MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER [email protected].
-
Upload
maximilian-strickland -
Category
Documents
-
view
227 -
download
1
Transcript of MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER [email protected].
![Page 1: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/1.jpg)
![Page 3: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/3.jpg)
CANCER SURVIVAL
Early Development
DRUG DEVELOPMENT
TOXICICOLOGY
TRANSPLANTATIONDEGENERATIVE DISEASES
TRAUMA:Spinal cordBurnsHead injury
AGING
TISSUEENGINEERING
![Page 4: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/4.jpg)
ALL STEM CELLS
CAN EITHER
-SELF-RENEW
and/or
-GENERATE SEVERALKINDS OF CELL TYPES
![Page 5: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/5.jpg)
SELF-RENEWAL
Stem Stem
StemStem Stem
Stem Stem
X
XX
StemX
![Page 6: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/6.jpg)
BLOOD STEM CELLS ARE PLURIPOTENT
![Page 7: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/7.jpg)
“-POTENCY”
• Multipotent: A few
• Pluripotent: A lot
• Totipotent: Every kind of cell including cells of the body (somatic) and cells of the germline (eggs, sperm)
![Page 8: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/8.jpg)
TOTIPOTENT
• ONLY EMBRYONIC STEM CELLS ARE CONSIDERED TOTIPOTENT
• BUT REALLY THEY ARE NOT TOTIPOTENT BECAUSE OF THE ISSUES OF COMPLEX ORGANIZATION
• ONLY THE FERTILIZED EGG
IS REALLY TOTIPOTENT
![Page 9: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/9.jpg)
WHERE DO YOU GET THEM?
ADULT STEM CELLS
-ANY STAGE OF EMBRYO
-ANY STAGE OF ADULTHOOD
EMBRYONIC STEM CELLS
-BLASTOCYST EMBRYOS
-SCNT: Somatic cell nuclear transfer
-PARTHENOTES
-iPS: Induced pluripotent cells
![Page 10: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/10.jpg)
University of Wisconsin website
![Page 11: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/11.jpg)
University of Wisconsin, 2001.
![Page 12: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/12.jpg)
University of Wisconsin, 2001.
![Page 13: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/13.jpg)
University of Wisconsin, 2001.
![Page 14: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/14.jpg)
. University of Wisconsin, 2001.
Embryonic stem cells are derived from the inner cell mass of the blastocyst stage embryo
![Page 15: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/15.jpg)
University of Wisconsin, 2001.
In the lab, trophoblast is removed and the embryonic stem cells singly selected from the inner cell mass
![Page 16: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/16.jpg)
University of Wisconsin, 2001.
ES cell cultivation in the laboratory: easier with mouse than human cells
![Page 17: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/17.jpg)
University of Wisconsin, 2001.
Using a variety of tools, in theory any cell type can be made
![Page 18: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/18.jpg)
![Page 19: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/19.jpg)
HUMAN EMBRYONIC STEM CELLS
.
![Page 20: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/20.jpg)
• Where they come from• Potency• Proliferative senesence (source material
abundance)
EMBRYONIC VS. ADULT STEM CELLS
Important differences:
![Page 21: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/21.jpg)
1997—DOLLY andTHE ERA OF CLONEDANIMALS
![Page 22: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/22.jpg)
+
![Page 23: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/23.jpg)
ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG4B.GIF
Blastocyst
Inner Cell Mass(Pluripotent)
Egg Cell (Remove Nucleus)
(Fusion)
Somatic Cell Nuclear Transfer
(Extract Inner Cell Mass)
Cultured PluripotentEmbryonic Stem Cells
Somatic Cell Nuclear Transfer: IS NOT HUMAN CLONING
Somatic Cell nucleus (any cell in the body other than an egg or germ cell)
(Stimulate Cell Division Process)
ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG3.GIF
![Page 24: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/24.jpg)
Patient advocacy for SCNT
• No immunologic barrier with cells generated from recipient
• Screening drugs for many common diseases using clones from families with inherited diseases
• First glimpse into early development
• Does not require use of embryos
![Page 25: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/25.jpg)
![Page 26: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/26.jpg)
![Page 27: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/27.jpg)
Use for parthenogenetic lines
• Genetic homozygosity
• Bank cells with specific MHC proteins
• Other uses? Engineer cells for HIV resistancemake HSC for marrow transplantation
• SCNT AND PARTHENOGENESIS REQUIRE AN EGG
• Human egg donation is not trivial
![Page 28: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/28.jpg)
All 3 germ layersrepresented-ectoderm-mesoderm-endoderm
Functional diffcell types
![Page 29: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/29.jpg)
How/why would this work?
• Huge interconnectedness of protein
networks
• Changes silencing status of whole genome: These factor awaken silenced genes all over the chromosomes
• Ultimate test of pluripotency: Make a whole organism
![Page 30: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/30.jpg)
iPS lines used to make mice
Reported simultaneouslyby 3 groups-Jaenisch (MIT)-Hochedlinger (Harvard)*-Yamanaka (Japan)
*20% of the 121 offspring developed tumors
-viral vectors?-not from vectors?
![Page 31: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/31.jpg)
Hard problems
• What are network requirements for totipotency?
• Still left with little control over differentiation– Transcription and environment– Functional integration into tissue
• ES vs. cancer: Many overlapping traits
• Scale-up/manufacture: unsolved
![Page 32: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/32.jpg)
Making ES cells easier than controlling them: MUSCLE
![Page 33: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/33.jpg)
?muscle fat
Positive and negative signals
redoxreduce oxidize
![Page 34: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/34.jpg)
CONTROL 2.
GUTSKINCARDIACMUSCLESKELETALMUSCLEPANCREATICBETACELLSHEPATOCYTESNEURONSSCHWANNCELLSASTROCYTESSMOOTHMUSCLEBONEPLATELETSREDCELLSWHITECELLSKUPFFERCELLSTENDON
![Page 35: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/35.jpg)
Complex development
• Recapitulate the uterine environment and signals– Engineering interface critical
• Recapitulate the developmental course
ESdefinitive endodermforegut endodermpancreatic endoderminsulin producing mature beta cells
(Dr. Melissa Carpenter, NOVOCELL)
![Page 36: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/36.jpg)
Growth cues to imitiate complex organization of embryos
![Page 37: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/37.jpg)
Critical issues for translation
OLIGODENDROCYTES ASTROCYTES
?Transplant progenitorsrisk of astrocyte scarTransplant mature oligodendrocytesthey don’t survive transplant
![Page 38: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/38.jpg)
Tumors and stem cells• Common traits: Undifferentiated, pluripotency, highly
proliferative, self-renewing, migration, common markers• Teratomas • Permissive environments • Cancer stem cells are those likely to escape treatment• Ultimately understanding stem cells will lead to
enormous gains in cancer biology• Chemotx wipes out stem cells?
![Page 39: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/39.jpg)
Inner core: Slowly dividing neuroepithealial cells—Roy et al, Nature Med 2006
![Page 40: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/40.jpg)
![Page 41: MARIE CSETE MD, PhD CHIEF SCIENTIFIC OFFICER mcsete@cirm.ca.gov.](https://reader036.fdocuments.net/reader036/viewer/2022062300/56649db45503460f94aa5953/html5/thumbnails/41.jpg)