1. UNDERSTANDING STEM CELL RESEARCH Larry Goldstein, Ph.D. Vice Chair, Public Policy Committee The American Society for Cell Biology

2. UNDERSTANDING THE DEBATE ABOUT HUMAN STEM CELL RESEARCH WHY ARE THESE TECHNOLOGIES NEEDED? WHY ARE THESE TECHNOLOGIES NEEDED? LIMITS OF ORGAN TRANSPLANT LIMITS OF ORGAN TRANSPLANT REGENERATIVE MEDICINE REGENERATIVE MEDICINE EMBRYONIC AND ADULT STEM CELLS EMBRYONIC AND ADULT STEM CELLS SOMATIC CELL NUCLEAR TRANSPLANTATION AND CLONING SOMATIC CELL NUCLEAR TRANSPLANTATION AND CLONING SCIENCE SCIENCE LEGAL SITUATION LEGAL SITUATION

3. CELLS ARE THE FUNCTIONAL UNIT OF THE HUMAN BODY CELLS ARE THE FUNCTIONAL UNIT OF THE HUMAN BODY SMALL BUSINESSES SMALL BUSINESSES CELLS HAVE DIFFERENT JOBS CELLS HAVE DIFFERENT JOBS SPECIALIZE/DIFFERENTIATED SPECIALIZE/DIFFERENTIATED PANCREATIC CELLS-INSULIN PANCREATIC CELLS-INSULIN NEURONS-TRANSMIT SIGNALS NEURONS-TRANSMIT SIGNALS HEART CELLS-CONTRACT TO PUMP BLOOD HEART CELLS-CONTRACT TO PUMP BLOOD MANY DISEASES ARE CAUSED BY BREAKDOWNS IN THE CELL MANY DISEASES ARE CAUSED BY BREAKDOWNS IN THE CELL SOMETIMES CELL ALIVE BUT DAMAGED SOMETIMES CELL ALIVE BUT DAMAGED SOMETIMES CELL DIES AND IS LOST SOMETIMES CELL DIES AND IS LOST BASIC PRINCIPLES

4. MANY DISEASES ARE ASSOCIATED WITH TISSUE DAMAGE OR LOSS ALZHEIMERS DISEASE-BRAIN CELLS (4 MILLION) ALZHEIMERS DISEASE-BRAIN CELLS (4 MILLION) PARKINSONS DISEASE-BRAIN CELLS (1.5 MILLION) PARKINSONS DISEASE-BRAIN CELLS (1.5 MILLION) RETINITIS PIGMENTOSA-RETINAL CELLS RETINITIS PIGMENTOSA-RETINAL CELLS CANCER-VARIOUS (8.2 MILLION) CANCER-VARIOUS (8.2 MILLION) DIABETES-PANCREATIC CELLS (16 MILLION) DIABETES-PANCREATIC CELLS (16 MILLION) MUSCULAR DYSTROPHY-MUSCLE MUSCULAR DYSTROPHY-MUSCLE HEART FAILURE AND OTHER CARDIOVASCULAR DISEASE-HEART MUSCLE (58 MILLION) HEART FAILURE AND OTHER CARDIOVASCULAR DISEASE-HEART MUSCLE (58 MILLION) KIDNEY AND LIVER DISEASE KIDNEY AND LIVER DISEASE SCIENCE 287:1423

5. USING TRANSPLANT ORGANS TO REPLACE DAMAGED TISSUE THE GOOD: THE GOOD: KNOWN SOURCES-LIVE DONOR OR CADAVER KNOWN SOURCES-LIVE DONOR OR CADAVER SURGICAL REPLACEMENT METHODS ADVANCED SURGICAL REPLACEMENT METHODS ADVANCED DONOR ORGAN ARCHITECTURE GENERALLY APPROPRIATE DONOR ORGAN ARCHITECTURE GENERALLY APPROPRIATE THE BAD: THE BAD: DIFFICULT TO FIND GENETICALLY MATCHED DONORS DIFFICULT TO FIND GENETICALLY MATCHED DONORS LONGEVITY AND SAFETY CAN BE PROBLEMATIC LONGEVITY AND SAFETY CAN BE PROBLEMATIC THE UGLY THE UGLY DONOR TISSUE NOT ALWAYS KNOWN, E.G., ALZHEIMERS OR PARKINSONS DONOR TISSUE NOT ALWAYS KNOWN, E.G., ALZHEIMERS OR PARKINSONS NEED FAR OUTSTRIPS SUPPLY NEED FAR OUTSTRIPS SUPPLY HOW MIGHT STEM CELLS HELP? HOW MIGHT STEM CELLS HELP?

6. HOW CAN STEM CELLS HELP? WHAT ARE STEM CELLS? WHAT ARE STEM CELLS? CELLS THAT CAN DIVIDE TO GIVE RISE TO: CELLS THAT CAN DIVIDE TO GIVE RISE TO: MORE STEM CELLS MORE STEM CELLS CELLS THAT CAN ADOPT SPECIALIZED JOBS CELLS THAT CAN ADOPT SPECIALIZED JOBS WHY ARE STEM CELLS PROMISING? WHY ARE STEM CELLS PROMISING? THE RAW MATERIAL TO REPLACED DAMAGED CELLS AND ORGANS? THE RAW MATERIAL TO REPLACED DAMAGED CELLS AND ORGANS? TOOLS TO UNDERSTAND AND COMBAT DISEASE TOOLS TO UNDERSTAND AND COMBAT DISEASE LIMITS OF ORGAN TRANSPLANT LIMITS OF ORGAN TRANSPLANT SOLUTION TO SUPPLY AND SOURCE PROBLEMS SOLUTION TO SUPPLY AND SOURCE PROBLEMS

7. OVERVIEW OF NORMAL MAMMALIAN DEVELOPMENT ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG1B2.GIF SPERM ZYGOTE (TOTIPOTENT) BLASTOCYSTFETUSFERTILIZATION INNER CELL MASS (PLURIPOTENT) IMPLANTATION EGG (OOCYTE) ADULT

8. EXAMPLES OF NATURALLY OCCURRING STEM CELLS ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG2.GIF TOTIPOTENT CELLS PLURIPOTENT STEM CELLS (EMBRYONIC STEM CELLS) OTHER COMMITTED STEM CELLS (NEURONS, ETC.) WHITE BLOOD CELLS PLATELETS RED BLOOD CELLS SPECIALIZED CELLS: BLOOD STEM CELLS ADULT STEM CELLS

9. SPERM ZYGOTE (TOTIPOTENT) BLASTOCYSTFETUSFERTILIZATION INNER CELL MASS (PLURIPOTENT) EGG (OOCYTE) ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG3.GIF ADULT HOW ARE EMBRYONIC STEM CELLS DERIVED? INNER CELL MASS CULTURED PLURIPOTENT STEM CELLS EMBRYONIC STEM CELLS (ES)

10. WHAT DO WE KNOW ABOUT EMBRYONIC STEM CELLS? STRONG, RELIABLE, HIGHLY REPRODUCIBLE DATA ESTABLISH PLURIPOTENCY (ALMOST 20 YEARS OF DATA ON EXPERIMENTAL ORGANISMS) STRONG, RELIABLE, HIGHLY REPRODUCIBLE DATA ESTABLISH PLURIPOTENCY (ALMOST 20 YEARS OF DATA ON EXPERIMENTAL ORGANISMS) SOLID THEORETICAL AND EXPERIMENTAL FOUNDATION TO: SOLID THEORETICAL AND EXPERIMENTAL FOUNDATION TO: INDUCE DEVELOPMENT OF SPECIALIZED CELL TYPES INDUCE DEVELOPMENT OF SPECIALIZED CELL TYPES SOLVE REJECTION PROBLEM SOLVE REJECTION PROBLEM CAN HAVE GOOD GROWTH PROPERTIES CAN HAVE GOOD GROWTH PROPERTIES PROMISING PROOF OF PRINCIPLE RESEARCH PROMISING PROOF OF PRINCIPLE RESEARCH

11. SCIENTIFIC ISSUES ABOUT POSSIBLE USE OF EMBRYONIC STEM CELLS TO TREAT DISEASE PRO: PRO: APPARENT PLURIPOTENCY-COULD GENERATE ANY CELL TYPE APPARENT PLURIPOTENCY-COULD GENERATE ANY CELL TYPE SOURCE-USUALLY FROZEN EMBRYOS REMAINING AFTER IVF SOURCE-USUALLY FROZEN EMBRYOS REMAINING AFTER IVF SUFFICIENT SUPPLY-CELLS HAVE SUBSTANTIAL GROWTH POTENTIAL ONCE DERIVED SUFFICIENT SUPPLY-CELLS HAVE SUBSTANTIAL GROWTH POTENTIAL ONCE DERIVED GENETIC MATCH TO LIMIT REJECTION-MHC REPLACEMENT AND OTHER IDEAS GENETIC MATCH TO LIMIT REJECTION-MHC REPLACEMENT AND OTHER IDEAS LONGEVITY-LIKELY TO BE SUBSTANTIAL LONGEVITY-LIKELY TO BE SUBSTANTIAL CON: CON: PROPER ARCHITECTURE-NEEDS WORK PROPER ARCHITECTURE-NEEDS WORK NOT YET KNOWN HOW TO CONTROL CELLS NOT YET KNOWN HOW TO CONTROL CELLS SAFETY-UNKNOWN SAFETY-UNKNOWN NEW REPLACEMENT METHODS NEEDED NEW REPLACEMENT METHODS NEEDED GENETIC MATCH/REJECTION GENETIC MATCH/REJECTION

12. SOME EXISTING EXAMPLES OF THE USE OF EMBRYONIC STEM CELLS PARTIAL REPAIR OF SPINAL CORD DAMAGE IN RAT PARTIAL REPAIR OF SPINAL CORD DAMAGE IN RAT PARTIAL REPAIR OF MULTIPLE SCLEROSIS MODEL IN RAT PARTIAL REPAIR OF MULTIPLE SCLEROSIS MODEL IN RAT PARTIAL REPAIR OF PARKINSONS MODEL IN RAT PARTIAL REPAIR OF PARKINSONS MODEL IN RAT INDUCED DIFFERENTIATION TO MUSCLE, NEURONS, PANCREATIC CELLS INDUCED DIFFERENTIATION TO MUSCLE, NEURONS, PANCREATIC CELLS STUDIES OF DISEASE MECHANISM, E.G., ALS STUDIES OF DISEASE MECHANISM, E.G., ALS REPEATED DEMONSTRATION THAT MOUSE EMBRYONIC STEM CELLS CAN CONTRIBUTE TO ANY ADULT TISSUE REPEATED DEMONSTRATION THAT MOUSE EMBRYONIC STEM CELLS CAN CONTRIBUTE TO ANY ADULT TISSUE

13. WHAT DO WE KNOW ABOUT ADULT STEM CELLS MOST WORK SUGGESTS RESTRICTED CAPACITY AND RESTRICTED GROWTH POTENTIAL MOST WORK SUGGESTS RESTRICTED CAPACITY AND RESTRICTED GROWTH POTENTIAL A COMPARATIVELY SMALL NUMBER OF RECENT EXPERIMENTS SUGGEST MORE POTENTIAL THAN ORIGINALLY THOUGHT A COMPARATIVELY SMALL NUMBER OF RECENT EXPERIMENTS SUGGEST MORE POTENTIAL THAN ORIGINALLY THOUGHT BUT, MANY OF THESE SURPRISING RECENT EXPERIMENTS- BUT, MANY OF THESE SURPRISING RECENT EXPERIMENTS- ARE NOT YET REPRODUCIBLE ARE NOT YET REPRODUCIBLE ARE CHARACTERIZED BY FLAWED DESIGN, FLAWED ASSAYS, OR POOR QUALITY DATA ARE CHARACTERIZED BY FLAWED DESIGN, FLAWED ASSAYS, OR POOR QUALITY DATA MOST EVALUATIONS OF EXISTING DATA BY EXPERTS ON ADULT STEM CELLS AND EXPERT SCIENTIFIC BODIES STATE THAT EVIDENCE DOES NOT SUPPORT THE CONTENTION THAT ADULT STEM CELLS CAN REPLACE EMBRYONIC STEM CELLS MOST EVALUATIONS OF EXISTING DATA BY EXPERTS ON ADULT STEM CELLS AND EXPERT SCIENTIFIC BODIES STATE THAT EVIDENCE DOES NOT SUPPORT THE CONTENTION THAT ADULT STEM CELLS CAN REPLACE EMBRYONIC STEM CELLS

14. SCIENTIFIC ISSUES ABOUT POSSIBLE USE OF ADULT STEM CELLS TO TREAT DISEASE PRO: PRO: SOURCE-BONE MARROW WELL KNOWN SOURCE-BONE MARROW WELL KNOWN GENETIC MATCH OK IF AUTOLOGOUS GENETIC MATCH OK IF AUTOLOGOUS GENETIC MATCH FOR BMT SOLVABLE GENETIC MATCH FOR BMT SOLVABLE CON CON UNKNOWN POTENCY-PLURIPOTENT, MULTIPOTENT, UNIPOTENT? UNKNOWN POTENCY-PLURIPOTENT, MULTIPOTENT, UNIPOTENT? RARE-NO SOURCE IDENTIFIED FOR MANY DISEASES RARE-NO SOURCE IDENTIFIED FOR MANY DISEASES SUBSTANTIAL GROWTH AND IDENTIFICATION ISSUES SUBSTANTIAL GROWTH AND IDENTIFICATION ISSUES PROPER ARCHITECTURE-NEEDS WORK PROPER ARCHITECTURE-NEEDS WORK LONGEVITY AND SAFETY ISSUES UNKNOWN LONGEVITY AND SAFETY ISSUES UNKNOWN NEW REPLACEMENT METHODS NEEDED NEW REPLACEMENT METHODS NEEDED GENETIC MATCH/REJECTION GENETIC MATCH/REJECTION

15. SOME EXAMPLES OF THE USE OF ADULT STEM CELLS BONE MARROW TRANSPLANTS BONE MARROW TRANSPLANTS PANCREATIC DUCTAL CELLS USED TO REPAIR MOUSE MODEL OF DIABETES PANCREATIC DUCTAL CELLS USED TO REPAIR MOUSE MODEL OF DIABETES MANY RECENT EXAMPLES OF DIFFERENTIATION IN VITRO AND ACROSS TYPICAL BOUNDARIES MANY RECENT EXAMPLES OF DIFFERENTIATION IN VITRO AND ACROSS TYPICAL BOUNDARIES INDUCED DIFFERENTIATION OF BONE MARROW CELLS AND CELLS FROM LIPOSUCTION TO MANY DIFFERENT CELL TYPES INDUCED DIFFERENTIATION OF BONE MARROW CELLS AND CELLS FROM LIPOSUCTION TO MANY DIFFERENT CELL TYPES INDUCED DIFFERENTIATION OF BRAIN STEM CELLS TO MANY DIFFERENT CELL TYPES INDUCED DIFFERENTIATION OF BRAIN STEM CELLS TO MANY DIFFERENT CELL TYPES -MUCH OF THE WORK IS RECENT AND CONTROVERSIAL -MORE WORK AND DEMONSTRATION OF REPRODUCIBILITY NEEDED!!

16. EXCERPTS FROM: STEM CELL RESEARCH SUCCESS IN US THE WORLD TODAY - THURSDAY, AUGUST 22, 2002 12:45 (HTTP://WWW.ABC.NET.AU/WORLDTODAY/S656192.HTM) BEN KNIGHT: YOU SAY IT'S THEORETICALLY POSSIBLE THAT ADULT CELLS MIGHT BE BETTER AT TREATING SOME DISEASES, EMBRYONIC CELLS MIGHT BE BETTER AT TREATING OTHER DISEASES. DO YOU HAVE ANY IDEA OF WHICH IS WHICH? CATHERINE VERFAILLE: AT THIS POINT, I THINK IT'S WAY TOO EARLY. FOR INSTANCE, THE EXAMPLE I ALWAYS USE, IS EMBRYONIC CELLS MAKE VERY READILY HEART MUSCLE CELLS, WHICH IS THUS FAR OFF AND VERY HARD TO DO WITH THE ADULT CELLS. SO FOR INSTANCE IF THAT'S HOLD TRUE, IF YOU THINK ABOUT READING HEART [UNCLEAR] DOWN THE LINE, YOU MAY HAVE TO RESORT BACK TO EMBRYONIC CELLS TO DO THAT AND THE ADULT CELLS MAY NOT TURN OUT TO BE FEASIBLE FOR THAT. BEN KNIGHT: YOU'RE CALLING EFFECTIVELY FOR TANDEM RESEARCH, HAVE YOU BEEN FOLLOWING THE DISCUSSION IN AUSTRALIA ON THIS SUBJECT? CATHERINE VERFAILLE: I HAVE, AND I COME FROM THE US WHERE THE SAME DISCUSSION WAS HELD ABOUT A YEAR AGO, AND THERE'S STILL ON-GOING DISCUSSIONS FOR THERAPEUTIC CLONING, WHICH IS SORT OF THE SAME DISCUSSION AT ONCE. AND SO I THINK MY MESSAGE HAS ALWAYS BEEN, EVEN THOUGH WE'RE EXCITED ABOUT THE ADULT CELLS, THAT IT'S TOO EARLY TO SAY THAT THEY WILL REPLACE EMBRYONIC STEM CELLS TO THE POINT THAT OUR INSTITUTION, THE STEM CELL INSTITUTE, WE ACTUALLY RECRUITED AND INVESTIGATED WHO HAS EXTENSIVE EXPERIENCE IN HUMAN EMBRYONIC STEM CELL WORK, SO WE'RE NOW IN A POSITION TO DO EXACTLY WHAT YOU MENTIONED, WHICH IS TO PARALLEL RESEARCH AND COMPARING AND CONTRASTING THE TWO CELL TYPES. © 2002 ABC | PRIVACY POLICY

17. ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG4B.GIF BLASTOCYST INNER CELL MASS (PLURIPOTENT) EGG (OOCYTE) (REMOVE OOCYTE NUCLEUS) FUSION SOMATIC CELL NUCLEAR TRANSFER WHAT IS NUCLEAR TRANSPLANT TECHNOLOGY? ADULT ??? INNER CELL MASS CULTURED PLURIPOTENT STEM CELLS

18. EXAMPLES OF NUCLEAR TRANSPLANTATION TO GENERATE ADULT ANIMALS SHEEP SHEEP CAT CAT GOAT GOAT COW COW PIG PIG MOUSE MOUSE BUT EFFICIENCY POOR AND FREQUENT ABNORMAL DEVELOPMENT BUT EFFICIENCY POOR AND FREQUENT ABNORMAL DEVELOPMENT IMPRINTING PROBLEMS MAY BE SEVERE IMPRINTING PROBLEMS MAY BE SEVERE LIKELY TO BE UNSUCCESSFUL OR DANGEROUS IN HUMANS! LIKELY TO BE UNSUCCESSFUL OR DANGEROUS IN HUMANS! SCIENCE 288:1723

19. SCIENTIFIC ISSUES ABOUT POSSIBLE USE OF NUCLEAR TRANSPLANT TO TREAT DISEASE PRO: PRO: SOURCE-ADULT CELLS AND OOCYTES SOURCE-ADULT CELLS AND OOCYTES THEORETICAL PLURIPOTENCY THEORETICAL PLURIPOTENCY SUFFICIENT SUPPLY-COULD BE LARGE SUFFICIENT SUPPLY-COULD BE LARGE GENETICALLY ALMOST IDENTICAL SO MINIMAL REJECTION GENETICALLY ALMOST IDENTICAL SO MINIMAL REJECTION LONGEVITY-LIKELY TO BE SUBSTANTIAL LONGEVITY-LIKELY TO BE SUBSTANTIAL CON CON PROPER ARCHITECTURE-NEEDS WORK PROPER ARCHITECTURE-NEEDS WORK NOT YET KNOWN HOW TO CONTROL CELLS NOT YET KNOWN HOW TO CONTROL CELLS SAFETY-UNKNOWN SAFETY-UNKNOWN NEW REPLACEMENT METHODS NEEDED NEW REPLACEMENT METHODS NEEDED

20. ETHICAL AND LEGAL ISSUES ABOUT NUCLEAR TRANSPLANT TECHNOLOGY CONTROVERSIAL ETHICAL STATUS OF EARLY HUMAN EMBRYO AND PRODUCT OF NUCLEAR TRANSPLANT CONTROVERSIAL ETHICAL STATUS OF EARLY HUMAN EMBRYO AND PRODUCT OF NUCLEAR TRANSPLANT PUBLIC ANTIPATHY TOWARDS CLONING PUBLIC ANTIPATHY TOWARDS CLONING NEED TO SAFEGUARD BENEFICIAL USES WHILE PROTECTING SOCIETY FROM ILLEGITIMATE USES NEED TO SAFEGUARD BENEFICIAL USES WHILE PROTECTING SOCIETY FROM ILLEGITIMATE USES LEGISLATIVE SITUATION LEGISLATIVE SITUATION WHERE TO DRAW THE LINE? WHERE TO DRAW THE LINE? CALIFORNIA CALIFORNIA HOUSE OF REPRESENTATIVES HOUSE OF REPRESENTATIVES SENATE SENATE CRIMINALIZING RESEARCH METHODS VS. WITHOLDING PUBLIC FUNDING CRIMINALIZING RESEARCH METHODS VS. WITHOLDING PUBLIC FUNDING

21. WHERE SHOULD WE DRAW THE LINE? ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG4B.GIF BLASTOCYST INNER CELL MASS (PLURIPOTENT) EGG (OOCYTE) (REMOVE OOCYTE NUCLEUS) FUSION SOMATIC CELL NUCLEAR TRANSFER ADULT ??? INNER CELL MASS CULTURED PLURIPOTENT STEM CELLS WELDON BROWNBACK CALIFORNIA HATCH-FEINSTEIN- KENNEDY-SPECTER -HARKIN