERS SO

660
00:20:59,720 --> 00:21:02,200
WE SAY OKAY THERE ARE A LOT OF

661
00:21:02,200 --> 00:21:04,600
LEVINE'S IN THE WORLD AND A LOT

662
00:21:04,600 --> 00:21:06,320
OF ARIEL'S IN THE WORLD BUT

663
00:21:06,320 --> 00:21:10,520
THERE ARE REALLY VERY FEW ARIEL

664
00:21:10,520 --> 00:21:11,800
LEVINES BUT THIS COMBINATORIAL

665
00:21:11,800 --> 00:21:14,880
DEFINITION OF FAMILY MEASURERS

666
00:21:14,880 --> 00:21:16,760
WITHIN INDIVIDUAL MARKERS ALLOWS

667
00:21:16,760 --> 00:21:18,600
US TO BE PRETTY SPECIFIC ABOUT

668
00:21:18,600 --> 00:21:19,000
THESE CELL TYPES.

669
00:21:19,000 --> 00:21:23,280
WE ALSO WANT TO SEE HOW THESE

670
00:21:23,280 --> 00:21:24,560
RELATE TO DEVELOPMENT PARTLY

671
00:21:24,560 --> 00:21:25,680
BECAUSE UNDERSTANDING THESE

672
00:21:25,680 --> 00:21:26,440
RELATIONSHIPS WILL GIVE US

673
00:21:26,440 --> 00:21:28,240
ACCESS TO ALL OF THE GREATER

674
00:21:28,240 --> 00:21:31,080
DIVERSITY THAT YOU MIGHT SEE

675
00:21:31,080 --> 00:21:31,840
DURING DEVELOPMENT, BUT ALSO

676
00:21:31,840 --> 00:21:33,240
BECAUSE IN THE SPINAL CORD,

677
00:21:33,240 --> 00:21:36,000
PARTICULARLY IN THE VEBTERAL

678
00:21:36,000 --> 00:21:36,920
HORN EMBRYONIC LINEAGE, KIND OF

679
00:21:36,920 --> 00:21:38,520
WHERE YOU COME FROM IS A HUGE

680
00:21:38,520 --> 00:21:40,240
DECIDER OF HOW WE THINK ABOUT

681
00:21:40,240 --> 00:21:40,920
FUNCTION.

682
00:21:40,920 --> 00:21:42,240
OT RPGHT HAND,OT DORSAL HORN

683
00:21:42,240 --> 00:21:44,880
IT'S NOT AT ALL, KIND OF YOU

684
00:21:44,880 --> 00:21:47,320
KNOW ABOUT MORE WHAT JOB YOU GET

685
00:21:47,320 --> 00:21:49,360
DONE, HOW YOU FUNCTION AMONGST

686
00:21:49,360 --> 00:21:50,800
THE COMMUNITY OF OTHER CELL

687
00:21:50,800 --> 00:21:52,200
TYPES SOPHISTICATED WE REALLY

688
00:21:52,200 --> 00:21:54,000
WANTED TO PROVIDE THIS COMBINED

689
00:21:54,000 --> 00:21:55,000
RESOLUTION ABOUT WHERE CELLS

690
00:21:55,000 --> 00:21:57,440
COME FROM AND WHAT THEY BECOME.

691
00:21:57,440 --> 00:22:00,120
SO HERE I'M SHOWING THE KIND OF

692
00:22:00,120 --> 00:22:01,800
CONONICLE CELL TYPES IN THE

693
00:22:01,800 --> 00:22:03,040
EMBRYONIC SPINAL CORD AND HERE

694
00:22:03,040 --> 00:22:04,640
ARE ALL OF THE CELL TYPES WE

695
00:22:04,640 --> 00:22:06,080
DETECT IN THE ADULT, AND YOU

696
00:22:06,080 --> 00:22:07,280
DON'T REALLY NEED TO WORRY TOO

697
00:22:07,280 --> 00:22:08,840
MUCH ABOUT THE DETAILS, BUT 1

698
00:22:08,840 --> 00:22:11,360
THING I REALLY WANT TO EMPHASIZE

699
00:22:11,360 --> 00:22:13,240
IS MULTIPLE THINGS HAPPEN HERE.

700
00:22:13,240 --> 00:22:15,440
WE SEE EXAMPLES OF DIVERGENCE,

701
00:22:15,440 --> 00:22:17,160
WHERE 1 DOMAIN WILL GIVE RISE TO

702
00:22:17,160 --> 00:22:19,800
MANY DIFFERENT CELL TYPES, WE

703
00:22:19,800 --> 00:22:21,760
ALSO SEE EXAMPLES OF CONVERGENCE

704
00:22:21,760 --> 00:22:23,000
WHERE A CELL TYPE THAT WE CARE

705
00:22:23,000 --> 00:22:26,440
ABOUT IN THE ADULT CAN COME FROM

706
00:22:26,440 --> 00:22:30,120
MULTIPLE EMBRYONIC DOMAINS.

707
00:22:30,120 --> 00:22:31,520
AND SO, OBVIOUSLY LINEAGE ISN'T

708
00:22:31,520 --> 00:22:33,200
DESTINY AND THE SPINAL CORD

709
00:22:33,200 --> 00:22:34,680
SHOWS THAT BEAUTIFULLY BUT THAT

710
00:22:34,680 --> 00:22:36,480
IT'S DEFINITELY IMPORTANT TO BE

711
00:22:36,480 --> 00:22:37,760
KEEPING IN MIND, SO THE HISTORY

712
00:22:37,760 --> 00:22:39,280
OF THE CELL TELLS US SOMETHING

713
00:22:39,280 --> 00:22:40,840
ABOUT WHAT WE THINK IT WILL DO

714
00:22:40,840 --> 00:22:48,240
IN THE ADULT BUT NOT EVERYBODY.

715
00:22:48,240 --> 00:22:49,600
SO AGAIN YOU DON'T NEED TO WORRY

716
00:22:49,600 --> 00:22:50,680
ABOUT THE DETAILS IN THIS TABLE

717
00:22:50,680 --> 00:22:51,640
BUT WHAT I WANT TO SHARE WITH

718
00:22:51,640 --> 00:22:53,280
YOU IS THAT WE'VE DONE THIS FOR

719
00:22:53,280 --> 00:22:54,560
ALL THE DIFFERENT CELL TYPES

720
00:22:54,560 --> 00:22:56,920
THAT WE HAVE A SENSE OF WHERE

721
00:22:56,920 --> 00:22:59,240
THEY'RE LOCATED, THEIR

722
00:22:59,240 --> 00:22:59,840
PREVALENCE, THEIR

723
00:22:59,840 --> 00:23:01,160
NEUROTRANSMITTER, THEIR FAMILY,

724
00:23:01,160 --> 00:23:02,200
THEIR MARKERS, THEIR LINEAGE,

725
00:23:02,200 --> 00:23:04,280
AND THAT WE HOPE WE CAN USE THIS

726
00:23:04,280 --> 00:23:08,000
KIND OF AS THE SKELETON, THE

727
00:23:08,000 --> 00:23:08,920
BEGINNINGS OF BUILDING A

728
00:23:08,920 --> 00:23:10,120
PERIODIC TABLE OF THE CELL TYPES

729
00:23:10,120 --> 00:23:11,760
OF THE SPINAL CORD.

730
00:23:11,760 --> 00:23:15,680
NOW, AGAIN, JUST TO KIND OF GIVE

731
00:23:15,680 --> 00:23:17,080
A CONCRETE EXAMPLE, OF WHY IT

732
00:23:17,080 --> 00:23:18,080
MATTERS OF THE DIFFERENT CELL

733
00:23:18,080 --> 00:23:19,520
TYPES, I WANT TO HIGHLIGHT A

734
00:23:19,520 --> 00:23:20,680
COUPLE FACTORS THAT ARE OVER

735
00:23:20,680 --> 00:23:25,760
HERE, SO FOR INSTANCE, NTS,

736
00:23:25,760 --> 00:23:27,920
CCCRAT, GRP, THESE ARE

737
00:23:27,920 --> 00:23:28,760
NEUROPEPTIDES THAT NEURONS USE

738
00:23:28,760 --> 00:23:30,720
TO SIGNAL TO EACH OTHER AND SEND

739
00:23:30,720 --> 00:23:31,680
BROAD INFORMATION TO THEIR

740
00:23:31,680 --> 00:23:35,920
NEIGHBORS SO I THINK IT'S REALLY

741
00:23:35,920 --> 00:23:37,040
IMPORTANT TO THINK ABOUT IF WE

742
00:23:37,040 --> 00:23:38,200
HAVE A TREATMENT THAT WILL

743
00:23:38,200 --> 00:23:40,000
TARGET 1 OF THESE, WHICH CELL

744
00:23:40,000 --> 00:23:41,720
TYPE IS DRESSING THAT GENE.

745
00:23:41,720 --> 00:23:43,560
WILL WE BE TURNING OFF THE

746
00:23:43,560 --> 00:23:44,880
FUNCTION IN GENERAL IN HOW CAN

747
00:23:44,880 --> 00:23:46,600
WE THINK ABOUT HOW THESE

748
00:23:46,600 --> 00:23:47,480
DIFFERENT NEURONS USE THESE

749
00:23:47,480 --> 00:23:48,760
GENES TO GET THE JOB DONE?

750
00:23:48,760 --> 00:23:51,520
SO THE OTHER THING WE CAN DO IS

751
00:23:51,520 --> 00:24:00,840
TAKE A BROADER OVER VIEW.

752
00:24:00,840 --> 00:24:02,600
WE CAN LOOK AT THEM 1 BY 1 AND

753
00:24:02,600 --> 00:24:06,080
WHAT CAN WE TAKE FROM THESE

754
00:24:06,080 --> 00:24:06,440
EVALUATIONS?

755
00:24:06,440 --> 00:24:08,200
DORSAL OVER VENTRAL IS A KEY

756
00:24:08,200 --> 00:24:10,400
THING AND IF WE LOOK AT THE

757
00:24:10,400 --> 00:24:11,000
FAMILY RELATIONSHIPS BETWEEN

758
00:24:11,000 --> 00:24:12,000
THESE DIFFERENT CELL TYPES WE

759
00:24:12,000 --> 00:24:13,240
SEE THAT IMMEDIATELY THE BIGGEST

760
00:24:13,240 --> 00:24:16,880
DIFFERENCE IS REALLY LOCATION.

761
00:24:16,880 --> 00:24:22,720
AND THEN WITHIN THAT EXCITA TO

762
00:24:22,720 --> 00:24:23,440
USINGED TO SEGGRIIGATE AND

763
00:24:23,440 --> 00:24:24,080
DISTINGUISH BETWEEN DIFFERENT

764
00:24:24,080 --> 00:24:25,560
CELL TYPES SO WE THINK THAT'S

765
00:24:25,560 --> 00:24:29,440
KIND OF REALLY INTERESTING AND

766
00:24:29,440 --> 00:24:31,080
THEN WE ASKED WHAT'S DIFFERENT,

767
00:24:31,080 --> 00:24:32,720
WHAT MAKES THE DORSAL HORN SO

768
00:24:32,720 --> 00:24:33,920
DIFFERENT ON THE VENTRAL HORN

769
00:24:33,920 --> 00:24:35,560
AND THE ANSWER WAS SOMETHING

770
00:24:35,560 --> 00:24:36,600
COMPLETELY UNEXPECTED TO US AT

771
00:24:36,600 --> 00:24:38,480
LEAST AND WHAT WE FOUND IS THAT

772
00:24:38,480 --> 00:24:42,280
THE GENES THAT CHARACTERIZE THE

773
00:24:42,280 --> 00:24:44,640
DORSAL HORN ALLOW CHANGE.

774
00:24:44,640 --> 00:24:46,200
SO THEY'RE IN GENERAL GENES THAT

775
00:24:46,200 --> 00:24:48,440
ARE ASSOCIATED WITH LONG-TERM

776
00:24:48,440 --> 00:24:50,040
POTENTIATION, WITH MEMORY, WITH

777
00:24:50,040 --> 00:24:51,320
LEARNING, WHEREAS THE GENES THAT

778
00:24:51,320 --> 00:24:53,280
ARE IN THE VENTRAL HORN ARE

779
00:24:53,280 --> 00:24:55,760
ASSOCIATED WITH 2 CELLS ADHERING

780
00:24:55,760 --> 00:24:59,040
TOGETHER AND MAKING A STRONG

781
00:24:59,040 --> 00:25:00,440
CONNECTION TO GENES THAT CREATE

782
00:25:00,440 --> 00:25:02,000
A NETWORK AROUND THE CELLS THAT

783
00:25:02,000 --> 00:25:03,840
PREVENTS THISEM FROM CHANGING

784
00:25:03,840 --> 00:25:05,200
AND WE THOUGHT, HOW INTERESTING

785
00:25:05,200 --> 00:25:06,760
IS IT THAT THE SENSORY 1S ARE

786
00:25:06,760 --> 00:25:09,560
SOMETHING YOU CAN KIND OF

787
00:25:09,560 --> 00:25:11,280
FLEXIBLY POTENTIALLY YOU KNOW

788
00:25:11,280 --> 00:25:12,720
RELEARN AND REWRITE WHERE THE

789
00:25:12,720 --> 00:25:14,680
VENTRAL 1S ARE LOCKED IN AND OF

790
00:25:14,680 --> 00:25:16,320
COURSE THIS IS AN ABSOLUTE BUT

791
00:25:16,320 --> 00:25:18,280
THIS GENERAL TREND WAS VERY

792
00:25:18,280 --> 00:25:18,760
INTERESTING TO US.

793
00:25:18,760 --> 00:25:21,960
AND I WILL JUST SHOW 1 EXAMPLE

794
00:25:21,960 --> 00:25:24,680
HERE SO THIS IS JUST KIND OF A

795
00:25:24,680 --> 00:25:26,560
HINT OF HOW GENE EXPRESSION FOR

796
00:25:26,560 --> 00:25:29,680
FUNCTIONAL PROPERTIES CAN BE

797
00:25:29,680 --> 00:25:32,680
HIGHLY SPECIFIC, KM2A IS A CORE

798
00:25:32,680 --> 00:25:33,600
LONG-TERM POTENTIATION FACTOR IS

799
00:25:33,600 --> 00:25:34,800
IT'S EXPRESS INDEED DORSAL CELL

800
00:25:34,800 --> 00:25:37,000
TYPES WHICH ARE FROM HERE TO

801
00:25:37,000 --> 00:25:37,240
HERE.

802
00:25:37,240 --> 00:25:38,680
AND INDEED IF WE LOOK AT THE

803
00:25:38,680 --> 00:25:40,120
PROTEIN FOR THIS GENE IN THE

804
00:25:40,120 --> 00:25:44,360
SPINAL CORD, IT HAS A REALLY

805
00:25:44,360 --> 00:25:45,600
SPECIFIC SPATIAL LOCALIZATION TO

806
00:25:45,600 --> 00:25:46,360
THE DORSAL HORN.

807
00:25:46,360 --> 00:25:55,600
CONVERSELY IF WE LOOK AT THE

808
00:25:55,600 --> 00:25:56,560
GENE FOR [INDISCERNIBLE] WE CAN

809
00:25:56,560 --> 00:25:58,120
SAY THIS IS STRONGLY ENRICHED IN

810
00:25:58,120 --> 00:26:00,240
THE VENTRAL HORN AND THIS GENE

811
00:26:00,240 --> 00:26:02,000
IS COMPONENT OF THE

812
00:26:02,000 --> 00:26:03,480
PERINEURONNAL NETS THAT CAN

813
00:26:03,480 --> 00:26:05,360
SURROUND NEURONS AND IT LOOKS

814
00:26:05,360 --> 00:26:07,120
DOWN THEIR PHYSICAL STRUCTURAL

815
00:26:07,120 --> 00:26:07,520
ABILITY TO CHANGE.

816
00:26:07,520 --> 00:26:11,200
AND SO WE KIND OF HAVE THIS

817
00:26:11,200 --> 00:26:12,960
LIKE, POINT CAUNTER POINT THAT

818
00:26:12,960 --> 00:26:16,280
WE REALLY COULD COME TO FROM AN

819
00:26:16,280 --> 00:26:17,560
UNBIASED LOOK FROM GENE

820
00:26:17,560 --> 00:26:17,840
EXPRESSION.

821
00:26:17,840 --> 00:26:20,960
AND THIS PROVIDES A LOT OF

822
00:26:20,960 --> 00:26:22,640
POTENTIAL FOR HYPOTHESIS

823
00:26:22,640 --> 00:26:23,600
GENERATION ABOUT HOW CHRONIC

824
00:26:23,600 --> 00:26:24,560
PAIN WHICH GENERALLY IS THOUGHT

825
00:26:24,560 --> 00:26:28,240
TO BE A DISEASE OF THE SENSORY

826
00:26:28,240 --> 00:26:29,280
SYSTEMS AND PLASTICITY THAT

827
00:26:29,280 --> 00:26:31,520
OCCURS IN THE SPINAL CORD.

828
00:26:31,520 --> 00:26:34,840
SEEMS TO BE PRIMED, WHEREAS THE

829
00:26:34,840 --> 00:26:36,000
MOTOR SYSTEM IS A LITTLE LOCK

830
00:26:36,000 --> 00:26:37,640
DOWN WHICH OF COURSE IN THE

831
00:26:37,640 --> 00:26:38,600
CONTEXT OF SPINAL CORD INJURY IS

832
00:26:38,600 --> 00:26:39,680
NOT WHAT WE WANT.

833
00:26:39,680 --> 00:26:42,440
NOW THAT WE KNOW THE TARGETS

834
00:26:42,440 --> 00:26:53,000
MAYBE WE CAN DO SOMETHING ABOUT

835
00:26:54,000 --> 00:26:54,200
THAT.

836
00:26:54,200 --> 00:26:56,360
WE ARE INTERESTED IN RELEASING

837
00:26:56,360 --> 00:26:58,160
THESE TOOLS OUT INTO THE

838
00:26:58,160 --> 00:27:00,120
COMMUNITY WE WE COLLABORATED TO

839
00:27:00,120 --> 00:27:00,720
CREATE A CLASSIFIER.

840
00:27:00,720 --> 00:27:01,920
SO ANYONE CAN COME ALONG WITH

841
00:27:01,920 --> 00:27:04,280
THE NEXT SET OF DATA AND USE

842
00:27:04,280 --> 00:27:07,680
LABEL TRANSFER AND NEURAL

843
00:27:07,680 --> 00:27:09,040
NETWORK AND WE TESTED ALL

844
00:27:09,040 --> 00:27:09,720
DIFFERENT POSSIBILITIES TO DO

845
00:27:09,720 --> 00:27:11,400
THIS AND THAT SEEMS TO BE THE

846
00:27:11,400 --> 00:27:16,480
BEST 1 FOR ALLOWING US TO BUILD

847
00:27:16,480 --> 00:27:18,320
A CLASSIFIER SO THAT ALL OF THE

848
00:27:18,320 --> 00:27:22,120
NEXT DATA WE HAVE CAN BE EASILY

849
00:27:22,120 --> 00:27:24,040
CLASSIFIED AND MADE THIS ALL

850
00:27:24,040 --> 00:27:25,000
PUBLICLY AVAILABLE WITH THIS

851
00:27:25,000 --> 00:27:30,840
RESOURCE THAT WAS BUILT BY AMARI

852
00:27:30,840 --> 00:27:31,760
[INDISCERNIBLE] AT NINDS AND

853
00:27:31,760 --> 00:27:33,920
IT'S USED BY HUNDREDS OF UNIQUE

854
00:27:33,920 --> 00:27:34,920
USERS EVERY MONTH, I ENCOURAGE

855
00:27:34,920 --> 00:27:39,080
TO YOU HAVE FUN WITH IT YOURSELF

856
00:27:39,080 --> 00:27:40,480
AND BASICALLY LIKE ALL OF THIS

857
00:27:40,480 --> 00:27:41,480
DATA OUT THERE, WE WANT TO THE

858
00:27:41,480 --> 00:27:46,320
FIELD TO BE ABLE TO USE IT, 1

859
00:27:46,320 --> 00:27:48,800
REASON IS WE WANT TO BE

860
00:27:48,800 --> 00:27:50,280
FOUNDATIONAL RESOURCE FOR PEOPLE

861
00:27:50,280 --> 00:27:53,480
STUDYING DISEASE AND SPINAL CORD

862
00:27:53,480 --> 00:27:55,600
INJURY.

863
00:27:55,600 --> 00:27:57,280
THIS IS ALL WILL THIS BE HELPFUL

864
00:27:57,280 --> 00:27:58,600
TO HUMAN PATIENTS AND I WANT TO

865
00:27:58,600 --> 00:28:00,000
PIVOT HERE AND TELL YOU ABOUT

866
00:28:00,000 --> 00:28:01,200
WHAT WE'RE LEARNING IN THE

867
00:28:01,200 --> 00:28:03,520
SPINAL CORD OR AT LEAST 1 FOCUS

868
00:28:03,520 --> 00:28:07,440
STORY ABOUT IT, ABOUT HUMAN

869
00:28:07,440 --> 00:28:09,000
BIOLOGY, SO I WANT TO START BY

870
00:28:09,000 --> 00:28:10,040
ACKNOWLEDGING THE PEOPLE WHO

871
00:28:10,040 --> 00:28:11,480
HAVE DONE THIS BECAUSE I THINK I

872
00:28:11,480 --> 00:28:13,320
WAS A LITTLE NAIVE ABOUT WHRA IT

873
00:28:13,320 --> 00:28:15,200
SEEKS TO DO WORK IN THE CLINICAL

874
00:28:15,200 --> 00:28:17,280
REALM AND THIS IS LIKE THE TIP

875
00:28:17,280 --> 00:28:19,080
OF THE ICEBERG OF TEAMS THAT ARE

876
00:28:19,080 --> 00:28:21,840
INVOLVED HERE AND SO, LIKE, MY

877
00:28:21,840 --> 00:28:24,160
GRATITUDE TO THEM, MY GRADDITUDE

878
00:28:24,160 --> 00:28:26,000
TO THE DONORS, THE TISSUE DONORS

879
00:28:26,000 --> 00:28:28,280
AND LIKE IT HAS REALLY BEEN

880
00:28:28,280 --> 00:28:30,040
QUITE AN ADVENTURE AND AN

881
00:28:30,040 --> 00:28:32,360
AMAZING TEAM COLLABORATION.

882
00:28:32,360 --> 00:28:33,600
SO, BASICALLY THIS WORK WAS DONE

883
00:28:33,600 --> 00:28:37,200
BY MY GROUP AT NIH, LED BY

884
00:28:37,200 --> 00:28:39,560
[INDISCERNIBLE], OUR VERY CLOSE

885
00:28:39,560 --> 00:28:40,920
COLLABORATORS AT COLUMBIA,

886
00:28:40,920 --> 00:28:42,680
[INDISCERNIBLE], WHERE DATA

887
00:28:42,680 --> 00:28:45,680
SCIENTISTS AND THEN 2 TEAMS OF

888
00:28:45,680 --> 00:28:46,960
NEUROSURGEONS AND BASIC

889
00:28:46,960 --> 00:28:49,480
RESEARCHERS AT THE UNIVERSITY OF

890
00:28:49,480 --> 00:28:53,320
OTTOWA, AND AT CNRS WHO

891
00:28:53,320 --> 00:28:54,040
BASICALLY HELPED US GET THE

892
00:28:54,040 --> 00:28:55,680
TISSUE AND I JUST WANT TO TAKE A

893
00:28:55,680 --> 00:28:58,120
SECOND HERE TO ALSO MENTION WHAT

894
00:28:58,120 --> 00:29:03,360
NEEDS TO BE DONE IN ORDER TO GET

895
00:29:03,360 --> 00:29:04,160
TO TISSUE WORKS.

896
00:29:04,160 --> 00:29:05,480
WHEN SPINAL CORD TISSUE STARTS

897
00:29:05,480 --> 00:29:09,640
TO DIE THE FIRST THING TO GOER

898
00:29:09,640 --> 00:29:10,840
MOTTO NEURONS, THEY'RE

899
00:29:10,840 --> 00:29:11,640
INCREDIBLY VULNERABLE, NOT JUST

900
00:29:11,640 --> 00:29:13,640
IN DISEASE BUT IN A TECHNICAL

901
00:29:13,640 --> 00:29:14,640
EXPERIMENTAL WAY AND THE SECOND

902
00:29:14,640 --> 00:29:16,720
THING THAT GOES IS THE ENTIRE

903
00:29:16,720 --> 00:29:18,400
VENTRAL HORN AND THE THIRD THING

904
00:29:18,400 --> 00:29:19,920
THAT GOES, IS NEURONS WE DON'T

905
00:29:19,920 --> 00:29:21,000
KNOW THEIR IDENTITY YET.

906
00:29:21,000 --> 00:29:23,000
SO IT WAS REALLY CRUCIAL TO US

907
00:29:23,000 --> 00:29:24,920
TO HAVE LITERALLY THE BEST

908
00:29:24,920 --> 00:29:25,920
POSSIBLE TISSUE, BECAUSE IF WE

909
00:29:25,920 --> 00:29:29,240
DO THIS A FEW TIMES NOW, WE CAN

910
00:29:29,240 --> 00:29:30,680
LAY THE FOUNDATION FOR MANY

911
00:29:30,680 --> 00:29:31,880
OTHER PEOPLE TO COME LATER AND

912
00:29:31,880 --> 00:29:34,080
USE THIS DATA AND WE TRIED

913
00:29:34,080 --> 00:29:35,160
TISSUE BANKS AND WE TRY

914
00:29:35,160 --> 00:29:36,280
DIFFERENT KINDS OF COLLABORATORS

915
00:29:36,280 --> 00:29:38,640
AND IN THE END WHAT WE REALLY

916
00:29:38,640 --> 00:29:40,920
FOUND IS THAT THE NEUROSURGEONS

917
00:29:40,920 --> 00:29:42,400
WHO COLLABORATE WITH ORGAN DONOR

918
00:29:42,400 --> 00:29:45,240
TEAM WHO IS GO IN VERY SHORTLY

919
00:29:45,240 --> 00:29:47,760
AFTER CLAMP, CAN EXTRACT FOR US,

920
00:29:47,760 --> 00:29:49,720
JUST ABSOLUTELY THE BEST TISSUE

921
00:29:49,720 --> 00:29:51,040
AND IT WAS REALLY CRITICAL IN

922
00:29:51,040 --> 00:29:52,800
BEING ABLE TO KIND OF--TO FEEL

923
00:29:52,800 --> 00:29:54,920
WE HAD AN UNBIASED LOOK AT THE

924
00:29:54,920 --> 00:29:57,040
CELL TYPES AS CLOSE AS POSSIBLE

925
00:29:57,040 --> 00:29:58,240
TO THE ENDOGENOUS STATE.

926
00:29:58,240 --> 00:30:00,520
SO, WE STARTED OUR STUDY WITH 7

927
00:30:00,520 --> 00:30:02,160
PATIENTS, WE NOW HAVE DIFFERENT

928
00:30:02,160 --> 00:30:06,240
TYPES OF DATA FROM MANY MORE,

929
00:30:06,240 --> 00:30:09,280
THEY WERE GENERALLY 50/80 YEARS

930
00:30:09,280 --> 00:30:10,600
OLD, I THINK 5 OR 6 OF THEM ARE

931
00:30:10,600 --> 00:30:13,440
STROKE AND THEN WE HAVE A

932
00:30:13,440 --> 00:30:14,480
MOTORCYCLE ACCIDENT BUT FOR THE

933
00:30:14,480 --> 00:30:15,840
MOST PART THESE ARE OLDER

934
00:30:15,840 --> 00:30:17,640
PATIENTS, HOWEVER, WE WERE ABLE

935
00:30:17,640 --> 00:30:19,880
TO GET INCREDIBLY HIGH QUALITY

936
00:30:19,880 --> 00:30:20,160
DATA.

937
00:30:20,160 --> 00:30:22,480
SO WE THEN PERFORMED SINGLE CELL

938
00:30:22,480 --> 00:30:23,880
SEQUENCING ON LUMBAR SPINAL CORD

939
00:30:23,880 --> 00:30:26,000
FROM EACH OF THESE DONORS, AND

940
00:30:26,000 --> 00:30:28,880
YOU CAN SEE KIND OF THE PLOTS OF

941
00:30:28,880 --> 00:30:30,840
THE DIFFERENT NUCLEI THAT I'M

942
00:30:30,840 --> 00:30:32,720
SHOWING HERE AND THE NUMBER OF

943
00:30:32,720 --> 00:30:34,440
NUCLEI THAT WE WERE ABLE EXTRACT

944
00:30:34,440 --> 00:30:35,720
THAT ARE HIGH QUALITY FROM EACH

945
00:30:35,720 --> 00:30:36,000
PATIENT.

946
00:30:36,000 --> 00:30:40,000
SO THIS IS A VERY LARGE DATA

947
00:30:40,000 --> 00:30:40,320
SET.

948
00:30:40,320 --> 00:30:41,440
WE CAN SUBDIVIDE THESE INTO THE

949
00:30:41,440 --> 00:30:44,200
CELL TYPES YOU MIGHT EXPECT, SO,

950
00:30:44,200 --> 00:30:45,960
WE REALLY DON'T KNOW TO WHAT

951
00:30:45,960 --> 00:30:47,360
EXTENT THIS IS GOING TO BE

952
00:30:47,360 --> 00:30:48,880
SOMEWHAT BI ASSED BY THE AGE OF

953
00:30:48,880 --> 00:30:50,840
OUR PATIENTS BUT SOME THINGS

954
00:30:50,840 --> 00:30:53,560
THAT WE NOTED ARE THERE'S A

955
00:30:53,560 --> 00:30:54,880
MASSIVE EXPANSION OFLET PERCENT,

956
00:30:54,880 --> 00:30:56,920
THE PROPORTION OF THE THE

957
00:30:56,920 --> 00:30:57,560
DENDRITIC CELLROCYTES COMPARED

958
00:30:57,560 --> 00:30:59,600
TO MOUSE, I AM SPECULATING

959
00:30:59,600 --> 00:31:00,640
WILDLY HERE BUT WE THINK THIS

960
00:31:00,640 --> 00:31:01,800
MIGHT BE KIND OF THE CORRELATE

961
00:31:01,800 --> 00:31:04,360
OF THE FACT THAT THERE'S AN

962
00:31:04,360 --> 00:31:06,680
EXPANSION OF THE WHITE MATTER OF

963
00:31:06,680 --> 00:31:07,840
THE LONGITUDINAL TRACKS IN THE

964
00:31:07,840 --> 00:31:09,320
HUMAN SPINAL CORD AND THAT THIS

965
00:31:09,320 --> 00:31:10,720
IS PROBABLY BECAUSE THE BRAIN

966
00:31:10,720 --> 00:31:12,760
AND SPINAL CORD IN HUMAN ARE

967
00:31:12,760 --> 00:31:14,160
EVEN MORE INTERCONNECTED AND OF

968
00:31:14,160 --> 00:31:15,760
COURSE, THERE'S JUST LARGER

969
00:31:15,760 --> 00:31:17,520
AMOUNT OF TISSUE IN HUMAN

970
00:31:17,520 --> 00:31:18,800
COMPARED TO MOUSE.

971
00:31:18,800 --> 00:31:21,040
WE ALSO SEE PROLIFERATING

972
00:31:21,040 --> 00:31:21,760
MICROGLUE MARIOUSA POPULATION

973
00:31:21,760 --> 00:31:23,040
WHICH IS INTERESTING, WE DID NOT

974
00:31:23,040 --> 00:31:25,440
SEE THAT IN MOUSE.

975
00:31:25,440 --> 00:31:26,920
AND OTHER POPULATIONS THAT ARE

976
00:31:26,920 --> 00:31:27,880
ACTUALLY QUITE SIMILAR TO WHAT

977
00:31:27,880 --> 00:31:30,440
WE'VE SEEN BEFORE AND YOU CAN

978
00:31:30,440 --> 00:31:32,000
HERE THAT PROPORTIONS ACROSS THE

979
00:31:32,000 --> 00:31:33,280
DIFFERENT SAMPLES LINE UP QUIELT

980
00:31:33,280 --> 00:31:35,760
NICELY AND THESE ARE VERY

981
00:31:35,760 --> 00:31:36,840
REPRODUCIBLE DATA.

982
00:31:36,840 --> 00:31:39,960
WE'VE ALSO MORE RECENTLY

983
00:31:39,960 --> 00:31:41,560
COLLABORATED WITH A GROUP AT

984
00:31:41,560 --> 00:31:43,880
NEW YORK HUMAN GENOME CENTER TO

985
00:31:43,880 --> 00:31:45,320
ADD A SPATIAL TRANSCRIPT OHMICS

986
00:31:45,320 --> 00:31:47,320
PIECE TO OUR STORY AND SO THIS

987
00:31:47,320 --> 00:31:49,600
IS NOW PERFORMING SEQUENCING ON

988
00:31:49,600 --> 00:31:52,360
SPINAL CORD TISSUE, WHERE WE

989
00:31:52,360 --> 00:31:53,880
KNOW EXACTLY WHERE EACH DOT IS

990
00:31:53,880 --> 00:31:56,880
AND WHAT RNA WAS IN THAT DOT AND

991
00:31:56,880 --> 00:31:58,880
WHEN WE LOOK AT FOR INSTANCE A

992
00:31:58,880 --> 00:32:02,720
MARKER OF THE MENING ES, WHERE

993
00:32:02,720 --> 00:32:03,320
WE WOULD EXPECT.

994
00:32:03,320 --> 00:32:08,000
HERE'S MIDLINE STRUCTURE THAT

995
00:32:08,000 --> 00:32:09,760
ALL DIFFERENT MENING ALL

996
00:32:09,760 --> 00:32:10,920
POPULATIONS, THEY'RE HERE IN THE

997
00:32:10,920 --> 00:32:13,240
CENTER WHERE WE EXPECT.

998
00:32:13,240 --> 00:32:13,920
ONE POPULATION OFASTROCYTES

999
00:32:13,920 --> 00:32:16,160
SEEMS TO BE IN THE WHITE MATTER

1000
00:32:16,160 --> 00:32:19,600
WHERE 2 OTHERS ARE IN THE GRAY

1001
00:32:19,600 --> 00:32:27,960
MATTER.

1002
00:32:27,960 --> 00:32:28,560
THAT'S INTERESTING.

1003
00:32:28,560 --> 00:32:30,560
SO ALL OF THIS LINES UP WITH

1004
00:32:30,560 --> 00:32:31,800
WHAT WE EXPECT CONFIRMING AGAIN

1005
00:32:31,800 --> 00:32:39,480
THIS IS A REALLY GOOD DATA SET.

1006
00:32:39,480 --> 00:32:41,160
WE CAN FIND MARKERS SO THIS

1007
00:32:41,160 --> 00:32:42,480
ALLOWS US TO SAY THERE ARE

1008
00:32:42,480 --> 00:32:43,160
PARTICULAR MARKERS THAT WOULD

1009
00:32:43,160 --> 00:32:45,160
SCR TO DO WITH PAIN OR SEX

1010
00:32:45,160 --> 00:32:46,880
DIFFERENCES IN HOW PAIN S&P

1011
00:32:46,880 --> 00:32:50,800
FORMED IN MICROGLUE MARIOUSA OR

1012
00:32:50,800 --> 00:32:52,240
IN ASTROCYTES SO THIS SETS THE

1013
00:32:52,240 --> 00:32:53,560
STAGE AS A RESOURCE THAT CAN BE

1014
00:32:53,560 --> 00:32:55,760
USE INDEED A LOT OF DIFFERENT

1015
00:32:55,760 --> 00:32:55,960
CONTEXT.

1016
00:32:55,960 --> 00:32:57,280
OVERALL THOUGH, WE FOUND, YOU

1017
00:32:57,280 --> 00:32:58,920
KNOW MOST OF THESE CELL TYPES

1018
00:32:58,920 --> 00:33:00,480
LOOK A LOOK LIKE WHAT WE WOULD

1019
00:33:00,480 --> 00:33:02,920
EXPECT BASED ON MOUSE, SO THIS

1020
00:33:02,920 --> 00:33:05,240
IS AN ALIGNMENT WHERE WE'RE

1021
00:33:05,240 --> 00:33:06,320
COMPARING THE HUMAN CELL TYPES

1022
00:33:06,320 --> 00:33:08,200
HERE AND THE MOUSE CELL TYPES

1023
00:33:08,200 --> 00:33:09,520
WE'VE SEEN BEFORE, AND YELLOW

1024
00:33:09,520 --> 00:33:11,360
SHOWS THERE'S A STRONG

1025
00:33:11,360 --> 00:33:12,280
CORRELATION BETWEEN THESE CELL

1026
00:33:12,280 --> 00:33:14,600
TYPES, CAN YOU SEE FOR INSTANCE

1027
00:33:14,600 --> 00:33:16,480
ALL OF THESE OLIGIO DENDRITIC

1028
00:33:16,480 --> 00:33:17,120
CELLROCYTES ARE CENTRAL TO EACH

1029
00:33:17,120 --> 00:33:18,960
OTHER AND HERE ARE THE

1030
00:33:18,960 --> 00:33:20,600
PRECURSORS, SO THEY KIND OF LIKE

1031
00:33:20,600 --> 00:33:26,960
LINE UP IN THESE NICE LITTLE

1032
00:33:26,960 --> 00:33:27,440
BLOCKS.

1033
00:33:27,440 --> 00:33:29,840
OKAY, WE THEN FOCUSED IN ON THE

1034
00:33:29,840 --> 00:33:31,280
NEURONAL SUBTYPES OF THE HUMAN

1035
00:33:31,280 --> 00:33:34,000
SPINAL CORD AND WE NAMED EACH OF

1036
00:33:34,000 --> 00:33:35,120
THEM BY THEIR NEUROTRANSMITTER

1037
00:33:35,120 --> 00:33:38,000
STATUS SO ARE THEY EXCITATORY OR

1038
00:33:38,000 --> 00:33:40,080
INHIBITOR EXPE ARE THEY DORSAL

1039
00:33:40,080 --> 00:33:41,040
OR MIDVENTRAL SENSE WE KNEW

1040
00:33:41,040 --> 00:33:43,440
ALREADY FROM OUR MOUSE WORK THAT

1041
00:33:43,440 --> 00:33:44,680
LOCATION WAS GOING TO BE A BIG

1042
00:33:44,680 --> 00:33:47,640
PIECE OF THE PUZZLE OF TRYING TO

1043
00:33:47,640 --> 00:33:48,880
ADVANCE CELL TYPE FUNCTION.

1044
00:33:48,880 --> 00:33:51,400
IN GENERAL, THE DORSAL CLUSTERS

1045
00:33:51,400 --> 00:33:53,720
WHICH ARE LISTED HERE, WHICH ARE

1046
00:33:53,720 --> 00:33:56,760
KIND OF FIRST, SO THEY'RE IN

1047
00:33:56,760 --> 00:33:59,680
THIS AREA, ARE MORE ROBUST,

1048
00:33:59,680 --> 00:34:00,640
THEY'RE EASIER TO DISTINGUISH

1049
00:34:00,640 --> 00:34:02,360
FROM EACH OTHER AND THE VENTRAL

1050
00:34:02,360 --> 00:34:03,880
1S ARE SLIGHTLY LESS, BECAUSE

1051
00:34:03,880 --> 00:34:06,000
AGAIN, THEY SEEM TO OVERLAP WITH

1052
00:34:06,000 --> 00:34:06,600
EACH OTHER, CONFIRM THAGOREAN

1053
00:34:06,600 --> 00:34:10,880
TREND THAT WE SAW IN THE MOUSE.

1054
00:34:10,880 --> 00:34:13,480
WE ALSO HAVE BEEN ABLE TO USE

1055
00:34:13,480 --> 00:34:14,240
FACIAL TRANSCRIPT ORDER OF

1056
00:34:14,240 --> 00:34:16,000
MICRONSICS TO LOOK AT THE

1057
00:34:16,000 --> 00:34:18,160
MARKERS OF THESE DIFFERENT CELL

1058
00:34:18,160 --> 00:34:19,480
TYPES AND CONFIRM THEM IN

1059
00:34:19,480 --> 00:34:21,280
TISSUE, SO FOR INSTANCE MOTOR

1060
00:34:21,280 --> 00:34:25,600
NEURONS ARE LOCATED DOWN HERE,

1061
00:34:25,600 --> 00:34:27,720
IN LAMINA 9 IN THE INTERIOR HORN

1062
00:34:27,720 --> 00:34:29,680
AND DIFFERENT MARKERS FOR

1063
00:34:29,680 --> 00:34:30,600
DIFFERENT DORSAL POPULATION SAYS

1064
00:34:30,600 --> 00:34:32,360
FOR INSTANCE, YOU CAN SEE IN THE

1065
00:34:32,360 --> 00:34:34,400
DORSAL HORNS OF THE SPINAL CORD,

1066
00:34:34,400 --> 00:34:37,280
SOME OF THEM ARE MET MIDDEEP

1067
00:34:37,280 --> 00:34:39,200
LEGION AND SOME OF THEM ARE UP

1068
00:34:39,200 --> 00:34:41,680
AT THE DORSAL PART OF THE SPINAL

1069
00:34:41,680 --> 00:34:43,560
CORD, AGAIN, GIVING US THIS IDEA

1070
00:34:43,560 --> 00:34:46,240
THAT DIFFERENT CELL TYPES ACROSS

1071
00:34:46,240 --> 00:34:49,040
THE ACCESS OF THE SPINAL CORD IN

1072
00:34:49,040 --> 00:34:51,040
A REALLY RELIABLE WAY.

1073
00:34:51,040 --> 00:34:53,000
AGAIN, WE COMPARED THESE 2, WHAT

1074
00:34:53,000 --> 00:34:55,880
WE KNEW ALREADY IN MOUSE, AND

1075
00:34:55,880 --> 00:34:57,520
THIS SHOWED US AGAIN, THAT

1076
00:34:57,520 --> 00:35:00,640
DORSAL CELL TYPES ARE HIGHLY

1077
00:35:00,640 --> 00:35:02,280
ORGANIZED, SO NICE BLOCKS OF

1078
00:35:02,280 --> 00:35:03,360
YELLOW HERE, SHOWING US THAT

1079
00:35:03,360 --> 00:35:05,000
GROUPS OF CELLS ARE HIGHLY

1080
00:35:05,000 --> 00:35:06,600
RELATED TO EACH OTHER BETWEEN

1081
00:35:06,600 --> 00:35:08,720
HUMAN AND MOUSE AND LESS SO IN

1082
00:35:08,720 --> 00:35:09,800
THE VENTRAL HORN BUT WE DON'T

1083
00:35:09,800 --> 00:35:12,000
THINK THAT THIS IS SAYING THAT

1084
00:35:12,000 --> 00:35:13,760
THE MOUSE AND HUMAN CELLS ARE

1085
00:35:13,760 --> 00:35:15,800
VENTRAL HORN ARE UNRELATED

1086
00:35:15,800 --> 00:35:17,240
RATHER BECAUSE THEY'RE CELL TYPE

1087
00:35:17,240 --> 00:35:18,800
ORGANIZATION IS SO DIFFERENT,

1088
00:35:18,800 --> 00:35:19,760
THIS REALLY ISN'T THE BEST WAY

1089
00:35:19,760 --> 00:35:26,680
TO THINK ABOUT THEM.

1090
00:35:26,680 --> 00:35:28,960
AND THIS ALLOWS US TO TO MAKE

1091
00:35:28,960 --> 00:35:31,080
MOU, OF THE CELL TYPES THAT ARE

1092
00:35:31,080 --> 00:35:31,920
CONSERVED BETWEEN MOUSE AND

1093
00:35:31,920 --> 00:35:33,640
MUSEUM MAN, AND WE'VE DONE THIS

1094
00:35:33,640 --> 00:35:36,080
AT A FAMILY LEVEL WHICH SEEMS TO

1095
00:35:36,080 --> 00:35:38,560
BE THE LEVEL IN DIFFERENT

1096
00:35:38,560 --> 00:35:39,120
SPECIES THATTA'S HIGHLY

1097
00:35:39,120 --> 00:35:40,720
CONSERVED AND OF COURSE THERE'S

1098
00:35:40,720 --> 00:35:43,280
DIVERSITY AT A FINER LEVEL IN

1099
00:35:43,280 --> 00:35:43,840
EACH SPECIES.

1100
00:35:43,840 --> 00:35:45,280
AFTER THAT, WE NOW HAVE MARKERS

1101
00:35:45,280 --> 00:35:47,440
THAT CHARACTERIZE EACH OF THESE

1102
00:35:47,440 --> 00:35:48,800
FAMILIES LES ACROSS SPECIES BUT

1103
00:35:48,800 --> 00:35:49,520
1 THING THAT'S REALLY

1104
00:35:49,520 --> 00:35:50,480
INTERESTING IS WE CAN START TO

1105
00:35:50,480 --> 00:35:59,440
LOOK AT WHAT MAKES THEM UNIQUE.

1106
00:35:59,440 --> 00:36:02,960
IN THE DORSAL EXCITE ATORY GROUP

1107
00:36:02,960 --> 00:36:05,040
FOR INSTANCE, 1 WE SEE THESE

1108
00:36:05,040 --> 00:36:08,400
CELLS ONLY IN THE HUMAN CORD

1109
00:36:08,400 --> 00:36:09,720
EXPRESS BASAL 2 WHICH YOU HEARD

1110
00:36:09,720 --> 00:36:11,240
ABOUT FROM THE RECENT NOBEL

1111
00:36:11,240 --> 00:36:14,640
PRIZE AND THE LOCAL WORK OF OUR

1112
00:36:14,640 --> 00:36:17,640
COLLEAGUE ALEX CHESLER AND

1113
00:36:17,640 --> 00:36:18,280
IMPORTANT FOR MECHANOITIZATION

1114
00:36:18,280 --> 00:36:19,560
AND WE HAVE NO IDEA WHAT THESE

1115
00:36:19,560 --> 00:36:21,320
CELLS WILL BE DOING WITH THAT

1116
00:36:21,320 --> 00:36:24,400
BUT IT'S INTERESTING TO THINK

1117
00:36:24,400 --> 00:36:26,240
ABOUT.

1118
00:36:26,240 --> 00:36:28,120
HAVING A PDGFR RECEPTOR IS

1119
00:36:28,120 --> 00:36:29,000
INTERESTING AND WOULD CONFER

1120
00:36:29,000 --> 00:36:30,480
PARTICULAR FUNCTIONS IN TERMS OF

1121
00:36:30,480 --> 00:36:32,120
TROAPIC SUPPORT ON THOSE CELLS

1122
00:36:32,120 --> 00:36:34,040
AND SIMILARLY FOR TGF BETA 1.

1123
00:36:34,040 --> 00:36:38,080
JUST AS AN EXAMPLE, THIS DORSAL

1124
00:36:38,080 --> 00:36:41,960
INHIBITORY GROUP, OVER HERE, HAS

1125
00:36:41,960 --> 00:36:43,320
PARTICULAR RECEPTORS THAT WE

1126
00:36:43,320 --> 00:36:45,360
THINK WOULD CONFER LIKE UNIQUE

1127
00:36:45,360 --> 00:36:47,040
FUNCTIONS ON HOW THIS CELL IS

1128
00:36:47,040 --> 00:36:48,800
LISTENING TO ITS ENVIRONMENT.

1129
00:36:48,800 --> 00:36:50,440
AND NOW I'M ACTUALLY GOING TO

1130
00:36:50,440 --> 00:36:52,040
FINALLY START THE PART WHERE THE

1131
00:36:52,040 --> 00:37:00,040
TITLE IS BASED ON THINKING ABOUT

1132
00:37:00,040 --> 00:37:01,760
HUMAN MOTONEURONS AND 1 THING

1133
00:37:01,760 --> 00:37:03,480
THAT JUMPED OUT AT US WAS THAT

1134
00:37:03,480 --> 00:37:04,800
HUMAN AND MOUSE WERE DIFFERENT

1135
00:37:04,800 --> 00:37:05,840
COMPARED TO OTHER CELL TYPES.

1136
00:37:05,840 --> 00:37:07,640
AND SOME OF THE FACTORS THAT

1137
00:37:07,640 --> 00:37:09,680
DISTINGUISH THE HUMAN

1138
00:37:09,680 --> 00:37:11,880
MOTONEURONS WHEN WE FIRST LOOKED

1139
00:37:11,880 --> 00:37:13,520
AT THEM, JUMPED OUT AT US EXTRA

1140
00:37:13,520 --> 00:37:15,040
BECAUSE THESE ARE GENES THAT ARE

1141
00:37:15,040 --> 00:37:16,800
ASSOCIATE WIDE ALS AND SO WE

1142
00:37:16,800 --> 00:37:18,360
TOOK A DEEPER DIVE AND WE LOOKED

1143
00:37:18,360 --> 00:37:21,080
ACROSS ALL OF THE DIFFERENT

1144
00:37:21,080 --> 00:37:22,400
GENES BETWEEN MOUSE AND

1145
00:37:22,400 --> 00:37:23,480
MOTONEURONS AND THIS WORK IS

1146
00:37:23,480 --> 00:37:24,400
DONE IN COLLABBUATION WITH

1147
00:37:24,400 --> 00:37:28,400
ANOTHER COLLEAGUE AT NIH CLAIR

1148
00:37:28,400 --> 00:37:29,800
[INDISCERNIBLE] AND HER STUDENT

1149
00:37:29,800 --> 00:37:32,000
[INDISCERNIBLE], AND THEY USED A

1150
00:37:32,000 --> 00:37:33,760
LARGE DATABASE OF MOUSE, MOTOR

1151
00:37:33,760 --> 00:37:35,520
NEURON DATA THAT THEY'VE CREATED

1152
00:37:35,520 --> 00:37:37,960
THAT ALLOWED THEM TO KIND OF

1153
00:37:37,960 --> 00:37:39,080
HAVE THE RESOLUTION, LOTS AND

1154
00:37:39,080 --> 00:37:40,600
LOTS OF CELLS TO BE ABLE TO

1155
00:37:40,600 --> 00:37:42,560
COMPARE BETWEEN MOUSE AND HUMAN.

1156
00:37:42,560 --> 00:37:45,120
AND AGAIN WHAT WE SEE HERE, IS

1157
00:37:45,120 --> 00:37:47,120
THAT I'M SHOWING ALS RELATED

1158
00:37:47,120 --> 00:37:49,240
GENES IN RED, MANY OF THE GENES

1159
00:37:49,240 --> 00:37:51,320
THAT ARE MOST DIFFERENT BETWEEN

1160
00:37:51,320 --> 00:37:53,760
MOUSE AND HUMAN ARE IN THOSE

1161
00:37:53,760 --> 00:37:55,160
CATEGORY INCLUDING S. O. D. 1

1162
00:37:55,160 --> 00:37:58,440
WHICH WAS 1 OF THE FIRST OR THE

1163
00:37:58,440 --> 00:38:01,640
FIRST GENE TO BE SHOWN TO BE

1164
00:38:01,640 --> 00:38:03,520
RELEVANT IN ALS OR A VARIANT OR

1165
00:38:03,520 --> 00:38:05,440
MUTATION OF IT IS RELEVANT IN

1166
00:38:05,440 --> 00:38:05,640
ALS.

1167
00:38:05,640 --> 00:38:07,880
AND WE THOUGHT THIS IS REALLY

1168
00:38:07,880 --> 00:38:10,400
INTERESTING, LIKE, WHY ARE HUMAN

1169
00:38:10,400 --> 00:38:12,040
MOTOR NEURONS HAVING THIS

1170
00:38:12,040 --> 00:38:12,840
PARTICULAR MOLECULAR SIGNATURE

1171
00:38:12,840 --> 00:38:15,720
THAT IS SO RELEVANT FIRST OF ALL

1172
00:38:15,720 --> 00:38:16,480
FOR UNDERSTANDING DISEASE BUT

1173
00:38:16,480 --> 00:38:19,920
WHY, WHAT ARE THEY DOING WITH

1174
00:38:19,920 --> 00:38:20,400
THESE GENES.

1175
00:38:20,400 --> 00:38:21,800
SO IN GENERAL WE TOOK A STEP

1176
00:38:21,800 --> 00:38:23,480
BACK AND SAID LET'S JUST ASK

1177
00:38:23,480 --> 00:38:26,240
WHAT ARE THE TOP MARKER GENES OF

1178
00:38:26,240 --> 00:38:27,680
HUMAN MOTOR NEURONS IN GENERAL,

1179
00:38:27,680 --> 00:38:29,680
NOT COMPARING THEM TO MOUSE, BUT

1180
00:38:29,680 --> 00:38:31,120
COMPARING THEM TO THE OTHER

1181
00:38:31,120 --> 00:38:32,520
NEURONS MAYBE ALL HUMAN NEURONS

1182
00:38:32,520 --> 00:38:36,320
HAVE MORE OF THOSE GENES AND SO,

1183
00:38:36,320 --> 00:38:37,640
WE LOOKEDDA THE GENES, OBVIOUSLY

1184
00:38:37,640 --> 00:38:39,840
THIS IS A MESS BUT WHAT I WANT

1185
00:38:39,840 --> 00:38:43,800
YOU TO FOCUS ON FIRST, WE FOUND

1186
00:38:43,800 --> 00:38:46,520
MARKERS OF COLO NERNLGIC CELLS,

1187
00:38:46,520 --> 00:38:47,720
THAT'S THE MOTOR NEURONS USE FOR

1188
00:38:47,720 --> 00:38:49,080
FUNCTION AND THEN WHAT WE SAW

1189
00:38:49,080 --> 00:38:50,440
REALLY, REAL LOAMACYY JUMPED OUT

1190
00:38:50,440 --> 00:38:52,080
AT US, SO THE BIGGEST FAMILY,

1191
00:38:52,080 --> 00:38:56,600
THIS IS A PROTEIN INTERACTION

1192
00:38:56,600 --> 00:38:58,520
NETWORK FROM STRING, THE BIGGEST

1193
00:38:58,520 --> 00:39:01,560
FAMILIES WE SAW HAD TO DO WITH

1194
00:39:01,560 --> 00:39:03,120
CYTOCELL SKELETON, MANY OF THESE

1195
00:39:03,120 --> 00:39:08,280
GENES WERE ACTUALLY ALS RELATED

1196
00:39:08,280 --> 00:39:12,280
INCLUDING STADTMAN 2, SDP 1,

1197
00:39:12,280 --> 00:39:14,840
PERIPH RIN, JEEPS THAT ARE KNOWN

1198
00:39:14,840 --> 00:39:16,200
TO HAVE CAUSATIVE VARIANTS AND

1199
00:39:16,200 --> 00:39:18,480
ALSO TO BE INVOLVED IN THE

1200
00:39:18,480 --> 00:39:20,800
BIOLOGY. 

1201
00:39:20,800 --> 00:39:24,520
SO FOR INSTANCE, STOCKMAN 2 IS A

1202
00:39:24,520 --> 00:39:26,080
TARGET OF PDB143, SO THIS

1203
00:39:26,080 --> 00:39:30,080
SURPRISED US BECAUSE FIRST OF

1204
00:39:30,080 --> 00:39:31,960
ALL, ALL CELLS NEED A

1205
00:39:31,960 --> 00:39:32,920
CYTOSKELETON AND THERE'S BEEN A

1206
00:39:32,920 --> 00:39:34,920
MYSTERY IN THE FIELD OF

1207
00:39:34,920 --> 00:39:36,760
NEURODEGENERATION ABOUT WHY SOME

1208
00:39:36,760 --> 00:39:38,520
CELL TYPES DEGENERATE AND I

1209
00:39:38,520 --> 00:39:39,920
THINK THE CONVENTIONAL WISDOM OR

1210
00:39:39,920 --> 00:39:42,080
AT LEAST THE BASE LINE

1211
00:39:42,080 --> 00:39:44,720
ASSUMPTION, LET'S SAY HAS BEEN

1212
00:39:44,720 --> 00:39:47,720
THAT GENES THAT CAUSE, LS OR

1213
00:39:47,720 --> 00:39:49,680
OTHER DEGENERATIVE DISEASES TEND

1214
00:39:49,680 --> 00:39:51,520
TO BE RELATIVELY UBIQUITOUSLY

1215
00:39:51,520 --> 00:39:52,280
EXPRESSED ACROSS NEURONS AND

1216
00:39:52,280 --> 00:39:54,520
THEN THE MYSTERY IS WHY DO SOME

1217
00:39:54,520 --> 00:39:55,920
NEURONS DEGENERATE AND I THINK

1218
00:39:55,920 --> 00:39:57,240
THAT THIS WAS REALLY SHOCKING TO

1219
00:39:57,240 --> 00:40:01,480
US TO THINK ABOUT SOME OF THESE

1220
00:40:01,480 --> 00:40:02,920
GENES BEING HIGHLY ENRICHED IN

1221
00:40:02,920 --> 00:40:04,280
MOTOR NEURONS TO THE POINT WHERE

1222
00:40:04,280 --> 00:40:06,480
THEY ARE THE SIGNATURE THAT

1223
00:40:06,480 --> 00:40:07,760
DEFINES HUMAN MOTOR NEURONS, NOT

1224
00:40:07,760 --> 00:40:09,320
TO SAY THEY'RE COMPLETELY ABSENT

1225
00:40:09,320 --> 00:40:12,680
FROM OTHER CELL TYPES, BUT

1226
00:40:12,680 --> 00:40:14,160
THERE'S CLEARLY LIKE A

1227
00:40:14,160 --> 00:40:14,960
COMPLETELY DIFFERENT SIGNATURE

1228
00:40:14,960 --> 00:40:20,760
IN TERMS OF THEIR EXPRESSION,

1229
00:40:20,760 --> 00:40:22,240
STOIK ORDER OF MICRONSETRY FOR

1230
00:40:22,240 --> 00:40:24,440
MOTOR NEURONS AND WE WERE

1231
00:40:24,440 --> 00:40:25,400
CURIOUS ABOUT PURSUING THAT

1232
00:40:25,400 --> 00:40:25,760
FURTHER.

1233
00:40:25,760 --> 00:40:27,280
SO HERE I'M SHOWING THE RAW DATA

1234
00:40:27,280 --> 00:40:28,680
BUT I KIND OF WANT TO GIVE AN

1235
00:40:28,680 --> 00:40:30,200
EXAMPLE, THIS IS LOOKING AT A

1236
00:40:30,200 --> 00:40:32,280
WHOLE BUNCH OF ALS RELATED

1237
00:40:32,280 --> 00:40:33,720
GENES, 2 DIFFERENT WAYS, HERE

1238
00:40:33,720 --> 00:40:36,480
I'M SHOWING YOU THE GENE

1239
00:40:36,480 --> 00:40:38,160
EXPRESSION PLOTTED ON THESE DOT

1240
00:40:38,160 --> 00:40:39,440
PLOTS WHERE EACH DOT IS A

1241
00:40:39,440 --> 00:40:41,000
NUCLEUS AND HERE I'M SHOWING YOU

1242
00:40:41,000 --> 00:40:45,400
BAR BLOTS WHERE YOU CAN SEE THE

1243
00:40:45,400 --> 00:40:46,280
OVERALL EXPRESSION LEVEL FOR

1244
00:40:46,280 --> 00:40:49,520
EACH OF OUR 7 PATIENTS FOR THE

1245
00:40:49,520 --> 00:40:50,520
FINDINGS ACROSS HAVE THES SO

1246
00:40:50,520 --> 00:40:56,520
WHAT YOU THINK YOU CAN PROBABLY

1247
00:40:56,520 --> 00:40:57,440
APPRECIATE IS PARTICULARLY THOSE

1248
00:40:57,440 --> 00:41:03,280
THAT HAVE DO WITH CYTOSKELETAL

1249
00:41:03,280 --> 00:41:04,640
STRUCTURE ARE YOU CAN SEE THAT

1250
00:41:04,640 --> 00:41:15,160
HERE, THEY ARE SEVERAL OF THE

1251
00:41:18,000 --> 00:41:19,680
KIND OF BIG SO YOU CAN SEE THOSE

1252
00:41:19,680 --> 00:41:21,200
3 HERE, AND HERE.

1253
00:41:21,200 --> 00:41:23,320
AND SO THE MOTOR NEURONS ARE IN

1254
00:41:23,320 --> 00:41:24,400
THIS COLUMN AND YOU SEE MAYBE

1255
00:41:24,400 --> 00:41:25,960
THEAR A BIT HIGHER BUT THIS

1256
00:41:25,960 --> 00:41:28,440
ISN'T NECESSARILY PART OF THE

1257
00:41:28,440 --> 00:41:30,000
METEOR NEURON SIGNATURE, WE

1258
00:41:30,000 --> 00:41:31,120
THINK THAT'S REALLY, REALLY

1259
00:41:31,120 --> 00:41:31,440
INTERESTING.

1260
00:41:31,440 --> 00:41:33,560
SO FIRST OF ALL, REMEMBER, WE

1261
00:41:33,560 --> 00:41:35,120
HAVE THESE LARGE DATABASES NOW,

1262
00:41:35,120 --> 00:41:36,680
WE CAN ASK, WHAT ARE THE CELLS

1263
00:41:36,680 --> 00:41:40,120
THAT THOSE GENES ARE IN,

1264
00:41:40,120 --> 00:41:42,480
UNFORTUNATELY THERE'S VERY

1265
00:41:42,480 --> 00:41:44,120
LITTLE TARDBP IN OUR DATA SET

1266
00:41:44,120 --> 00:41:45,960
BUT WE CAN ASK FOR EACH DISEASE

1267
00:41:45,960 --> 00:41:50,240
CAUSING GENE OR VARIANTS THAT

1268
00:41:50,240 --> 00:41:51,520
ARE WITH THE VALID AND RELIABLE

1269
00:41:51,520 --> 00:41:52,600
YAIBILITY OF HOW DIFFERENT

1270
00:41:52,600 --> 00:41:53,680
DISEASES PLAY OUT, WHAT CELLS

1271
00:41:53,680 --> 00:41:55,200
MIGHT BE GOOD TARGETS IN TERNALS

1272
00:41:55,200 --> 00:41:56,280
OF THINKING ABOUT EXPRESSION

1273
00:41:56,280 --> 00:41:58,000
PATTERN BUT MORE IMPORTANTLY, I

1274
00:41:58,000 --> 00:41:59,480
THINK IT GIVE US A REALLY,

1275
00:41:59,480 --> 00:42:00,920
REALLY STRONG LEAD ON THINKING

1276
00:42:00,920 --> 00:42:03,160
ABOUT, THE STRUCTURE OF MOTOR

1277
00:42:03,160 --> 00:42:06,760
NEURONS AND WHY THAT MIGHT

1278
00:42:06,760 --> 00:42:07,560
CONFER ALS VULNERABILITY.

1279
00:42:07,560 --> 00:42:09,360
SO WE DECIDED WE NEED TO

1280
00:42:09,360 --> 00:42:10,440
VALIDATE THAT FINDING BECAUSE IT

1281
00:42:10,440 --> 00:42:11,680
SEEMED TO US VERY IMPORTANT AND

1282
00:42:11,680 --> 00:42:12,920
WE HAVE 3 DIFFERENT WAYS TO DO

1283
00:42:12,920 --> 00:42:16,040
IT SO THE FIRST IS CELL TARGETED

1284
00:42:16,040 --> 00:42:17,200
PROTEOMIC PROFILING AND FOR THIS

1285
00:42:17,200 --> 00:42:18,960
WE COLLABORATED WITH MICHAEL

1286
00:42:18,960 --> 00:42:20,080
WARD'S LAB, ANOTHER COLLEAGUE AT

1287
00:42:20,080 --> 00:42:21,800
NIH AND I HOPE YOU ARE GETTING

1288
00:42:21,800 --> 00:42:23,720
THE THEME HERE LIKE WE REALLY

1289
00:42:23,720 --> 00:42:25,440
LIKE OUR NEIGHBORS.

1290
00:42:25,440 --> 00:42:27,600
SO WE TOOK 3 TISSUE FROM 3

1291
00:42:27,600 --> 00:42:30,800
DIFFERENT DONORS AND WE USED

1292
00:42:30,800 --> 00:42:32,440
ANTIBODY BINDING TO BRING HRP,

1293
00:42:32,440 --> 00:42:35,240
THAT WE COULD THEN PULL ALL OF

1294
00:42:35,240 --> 00:42:39,400
THESE LOCALLY LABELED PROTEINS,

1295
00:42:39,400 --> 00:42:43,720
AND ASK WHICH ARE THERE BASED ON

1296
00:42:43,720 --> 00:42:45,360
THE INITIAL BAIT AND WE USE 2

1297
00:42:45,360 --> 00:42:47,240
DIFFERENT BAITS AND OUR ANALYSIS

1298
00:42:47,240 --> 00:42:48,520
FOR THIS IS BY MASS SPEC SO WE

1299
00:42:48,520 --> 00:42:51,960
CAN LOOK AT PROTEINS, WE'RE NOT

1300
00:42:51,960 --> 00:42:52,880
TALKING ABOUT TRANSCRIPTS IMORP.

1301
00:42:52,880 --> 00:42:54,440
AND WE CAN EITHER LOOK AT ALL

1302
00:42:54,440 --> 00:42:56,240
NEURONS, OR WE CAN LOOK AT MOTOR

1303
00:42:56,240 --> 00:43:01,600
NEURONS AND SO THIS IS WITH NEW

1304
00:43:01,600 --> 00:43:03,040
M AND THIS IS WITH

1305
00:43:03,040 --> 00:43:04,680
[INDISCERNIBLE] WHICH IS MOTOR

1306
00:43:04,680 --> 00:43:05,280
SPECIFIC.

1307
00:43:05,280 --> 00:43:08,200
AND WE CAN ASK WHICH PROTEINS

1308
00:43:08,200 --> 00:43:09,680
ARE PREVENTIVE RENTERALLY YOWND

1309
00:43:09,680 --> 00:43:11,200
IN THIS POPULATION COMPARE TO

1310
00:43:11,200 --> 00:43:12,760
THIS POPULATION AND INDEED WE

1311
00:43:12,760 --> 00:43:14,360
FOUND MANY OF THE HITS THAT WE

1312
00:43:14,360 --> 00:43:17,240
WERE REALLY INTERESTED IN FROM

1313
00:43:17,240 --> 00:43:18,920
ALS RISK, ACTUALLY ARE ENRICHED

1314
00:43:18,920 --> 00:43:20,480
IN HUMAN MOTOR NEURONS, USING

1315
00:43:20,480 --> 00:43:22,000
FIRST OF ALL, I JUST WANT TO

1316
00:43:22,000 --> 00:43:23,800
EMPHASIZE THIS AS NOW LOOKING AT

1317
00:43:23,800 --> 00:43:28,760
THE PROTEIN LEVEL, BUT ALSO VERY

1318
00:43:28,760 --> 00:43:29,560
INDEPENDENT TYPE VALIDATION.

1319
00:43:29,560 --> 00:43:31,800
WE TEXT ASKED IN OUR SPATIAL

1320
00:43:31,800 --> 00:43:33,360
TRANSCRIPT OHMICS DO WE SEE THE

1321
00:43:33,360 --> 00:43:35,240
SAME PROFILE, AGAIN THIS, IS AN

1322
00:43:35,240 --> 00:43:38,280
UNBIASED DIFFERENT SET OF

1323
00:43:38,280 --> 00:43:39,440
TISSUE, LOOKING AT GENE

1324
00:43:39,440 --> 00:43:41,960
EXPRESSION AND AGAIN, WE FOUND

1325
00:43:41,960 --> 00:43:44,080
THAT MANY OF THESE GENES ARE

1326
00:43:44,080 --> 00:43:46,200
ENRICH INDEED THE MOTOR NEURON

1327
00:43:46,200 --> 00:43:50,000
AREA, ALTHOUGH WE FOUND OPTN WAS

1328
00:43:50,000 --> 00:43:51,440
NOT IN THIS PARTICULAR DATA SET.

1329
00:43:51,440 --> 00:43:53,560
HOWEVER, YOU DO SEE, PLENTY OF

1330
00:43:53,560 --> 00:43:55,440
RNA ELSEWHERE AND TO SOME EXTENT

1331
00:43:55,440 --> 00:43:57,720
THIS CAN ALSO BE FROMAXONS

1332
00:43:57,720 --> 00:44:00,280
COMING IN FROM OTHER TISSUE.

1333
00:44:00,280 --> 00:44:02,280
FINALLY WE LOOK TO SEE KIND OF

1334
00:44:02,280 --> 00:44:03,560
OLD FASHIONED LET'S JUST PUT

1335
00:44:03,560 --> 00:44:05,080
ANTIBODIES ON THE TISSUE AND ASK

1336
00:44:05,080 --> 00:44:06,840
WHERE WE FIND THE PROTEINS OF

1337
00:44:06,840 --> 00:44:09,440
SEVERAL OF OUR MOST INTERESTING

1338
00:44:09,440 --> 00:44:10,320
GENE CANDIDATES HERE.

1339
00:44:10,320 --> 00:44:13,760
AND SO WHAT I'M SHOWING YOU HERE

1340
00:44:13,760 --> 00:44:15,840
IS ADULT HUMAN LUMBAR SPINAL

1341
00:44:15,840 --> 00:44:18,960
CORD STAINED FOR JUST A GENERAL

1342
00:44:18,960 --> 00:44:19,720
NEURAL MARKER OR 6 DIFFERENT

1343
00:44:19,720 --> 00:44:20,960
GENES THAT ARE ASSOCIATED WITH

1344
00:44:20,960 --> 00:44:23,680
ALS, AND I THINK YOU CAN

1345
00:44:23,680 --> 00:44:25,320
PROBABLY APPRECIATE THAT LIKE IN

1346
00:44:25,320 --> 00:44:26,560
GENERAL, THESE ARE DEFINITELY

1347
00:44:26,560 --> 00:44:28,400
ENRICHED IN THE MOTOR NEURON

1348
00:44:28,400 --> 00:44:32,360
AREA, JUST VISUALLY,

1349
00:44:32,360 --> 00:44:32,680
IMMEDIATELY.

1350
00:44:32,680 --> 00:44:35,640
SO IF WE LOOK AT LAMINA 3-4 IN

1351
00:44:35,640 --> 00:44:37,600
THE AREA OF THE SPINAL CORD, WE

1352
00:44:37,600 --> 00:44:39,000
SEE SOME STAINING BUT NOT MUCH

1353
00:44:39,000 --> 00:44:43,560
WHEREAS IF WE LOOK AT THE MOTOR

1354
00:44:43,560 --> 00:44:44,800
NEURON REGION, WE SEE LOVELY

1355
00:44:44,800 --> 00:44:46,800
LABELING IN THE MOTOR NIEWFONS,

1356
00:44:46,800 --> 00:44:48,040
AND WE QUANTIFIED THIS OF COURSE

1357
00:44:48,040 --> 00:44:50,640
TO MAKE SURE IT'S REPRODUCIBLE

1358
00:44:50,640 --> 00:44:51,400
ACROSS DIFFERENT DONORS AND

1359
00:44:51,400 --> 00:44:52,360
BASICALLY WHAT WE WERE ABLE TO

1360
00:44:52,360 --> 00:44:55,120
SHOW IS THAT EACH OF THESE GENES

1361
00:44:55,120 --> 00:44:56,920
ARE ENRICHED EXCEPT FOR SOD 1,

1362
00:44:56,920 --> 00:44:59,560
WHICH IS CERTAINLY NOT

1363
00:44:59,560 --> 00:45:01,760
UBIQUITOUS BUT WE DIDN'T SEE A

1364
00:45:01,760 --> 00:45:02,840
PROTEIN LEVEL ENRICHMENT

1365
00:45:02,840 --> 00:45:04,120
ALTHOUGH THERE'S CLEARLY A

1366
00:45:04,120 --> 00:45:14,600
STRONG RNA LEVEL ENRICHMENT.

1367
00:45:16,200 --> 00:45:20,200
SO WHY DO THEY NEED A

1368
00:45:20,200 --> 00:45:20,640
CYTOICLETAL SIGNATURE.

1369
00:45:20,640 --> 00:45:21,840
AND 1 THING THAT CAUGHT OUR EYE

1370
00:45:21,840 --> 00:45:24,040
IS THESE GENES ARE NOT INVOLVED

1371
00:45:24,040 --> 00:45:25,400
FOR INSTABILITY AND ALTHOUGH

1372
00:45:25,400 --> 00:45:28,880
SOME OF THEM ARE AND THAT'S KIND

1373
00:45:28,880 --> 00:45:30,080
OF COOL, BUT THEY'RE ALSO

1374
00:45:30,080 --> 00:45:32,720
INVOLVED IN SYSTEM, SO THESE 4

1375
00:45:32,720 --> 00:45:34,520
FACTORS HERE, IF YOU OVERTRUST

1376
00:45:34,520 --> 00:45:36,240
THEM IN TRANSGENIC MICE, EITHER

1377
00:45:36,240 --> 00:45:37,680
THE HUMAN VERSION OR REALLY HIGH

1378
00:45:37,680 --> 00:45:44,320
LEVELS OF THE MOUSE VERSION,

1379
00:45:44,320 --> 00:45:46,200
THEY WILL MAKE THOSE GROW, SWELL

1380
00:45:46,200 --> 00:45:47,760
AND DEGENERATE AND WE THOUGHT

1381
00:45:47,760 --> 00:45:49,280
PERHAPS THERE'S A LINK HERE

1382
00:45:49,280 --> 00:45:50,240
BETWEEN THE MOTOR NEURON

1383
00:45:50,240 --> 00:45:51,440
SIGNATURE WE OBSERVE AND THE

1384
00:45:51,440 --> 00:45:52,120
CELL SIZE.

1385
00:45:52,120 --> 00:45:53,840
SO WE WANTED TO PROBE THAT

1386
00:45:53,840 --> 00:45:55,840
DIRECTLY AND FIRST OF WE ASKED,

1387
00:45:55,840 --> 00:45:58,600
OKAY, WE ALL KNOW HUMAN MOTOR

1388
00:45:58,600 --> 00:45:59,560
NEURNEURONS ARE BIG, BUT HOW BIG

1389
00:45:59,560 --> 00:46:00,800
AND HOW DOES THAT COMPARE, LIKE

1390
00:46:00,800 --> 00:46:11,320
WHAT ARE WE VEYING THAT RELATIVE

1391
00:46:12,160 --> 00:46:12,360
TO.

1392
00:46:12,360 --> 00:46:14,640
THESE ARE NOT AT SCALE, CAN YOU

1393
00:46:14,640 --> 00:46:16,040
SEE THE BARS ARE DIFFERENT BUT

1394
00:46:16,040 --> 00:46:19,160
IF WE LOOK IN THE DORSAL FORM

1395
00:46:19,160 --> 00:46:20,720
AND THESE ARE AT SCALE, THESE

1396
00:46:20,720 --> 00:46:22,720
ARE EXACTLY LIKE THE MICE SPINAL

1397
00:46:22,720 --> 00:46:25,000
CORD, IF IN FACT IF WE MAKE A

1398
00:46:25,000 --> 00:46:26,040
HISTOGRAM HERE OF THE DIFFERENT

1399
00:46:26,040 --> 00:46:27,240
SIZES YOU CAN SEE THAT BASIC LYE

1400
00:46:27,240 --> 00:46:29,960
THE MOUSE IN BLUE AND THE HUMAN

1401
00:46:29,960 --> 00:46:32,280
IN SALMON LINE UP ALMOST

1402
00:46:32,280 --> 00:46:33,480
PERFECTLY FOR ALMOST ALL OF THE

1403
00:46:33,480 --> 00:46:34,720
DIFFERENT AREAS OF THE SPINAL

1404
00:46:34,720 --> 00:46:37,160
CORD EXCEPT WHEN WE GET TO MOTOR

1405
00:46:37,160 --> 00:46:39,280
NEURONS SO WHAT WE FOUND IS THAT

1406
00:46:39,280 --> 00:46:40,560
HUMAN NEURONS, MOTOR NEURONS ARE

1407
00:46:40,560 --> 00:46:43,840
NOT JUST LARGE, THEY'RE REALLY

1408
00:46:43,840 --> 00:46:48,120
LARGE, RELATIVE BOTH TO THEIR

1409
00:46:48,120 --> 00:46:49,400
CONSERVED SPECIES COUNTERPART IN

1410
00:46:49,400 --> 00:46:51,160
MOUSE BUT ALSO RELATIVE TO OTHER

1411
00:46:51,160 --> 00:46:52,440
HUMAN NEURONS SO THEY'VE KIND OF

1412
00:46:52,440 --> 00:46:53,800
GROWN LIKE OUT OF SCALE, WITH

1413
00:46:53,800 --> 00:46:56,560
ALL OF THE REST OF THE SPINAL

1414
00:46:56,560 --> 00:46:56,920
CORD TISSUE.

1415
00:46:56,920 --> 00:47:00,840
IN FACT, THE LARGEST 1S WE FOUND

1416
00:47:00,840 --> 00:47:03,680
WHICH ARE 120-MICRONS ACROSS,

1417
00:47:03,680 --> 00:47:04,760
BASICALLY IN THE RANGE OF LIKE

1418
00:47:04,760 --> 00:47:06,520
AS BIG AS VERTEBRATE NEURONS

1419
00:47:06,520 --> 00:47:09,280
GET, SO THEY ARE AS BIG FOR

1420
00:47:09,280 --> 00:47:12,320
INSTANCE AS ELEPHANT MOTOR

1421
00:47:12,320 --> 00:47:14,400
NEURONS OR SALMON

1422
00:47:14,400 --> 00:47:17,560
[INDISCERNIBLE] CELLS O HUMAN

1423
00:47:17,560 --> 00:47:18,920
BET CELLS, THEY ARE PUSHING THE

1424
00:47:18,920 --> 00:47:20,360
LIMITS OF WHAT THE CELLS CAN BE.

1425
00:47:20,360 --> 00:47:22,160
WE WANTED TO KNOW IF THE GENE

1426
00:47:22,160 --> 00:47:23,240
SIGNATURE COULD BE RELATED TO

1427
00:47:23,240 --> 00:47:24,760
THAT, AND THIS IS CORRELATIVE

1428
00:47:24,760 --> 00:47:27,400
DATA BUT I THINK IT'S SUPER

1429
00:47:27,400 --> 00:47:27,600
COOL.

1430
00:47:27,600 --> 00:47:29,560
SO BASICALLY WHAT WE DID IS WE

1431
00:47:29,560 --> 00:47:31,600
MEASURED ALL THESE CELLS WITH

1432
00:47:31,600 --> 00:47:33,040
THE GENE EXPRESSION, WHETHER THE

1433
00:47:33,040 --> 00:47:34,680
CELLS WERE NOT IN ALMOST

1434
00:47:34,680 --> 00:47:35,640
IMPEDIMENTSAIN 9, WE SEE A LARGE

1435
00:47:35,640 --> 00:47:38,000
GROUP HERE THAT WE THINK MIGHT

1436
00:47:38,000 --> 00:47:39,400
BE PROJECTION NEURONS AND/OR IN

1437
00:47:39,400 --> 00:47:42,880
LAMINA 9 WHERE THE MOTOR NEURONS

1438
00:47:42,880 --> 00:47:44,400
RESIDE AND WE FOUND THAT MANY

1439
00:47:44,400 --> 00:47:46,160
MUCH THESE MARKERS TEND TO BE

1440
00:47:46,160 --> 00:47:47,120
ASSOCIATED WITH INCREASED CELL

1441
00:47:47,120 --> 00:47:49,200
SIZE, WHETHER THE CELLS WERE

1442
00:47:49,200 --> 00:47:50,080
INLAMINA 9 OR NOT.

1443
00:47:50,080 --> 00:47:53,800
SO WE THINK THIS CYTOSKELETAL

1444
00:47:53,800 --> 00:47:55,640
ALS RELATED GENE SIGNATURE AND

1445
00:47:55,640 --> 00:47:57,400
ASSOCIATED WITH LARGE CELLICIZE

1446
00:47:57,400 --> 00:47:59,000
IN YOU HAD MOTOR NEURONS SO LET

1447
00:47:59,000 --> 00:48:00,200
ME BRING THAT TOGETHER, A LITTLE

1448
00:48:00,200 --> 00:48:02,760
BIT AND AGAIN THIS IS A VERY

1449
00:48:02,760 --> 00:48:03,960
SPECULATIVE MODEL AND WE'RE JUST

1450
00:48:03,960 --> 00:48:06,400
KIND OF EARLY DAYS IN FOLLOWING

1451
00:48:06,400 --> 00:48:09,040
UP ALL OF THESE FUN SIGNATURES

1452
00:48:09,040 --> 00:48:11,320
THAT WE SEE, IS BASICALLY WE

1453
00:48:11,320 --> 00:48:12,720
THINK, OKAY, OBVIOUSLY HUMANS

1454
00:48:12,720 --> 00:48:14,640
ARE BIGGER THAN MICE, THERE'S A

1455
00:48:14,640 --> 00:48:18,240
MASSIVE SCALING OF BODY SIZE AND

1456
00:48:18,240 --> 00:48:20,600
THERE IS NOT THE SAME SCALING

1457
00:48:20,600 --> 00:48:21,920
FOR THE SIGNIFICANT MAJORITY OF

1458
00:48:21,920 --> 00:48:23,320
NEURONS IN THE SPINAL CORD.

1459
00:48:23,320 --> 00:48:26,160
SO ACTUALLY THE MEDIAN IS VERY

1460
00:48:26,160 --> 00:48:29,160
SLIGHTLY LARGER IN HUMAN

1461
00:48:29,160 --> 00:48:30,080
COMPARED TO MOUSE.

1462
00:48:30,080 --> 00:48:31,160
EXCEPT FOR MOTOR NEURONS SO

1463
00:48:31,160 --> 00:48:32,840
THEY'RE THE 1S AND OBVIOUSLY

1464
00:48:32,840 --> 00:48:34,920
THEY DON'T SCALE IN PROPORTION

1465
00:48:34,920 --> 00:48:37,280
TO BODY SIZE BUT THEY ARE MUCH

1466
00:48:37,280 --> 00:48:38,600
LARGER THAN THE NEURONS AND IN

1467
00:48:38,600 --> 00:48:39,560
ORDER TO SUSTAIN THAT, THEY

1468
00:48:39,560 --> 00:48:41,400
NEEDED TO HAVE A SLIGHTLY

1469
00:48:41,400 --> 00:48:43,960
DIFFERENT MAKE UP OF THEIR

1470
00:48:43,960 --> 00:48:46,160
CYTOSKELETON IN TERMS OF THE

1471
00:48:46,160 --> 00:48:48,040
LEVELS THEY EXPRESS AND ALSO THE

1472
00:48:48,040 --> 00:48:50,680
IDENTITY OF THE DIFFERENT

1473
00:48:50,680 --> 00:48:52,400
PROTEINS AND THEIR CYTOSKELETON

1474
00:48:52,400 --> 00:48:55,080
AND THAT IT'S THE SAME NEED TO

1475
00:48:55,080 --> 00:48:57,560
HAVE THESE PARTICULAR SIGNATURE

1476
00:48:57,560 --> 00:48:59,360
THAT THEN CONFERS THEIR

1477
00:48:59,360 --> 00:49:00,360
SUSCEPTIBILITY TO DEGENERATION

1478
00:49:00,360 --> 00:49:03,440
AND SO IT'S KIND OF THIS LIKE, I

1479
00:49:03,440 --> 00:49:04,400
ALMOST PICTURE THEM LIKE

1480
00:49:04,400 --> 00:49:05,560
TETERING AT THE EDGE OF WHAT

1481
00:49:05,560 --> 00:49:06,880
NEURONS SHOULD BE AND WE SHOULD

1482
00:49:06,880 --> 00:49:07,880
BE INCREDIBLE LOAMACYY GRATEFUL

1483
00:49:07,880 --> 00:49:09,480
THAT FOR THE MOST PART THEY SEEM

1484
00:49:09,480 --> 00:49:11,800
TO FUNCTION WELL, BUT THEN IN

1485
00:49:11,800 --> 00:49:16,760
THE CONTEXT OF DISEASE, IT'S

1486
00:49:16,760 --> 00:49:18,200
JUST TOO MUCH AND THESE CELLS

1487
00:49:18,200 --> 00:49:20,400
DIE, IT'S INTERESTING TO THINK

1488
00:49:20,400 --> 00:49:23,400
ABOUT LINKING GENE EXPRESSION

1489
00:49:23,400 --> 00:49:27,120
WITH CELL IDENTITY AND THEN,

1490
00:49:27,120 --> 00:49:28,920
RELATEDLY, WITH SYSTEM WIDE

1491
00:49:28,920 --> 00:49:30,760
FUNCTION AND VULNERABILITY AND

1492
00:49:30,760 --> 00:49:31,320
THAT PROVIDES HOPEFULLY AN

1493
00:49:31,320 --> 00:49:33,800
EXAMPLE OF HOW WE CAN MAKE THIS

1494
00:49:33,800 --> 00:49:35,640
KIND OF ASSOCIATION AND LEARN

1495
00:49:35,640 --> 00:49:37,160
ABOUT THE BASIC BIOLOGY THAT IS

1496
00:49:37,160 --> 00:49:40,560
GIVING RISE TO DISEASE.

1497
00:49:40,560 --> 00:49:42,720
SO, WHOOPS I DON'T KNOW WHY IT

1498
00:49:42,720 --> 00:49:44,000
CLOSED OUT OF THAT SO QUICKLY

1499
00:49:44,000 --> 00:49:45,520
BUT I REALLY WANT TO THANK THE

1500
00:49:45,520 --> 00:49:46,440
PEOPLE THAT COLLABORATED WITH ME

1501
00:49:46,440 --> 00:49:49,760
AND IN MY LAB WHO CONTRIBUTED TO

1502
00:49:49,760 --> 00:49:51,800
THIS WORK, IN TERMS OF THE

1503
00:49:51,800 --> 00:49:53,000
HARMONIZED ANALYSIS THAT I

1504
00:49:53,000 --> 00:49:55,680
SHARED WITH YOU, DANIEL AND

1505
00:49:55,680 --> 00:50:00,200
RYAN, DID THE LION'S SHARE OF

1506
00:50:00,200 --> 00:50:01,320
THAT WORK, [INDISCERNIBLE] FROM

1507
00:50:01,320 --> 00:50:02,680
MY LAB LED THE HUMAN WORK AND

1508
00:50:02,680 --> 00:50:04,840
THAT WAS A VERY CLOSE

1509
00:50:04,840 --> 00:50:05,240
PARTNERSHIP WITH

1510
00:50:05,240 --> 00:50:05,600
[INDISCERNIBLE].

1511
00:50:05,600 --> 00:50:08,160
AND THEN MY LAB, WHOSE JUST LIKE

1512
00:50:08,160 --> 00:50:10,000
AMAZING, AND MOST OF OUR WORK IS

1513
00:50:10,000 --> 00:50:11,400
ACTUALLY ON MOTOR CONTROL, SO I

1514
00:50:11,400 --> 00:50:13,040
DIDN'T GET TO SHARE THAT WITH

1515
00:50:13,040 --> 00:50:14,560
YOU TODAY, BUT I--THEY'RE JUST

1516
00:50:14,560 --> 00:50:17,040
AMAZING AND I WANT TO THANK THEM

1517
00:50:17,040 --> 00:50:18,920
FOR ALL--JUST BEING MY SCIENCE

1518
00:50:18,920 --> 00:50:20,240
PARTNERS, AND THEN TO ALSO

1519
00:50:20,240 --> 00:50:22,240
REALLY MENTION SOME OF OUR OTHER

1520
00:50:22,240 --> 00:50:24,840
COLLABORATORS ON THE HARMONIZED

1521
00:50:24,840 --> 00:50:25,440
ANALYSIS, STEPHANIE AND CLAIR

1522
00:50:25,440 --> 00:50:27,240
AND AS I MENTIONED, JUST THE

1523
00:50:27,240 --> 00:50:28,280
BEGINNING, THE TIP OF THE

1524
00:50:28,280 --> 00:50:29,720
ICEBERG OF A MASSIVE TEAM THAT

1525
00:50:29,720 --> 00:50:31,600
WORKED WITH US ON THE HUMAN

1526
00:50:31,600 --> 00:50:32,720
PROJECT AND CONTINUES TO AS WE

1527
00:50:32,720 --> 00:50:36,240
KIND OF TRY TO GET TO THAT NEXT

1528
00:50:36,240 --> 00:50:36,720
LEVEL OF UNDERSTANDING.

1529
00:50:36,720 --> 00:50:38,440
AND THANK YOU VERY MUCH FOR YOUR

1530
00:50:38,440 --> 00:50:38,760
ATTENTION.

1531
00:50:38,760 --> 00:50:49,040
I LOOK FORWARD TO YOUR

1532
00:50:49,040 --> 00:50:50,080
QUESTIONS.

1533
00:50:50,080 --> 00:50:51,960
>> DR. LEVINE, HAD TROUBLE

1534
00:50:51,960 --> 00:50:53,880
GETTING MYSELF OFFVIDEO HERE,

1535
00:50:53,880 --> 00:50:55,440
THAIRK YOU SO MUCH FOR SHARING

1536
00:50:55,440 --> 00:50:58,880
YOUR WORK AND FOLLOWING US TO

1537
00:50:58,880 --> 00:51:00,400
HAVE DEEPER AND INTO THE

1538
00:51:00,400 --> 00:51:01,080
DIFFERENT MOTOR NEURON CELL

1539
00:51:01,080 --> 00:51:05,760
TYPES AND WHAT THAT MIGHT OFFER

1540
00:51:05,760 --> 00:51:08,080
US, SO AS A BACKGROUND, JUST 1

1541
00:51:08,080 --> 00:51:10,640
QUESTION, WHAT ARE THE

1542
00:51:10,640 --> 00:51:13,280
IMPLICATIONS FOR THIS IN TERMS

1543
00:51:13,280 --> 00:51:15,560
OF POTENTIAL TREATMENT OR

1544
00:51:15,560 --> 00:51:18,280
THERAPEUTICS THAT ARE INVOLVED

1545
00:51:18,280 --> 00:51:18,680
WITH THE ALS?

1546
00:51:18,680 --> 00:51:20,920
>> YEAH, I THINK THAT'S
THE KEY

1547
00:51:20,920 --> 00:51:25,200
QUESTION AND I WOULD SAY, IT'S

1548
00:51:25,200 --> 00:51:27,440
COMPLICATED FOR THE MOST PART,

1549
00:51:27,440 --> 00:51:30,200
YOU KNOW I THINK IN THE

1550
00:51:30,200 --> 00:51:33,280
TREATMENT SPACE ALS HAS BEEN

1551
00:51:33,280 --> 00:51:33,960
INCREDIBLY FRUSTRATING TO BE

1552
00:51:33,960 --> 00:51:35,200
FRANK AND 1 THING THAT CONCERNS

1553
00:51:35,200 --> 00:51:36,520
ME A LITTLE BIT AND I SHOULD SAY

1554
00:51:36,520 --> 00:51:38,280
THIS REALLY COMES FROM

1555
00:51:38,280 --> 00:51:40,160
DISCUSSIONS WITH MICHAEL WARD MY

1556
00:51:40,160 --> 00:51:41,320
COLLEAGUE HERE WHO'S FOCUS IS

1557
00:51:41,320 --> 00:51:45,280
MORE IN THE ALS,

1558
00:51:45,280 --> 00:51:47,000
FDD DEGENERATIVE SPACE, SOME OF

1559
00:51:47,000 --> 00:51:47,880
THE THERAPIES ARE BEING

1560
00:51:47,880 --> 00:51:50,800
ATTEMPTED RELY ON US -ING

1561
00:51:50,800 --> 00:51:52,000
OLIGOs TO REDUCE LEVELS OF

1562
00:51:52,000 --> 00:51:52,840
EXPRESSION OF SOME OF THE GENES

1563
00:51:52,840 --> 00:51:57,400
THAT ARE ASSOCIATE WIDE ALS. 

1564
00:51:57,400 --> 00:51:58,960
AND I THINK THAT WHEN WE THINK

1565
00:51:58,960 --> 00:52:00,800
ABOUT DOING THAT, THERE REALLY

1566
00:52:00,800 --> 00:52:04,920
IS A RISK THAT YOU'RE NOW TAKING

1567
00:52:04,920 --> 00:52:06,440
A HAMMER TO MANY DIFFERENT CELL

1568
00:52:06,440 --> 00:52:09,080
TYPES BUT IN PARTICULAR, YOU'RE

1569
00:52:09,080 --> 00:52:10,640
MANIPULATING GENE EXPRESSION OF

1570
00:52:10,640 --> 00:52:12,240
HEALTHY MOTOR NEURONS AS WELL,

1571
00:52:12,240 --> 00:52:13,560
THESE ARE NOT JUST KIND OF GENES

1572
00:52:13,560 --> 00:52:15,920
THAT ARE OUT THERE, EQUALLY

1573
00:52:15,920 --> 00:52:17,400
DISTRIBUTED AMONGST ALL NEURONS,

1574
00:52:17,400 --> 00:52:19,480
BUT THESE ARE MOTOR NEURON

1575
00:52:19,480 --> 00:52:22,760
GENES, THESE ARE THE GENES MOTOR

1576
00:52:22,760 --> 00:52:24,600
NEURONS NEEDAD A PHYSIOLOGICAL

1577
00:52:24,600 --> 00:52:30,560
LEVEL TO HAVE THEIR FUNCTION.

1578
00:52:30,560 --> 00:52:32,080
IT'S WELL BEYOND TO SPECULATE IN

1579
00:52:32,080 --> 00:52:34,440
TERMS OF WHETHER IT'S COUNTED

1580
00:52:34,440 --> 00:52:36,760
FOR THE DISAPPOINTING RESULTS

1581
00:52:36,760 --> 00:52:37,920
WITH THE OLIGOs BUT IT'S

1582
00:52:37,920 --> 00:52:39,120
SOMETHING WE NEED TO KEEP IN

1583
00:52:39,120 --> 00:52:40,640
MIND AS WE DEVELOP THE NEXT

1584
00:52:40,640 --> 00:52:42,840
VERSION OF THEM FOR INSTANCE,

1585
00:52:42,840 --> 00:52:44,840
HAVING THEM BE ALLELE SPECIFIC

1586
00:52:44,840 --> 00:52:46,160
TO GENETIC VARIANTS OR MUTATIONS

1587
00:52:46,160 --> 00:52:48,000
THAT ARE DISEASE CAUSING AS

1588
00:52:48,000 --> 00:52:52,560
OPPOSE TO JUST MANIPULATING

1589
00:52:52,560 --> 00:52:52,920
PROTEIN LEVELS.

1590
00:52:52,920 --> 00:52:57,600
WHICH I THINK WILL REALLY NEED

1591
00:52:57,600 --> 00:52:58,920
TO BE CONSIDERED; YEAH.

1592
00:52:58,920 --> 00:53:00,200
>> THANK YOU VERY MUCH.

1593
00:53:00,200 --> 00:53:06,080
YOU KNOW THE DONORS YOU USED

1594
00:53:06,080 --> 00:53:08,640
WERE ON THE ALTHOUGH YOU'RE IN

1595
00:53:08,640 --> 00:53:10,400
THE AGE GROUP, YOU DON'T SAY

1596
00:53:10,400 --> 00:53:12,880
OLDER, SO COULD THIS BE AN AGING

1597
00:53:12,880 --> 00:53:13,160
SIGNATURE?

1598
00:53:13,160 --> 00:53:15,080
>> IT'S A GREAT QUESTION.

1599
00:53:15,080 --> 00:53:16,360
WE DON'T THINK SO AND THE REASON

1600
00:53:16,360 --> 00:53:19,120
IS AT LEAST THAT WE'VE LOOKED IN

1601
00:53:19,120 --> 00:53:20,960
MOUSE AND IT DOESN'T SEEM TO

1602
00:53:20,960 --> 00:53:22,520
INCREASE WITH AGE IN MICE, SO

1603
00:53:22,520 --> 00:53:25,040
FIRST OF ALL WE THINK IT'S

1604
00:53:25,040 --> 00:53:26,360
SPECIES SPECIFIC DIFFERENCE BUT

1605
00:53:26,360 --> 00:53:28,320
SOME OF OUR VALIDATING TISSUE

1606
00:53:28,320 --> 00:53:31,520
CAME FROM YOUNGER PATIENTS.

1607
00:53:31,520 --> 00:53:33,080
SO WE HAD--THE INITIAL DISCOVERY

1608
00:53:33,080 --> 00:53:36,560
WAS BASED ON OUR DATA SET FROM

1609
00:53:36,560 --> 00:53:37,760
50-80 YEAR-OLDS BUT WE'VE BEEN

1610
00:53:37,760 --> 00:53:39,520
REALLY CAREFUL AS WE GO BACK NOW

1611
00:53:39,520 --> 00:53:42,240
AND VALIDATE SOME OF OUR

1612
00:53:42,240 --> 00:53:43,720
FINDINGS IN INDEPENDENT TISSUE,

1613
00:53:43,720 --> 00:53:44,880
TO USE YOUNGER MATERIAL AS WELL,

1614
00:53:44,880 --> 00:53:47,800
AND WE SEE THE SAME THINGS

1615
00:53:47,800 --> 00:53:51,200
THERE, SO THE BIG RESOURCE, I

1616
00:53:51,200 --> 00:53:52,680
CAN'T SWEAR THERE AREN'T AGE

1617
00:53:52,680 --> 00:53:53,840
RELATED FEATURES IN THERE, BUT

1618
00:53:53,840 --> 00:53:55,120
THE CORE FINDING I SHARED WITH

1619
00:53:55,120 --> 00:53:57,320
YOU TODAY ABOUT THE ALS RELATED

1620
00:53:57,320 --> 00:53:59,160
GENES IN HUMAN MOTOR NEURONS WE

1621
00:53:59,160 --> 00:54:04,880
THINK IS A GENERAL FINDING AT

1622
00:54:04,880 --> 00:54:05,320
LEAST IN ADULTHOOD.

1623
00:54:05,320 --> 00:54:06,200
>> YOU KNOW WITH REGARDS
TO

1624
00:54:06,200 --> 00:54:08,800
THAT, DO YOU THINK THAT--CAN YOU

1625
00:54:08,800 --> 00:54:10,280
SPECULATE WHY SOME OF THESE

1626
00:54:10,280 --> 00:54:14,200
NEURONS WITH LONG AXONS COULD

1627
00:54:14,200 --> 00:54:16,960
HAVE THIS SIGNATURE WHILE OTHERS

1628
00:54:16,960 --> 00:54:17,200
DO NOT?

1629
00:54:17,200 --> 00:54:19,200
>> YEAH, AND HERE I'M
DEFINITELY

1630
00:54:19,200 --> 00:54:23,720
SPECULATING, JUST TO BE CLEAR.

1631
00:54:23,720 --> 00:54:27,720
I WOULD SAY IT SEEMS TO BE MANY

1632
00:54:27,720 --> 00:54:29,520
LONG NEURONS HAVE THESE GENES,

1633
00:54:29,520 --> 00:54:30,200
NOT ALL.

1634
00:54:30,200 --> 00:54:32,480
AND MANY LONG NEURONS ARE

1635
00:54:32,480 --> 00:54:34,040
VULNERABILITY TO DEGENERATION,

1636
00:54:34,040 --> 00:54:35,640
NOT ALL.

1637
00:54:35,640 --> 00:54:40,480
AND I THINK ABOUT A GOOD COUNTER

1638
00:54:40,480 --> 00:54:42,840
POINT IS THE ASCENDING NEURONS

1639
00:54:42,840 --> 00:54:44,600
THAT CONVEY PAIN SIGNALS SO THEY

1640
00:54:44,600 --> 00:54:46,680
HAVE VERY SMALL CELL BODIES AND

1641
00:54:46,680 --> 00:54:47,720
THEY'RE NOT PRONE TO

1642
00:54:47,720 --> 00:54:48,760
GERONTOLOGYSTS GENERATION AS FAR

1643
00:54:48,760 --> 00:54:55,560
AS WE KNOW IN SOME OF THE

1644
00:54:55,560 --> 00:54:56,080
GERONTOLOGYSTS GENRATIVE

1645
00:54:56,080 --> 00:54:57,080
DISEASES, SO IT DOESN'T JUST

1646
00:54:57,080 --> 00:54:59,320
TAKE OUT UPPER AND LOWER NEURONS

1647
00:54:59,320 --> 00:55:00,720
IT ALSO TAKES OUT OTHER LARGE

1648
00:55:00,720 --> 00:55:03,400
NEURONS IN THE SPINAL CORD WITH

1649
00:55:03,400 --> 00:55:05,840
DISEASE PROGRESS INCLUDING

1650
00:55:05,840 --> 00:55:06,760
SPINAL CEREBELLAR NEURONS BUT

1651
00:55:06,760 --> 00:55:09,160
THIS OTHER GROUP OF PROJECTION

1652
00:55:09,160 --> 00:55:10,480
NEURONS THAT DP FROM THE SPINAL

1653
00:55:10,480 --> 00:55:12,440
CORD UP TO BRAIN ARE LITERALLY

1654
00:55:12,440 --> 00:55:14,200
JUST AS LONG, RIGHT?

1655
00:55:14,200 --> 00:55:15,400
THEY HAVE TO TRAVERSE ALL THE

1656
00:55:15,400 --> 00:55:17,240
SAME TISSUE AND YET THEY DON'T

1657
00:55:17,240 --> 00:55:18,320
DEGENERATE AND CERTAINLY IT'S

1658
00:55:18,320 --> 00:55:20,240
NOT OFLE FOR US TO SUGGIEST THAT

1659
00:55:20,240 --> 00:55:21,160
CELL SIZE IS A COMOPPOSITE

1660
00:55:21,160 --> 00:55:23,040
BEHAVIORIAL PHENOTYPENT OF THIS,

1661
00:55:23,040 --> 00:55:24,760
CELL BODY SIZE, THAT'S AN

1662
00:55:24,760 --> 00:55:25,640
ESTABLISHED CONCEPT IN THE FIELD

1663
00:55:25,640 --> 00:55:29,880
BUT I THINK THE OTHER PIECE IS

1664
00:55:29,880 --> 00:55:30,080
USE.

1665
00:55:30,080 --> 00:55:32,080
SO HOPEFULLY YOUR PAIN NEURONS

1666
00:55:32,080 --> 00:55:35,120
ARE RARELY USED AND THEY'RE AS A

1667
00:55:35,120 --> 00:55:37,160
RESULT RELATIVELY QUIESCENT BUT

1668
00:55:37,160 --> 00:55:38,080
YOUR MOTOR NEURONS YOU'RE USING

1669
00:55:38,080 --> 00:55:40,160
ALL THE TIME AND YOUR SPINAL

1670
00:55:40,160 --> 00:55:41,920
NEURONS YOU'RE USING ALL THE

1671
00:55:41,920 --> 00:55:42,120
TIME.

1672
00:55:42,120 --> 00:55:44,320
AND I WONDER IF THIS IS REALLY A

1673
00:55:44,320 --> 00:55:50,520
COMBINATION OF MAYBE 3 THINGS.

1674
00:55:50,520 --> 00:55:52,440
CELL SIZE, SELL PHYSIOLOGY, KIND

1675
00:55:52,440 --> 00:55:54,160
OF THE RELATIVELY ACTIVE STATE

1676
00:55:54,160 --> 00:55:56,040
AND THE THIRD PEEZ IS MAYBE

1677
00:55:56,040 --> 00:55:58,640
WHERE AND TEAR, SO A LOT OF

1678
00:55:58,640 --> 00:56:00,560
THESE NEURONS ARE PHYSICALLY

1679
00:56:00,560 --> 00:56:03,120
CHALLENGED ALL THE TIME, RIGHT?

1680
00:56:03,120 --> 00:56:03,840
YOUR MOTOR NEURONAXONS ARE

1681
00:56:03,840 --> 00:56:04,880
GETTING OUT INTO THE BODY AND

1682
00:56:04,880 --> 00:56:07,600
EVERY TIME YOU MOVE A JOINT,

1683
00:56:07,600 --> 00:56:18,120
YOU'RE WORKING THATAXON AND I

1684
00:56:19,080 --> 00:56:20,560
THINK THAT THAT AND TRACK THEM

1685
00:56:20,560 --> 00:56:22,400
THAT ARE COMING IN THE BODY AND

1686
00:56:22,400 --> 00:56:24,680
HAVE THIS SENSORY AS WELL BUT

1687
00:56:24,680 --> 00:56:27,640
SENSORY NEURONS REGENERATE AND

1688
00:56:27,640 --> 00:56:30,040
I'M SPECULATING WILDLY HERE, IT

1689
00:56:30,040 --> 00:56:32,480
RESPONDS TO THE NEED FOR

1690
00:56:32,480 --> 00:56:34,000
ADOMAINICATING STRETCH AND THE

1691
00:56:34,000 --> 00:56:36,200
ABILITY TO DO THAT AND FOR SOME

1692
00:56:36,200 --> 00:56:37,160
REASON MOTOR NEURONS DON'T HAVE

1693
00:56:37,160 --> 00:56:40,400
IT AND SO, THEY NEED TO KIND OF

1694
00:56:40,400 --> 00:56:41,760
COMPENSATE INSTEAD BY MAYBE

1695
00:56:41,760 --> 00:56:45,120
HAVING A LOCK DOWN REALLY STABLE

1696
00:56:45,120 --> 00:56:46,800
CYTOSKELETON, I MEAN AGAIN

1697
00:56:46,800 --> 00:56:48,960
REALLY, REALLY SPECULATING BUT I

1698
00:56:48,960 --> 00:56:50,720
THINK THAT MOVING FORWARD HAVING

1699
00:56:50,720 --> 00:56:54,400
A GREATER RESOLUTION FOR

1700
00:56:54,400 --> 00:56:56,680
INSTANCE OF VULNERABLABLE

1701
00:56:56,680 --> 00:56:58,000
POPULATIONS OF MOTOR NEURONS

1702
00:56:58,000 --> 00:56:59,280
WITH RESILIENCE WILL GIVE US

1703
00:56:59,280 --> 00:57:09,160
FURTHER INSIGHT INTO THAT.

1704
00:57:09,160 --> 00:57:09,920
>> THANK YOU.

1705
00:57:09,920 --> 00:57:11,200
FINALLY DO YOU PREDICT THAT THIS

1706
00:57:11,200 --> 00:57:12,520
WILL SET A DIFFERENT SET OF

1707
00:57:12,520 --> 00:57:13,640
MOTOR GENERALLABILITY TO

1708
00:57:13,640 --> 00:57:14,360
DEGENERATION.

1709
00:57:14,360 --> 00:57:15,720
>>YES, AND I THINK IT'S A

1710
00:57:15,720 --> 00:57:17,120
QUESTION FOR THE FUTURE.

1711
00:57:17,120 --> 00:57:21,240
I THINK THAT MY GUESS IS THAT

1712
00:57:21,240 --> 00:57:22,520
THE PARTICULAR RATIOS BETWEEN

1713
00:57:22,520 --> 00:57:25,240
THESE FACTORS WILL MATTER A LOT

1714
00:57:25,240 --> 00:57:26,520
AND THAT THOSE SUBTLE

1715
00:57:26,520 --> 00:57:27,920
DIFFERENCES WILL BE SOMETHING

1716
00:57:27,920 --> 00:57:31,240
THAT WE CAN BEST ASSESS BY

1717
00:57:31,240 --> 00:57:33,120
COMPARING FOR INSTANCE DIFFERENT

1718
00:57:33,120 --> 00:57:35,200
POPULATIONS OF MOTOR NEURONS AND

1719
00:57:35,200 --> 00:57:36,720
ALSO, NOW THAT SO MANY PEOPLE

1720
00:57:36,720 --> 00:57:38,280
ARE USING SINGLE CELL SEQUENCING

1721
00:57:38,280 --> 00:57:42,280
WE CAN TAKE DATA THAT PEOPLE GET

1722
00:57:42,280 --> 00:57:44,600
FROM FOR INSTANCE CELLS THAT

1723
00:57:44,600 --> 00:57:46,120
SHOW DIFFERENT VULNERABILITY TO

1724
00:57:46,120 --> 00:57:47,520
DEGENERATION, AND START TRYING

1725
00:57:47,520 --> 00:57:50,200
TO REALLY UNPACK WHAT ARE THE

1726
00:57:50,200 --> 00:57:53,000
COMMON SIGNATURES EITHER AT A

1727
00:57:53,000 --> 00:57:53,760
MORPHOLOGICAL LEVEL,

1728
00:57:53,760 --> 00:57:54,840
PHYSIOLOGICAL LEVEL AND HERE, OF

1729
00:57:54,840 --> 00:57:57,200
COURSE AT THE MOLECULAR LEVEL

1730
00:57:57,200 --> 00:57:58,600
THAT REALLY ALLOWS US TO KIND OF

1731
00:57:58,600 --> 00:58:01,000
ZOOM OUT AND SEE WHAT'S THE

1732
00:58:01,000 --> 00:58:05,960
COMMON POINT OF VIEW.

1733
00:58:05,960 --> 00:58:07,800
>> OKAY.

1734
00:58:07,800 --> 00:58:08,440
>> WELL, DR. LEVINE, THANK
YOU

1735
00:58:08,440 --> 00:58:10,040
VERY MUCH AGAIN FOR SHARING YOUR

1736
00:58:10,040 --> 00:58:11,200
GREAT FASCINATING WORK AND YOUR

1737
00:58:11,200 --> 00:58:11,400
TALK.

1738
00:58:11,400 --> 00:58:13,480
ALL OF US HERE AT NIH COMMUNITY

1739
00:58:13,480 --> 00:58:14,360
APPRECIATE THAT.

1740
00:58:14,360 --> 00:58:15,920
AND WE WISH YOU THE BEST OF LUCK

1741
00:58:15,920 --> 00:58:17,640
WITH YOUR FUTURE INVESTIGATIONS.

1742
00:58:17,640 --> 00:58:18,520
>> THANK YOU SO MUCH.

1743
00:58:18,520 --> 00:58:20,320
>> AND TO EVERYONE ELSE
HAVE A

1744
00:58:20,320 --> 00:58:20,720
WONDERFUL AFTERNOON.

1745
00:58:20,720 --> 00:58:31,200
THANK YOU FOR JOINING US.