Stem Cells: Stem Cells: Scientific Scientific

Potential and Potential and AlternativesAlternatives

Glenn Sauer, Ph.D.Glenn Sauer, Ph.D.

Biology DepartmentBiology Department

Fairfield UniversityFairfield University

Scientific Scientific

PrinciplesPrinciples

What are stem What are stem cells?cells?

How are they used?How are they used? What is the What is the

potential for potential for therapeutic therapeutic applications?applications?

More information:More information: www.nih.govwww.nih.gov

Review of TerminologyReview of Terminology DNADNA - deoxyribonucleic acid, makes up genes - deoxyribonucleic acid, makes up genes GeneGene - functional unit of heredity, a segment of - functional unit of heredity, a segment of

DNA located at a specific site on a DNA located at a specific site on a chromosome; genes direct the formation of chromosome; genes direct the formation of proteins.proteins.

NucleusNucleus - a membrane bound structure in the - a membrane bound structure in the cell which contains the chromosomes.cell which contains the chromosomes.

CellCell - the basic unit of life, all living organisms - the basic unit of life, all living organisms are made up of cellsare made up of cells somatic cellsomatic cell - a cell of the body (220 types in - a cell of the body (220 types in

humans)humans) germ cellgerm cell - an egg or sperm - an egg or sperm

Differentiation of Human Differentiation of Human TissuesTissues

Early embryonic Early embryonic cells cells unspecializedunspecialized

Three primary Three primary tissue layers:tissue layers: EctodermEctoderm MesodermMesoderm EndodermEndoderm

All tissues All tissues develop from develop from herehere

Adult Stem CellsAdult Stem CellsStem cellsStem cells = cells that = cells that

havehave the ability to the ability to divide for indefinite divide for indefinite periods and give rise to periods and give rise to specialized cellsspecialized cells

Progenitor cellsProgenitor cells = = partially specialized partially specialized cells that can give rise cells that can give rise to particular cell typesto particular cell types

Stem Cells of the Bone Stem Cells of the Bone MarrowMarrow

The Problem of Cell The Problem of Cell PotencyPotency Unipotent - Unipotent - cell divides to produce same cell cell divides to produce same cell

type; most cellstype; most cells MultipotentMultipotent -- can give rise to some cell types; can give rise to some cell types;

adult stem cellsadult stem cells PluripotentPluripotent -- able to give rise to most cell able to give rise to most cell

types; embryonic, very small number of adult types; embryonic, very small number of adult stem cellsstem cells

Totipotent - Totipotent - unlimited cabability; can give unlimited cabability; can give rise to all cell types; only in early embryosrise to all cell types; only in early embryos

Early Embryological Early Embryological DevelopmentDevelopment

Derivation of Human Derivation of Human Pluripotent Stem CellsPluripotent Stem Cells

John Gearhart (1998)John Gearhart (1998) - embryonic germ (EG) - embryonic germ (EG) cells cultured from gonadal ridge of 5- to 9-cells cultured from gonadal ridge of 5- to 9-week old fetal tissue obtained from elective week old fetal tissue obtained from elective abortions. abortions. Proc. Natl. Acad. Sci. USA Proc. Natl. Acad. Sci. USA 95: 95: 13726-13731.13726-13731.

James Thomson (1998)James Thomson (1998) - embryonic stem (ES) - embryonic stem (ES) cells derived from inner cell mass of blastocysts cells derived from inner cell mass of blastocysts created through created through in vitroin vitro fertilization procedures fertilization procedures and donated for research purposes. and donated for research purposes. Science Science 282: 1145-1147. 282: 1145-1147.

Derivation of hES CellsDerivation of hES Cells ““Excess” frozen blastocysts Excess” frozen blastocysts

donated from fertility clinicsdonated from fertility clinics Inner cell mass (embryo) Inner cell mass (embryo)

separated from trophoblast separated from trophoblast (placenta)(placenta)

Cells dissociated and Cells dissociated and cultured in laboratorycultured in laboratory

Can be made to Can be made to differentiate using chemical differentiate using chemical signalssignals

Applications of Pluripotent Stem Applications of Pluripotent Stem CellsCells

Basic research in human developmentBasic research in human development ““decision-making genes” (birth defects, decision-making genes” (birth defects,

cancer)cancer) Drug developmentDrug development

human cell lines for all cell typeshuman cell lines for all cell types Cell therapiesCell therapies

replacement tissue for degenerative replacement tissue for degenerative conditions (Parkinson’s and Alzheimer’s conditions (Parkinson’s and Alzheimer’s disease, diabetes, heart disease, stroke, disease, diabetes, heart disease, stroke, arthritis)arthritis)

Example: DiabetesExample: Diabetes Insufficient insulin Insufficient insulin

production in production in pancreaspancreas

Insulin needed for Insulin needed for glucose uptakeglucose uptake

““Islet-like” cells Islet-like” cells derived from stem derived from stem cells produce insulincells produce insulin

Eliminates need for Eliminates need for insulin injectionsinsulin injections

Scientific Challenges Scientific Challenges Remaining Remaining

Understanding of cellular events Understanding of cellular events that lead to differentiation and that lead to differentiation and specializationspecialization

Immunologic rejection - Can stem Immunologic rejection - Can stem cells be modified to minimize cells be modified to minimize tissue incompatibility?tissue incompatibility?

Time of development and expense Time of development and expense of treatmentsof treatments

Rejection: Possible Rejection: Possible SolutionsSolutions

Genetic Genetic engineeringengineering

Somatic cell Somatic cell nuclear nuclear transfer (SCNT)transfer (SCNT) develops into a develops into a

blastocyst blastocyst Dolly the sheepDolly the sheep

cloning cloning (banned by (banned by Congress)Congress)

The The ControversyControversy

Tremendous Tremendous potentialpotential scientific communityscientific community medical professionmedical profession patient advocatespatient advocates

Religious/ethical Religious/ethical conflictconflict human dignityhuman dignity abortion issueabortion issue

When does “Human” Life When does “Human” Life Begin?Begin?

Genetic view - Genetic view - at conception (fertilization)at conception (fertilization) Embryologic view - Embryologic view - after 14 days when after 14 days when

each embryo can produce each embryo can produce onlyonly one one individualindividual

Mental activity view -Mental activity view - after 25 weeks when after 25 weeks when the human-specific EEG can be measured the human-specific EEG can be measured (death is defined as the loss of EEG)(death is defined as the loss of EEG)

Birthday view - Birthday view - life begins when infant is life begins when infant is “metabolically” independent of mother“metabolically” independent of mother

The Bush Decision - Aug 9, The Bush Decision - Aug 9, 20012001

““We must proceed with great care” - We must proceed with great care” - limited approval for ongoing research.limited approval for ongoing research.

Fully funded:Fully funded: adult stem cells, umbilical cord adult stem cells, umbilical cord Restricted:Restricted: embryonic (existing cell lines only) embryonic (existing cell lines only)

64 existing lines 64 existing lines 20 in United States20 in United States Sweden, India, Australia, IsraelSweden, India, Australia, Israel

Unfunded:Unfunded: new donor embryos, cloned embryos new donor embryos, cloned embryos

Total federal funding for 2001: $ 250 MTotal federal funding for 2001: $ 250 M

Reaction to Bush DecisionReaction to Bush Decision ScientistsScientists

some $$ better than nonesome $$ better than none 64 cell lines not enough64 cell lines not enough concerns about controlconcerns about control

Conservative ChristiansConservative Christians relief that more research relief that more research

is not allowedis not allowed broken campaign promisebroken campaign promise

Patient AdvocatesPatient Advocates cautious optimismcautious optimism emotional pleas for more emotional pleas for more

$$$$

Religions Ponder the IssueReligions Ponder the Issue Roman Catholic, Evangelical ChristiansRoman Catholic, Evangelical Christians - -

opposed since stem cells are derived opposed since stem cells are derived from the destruction of embryosfrom the destruction of embryos

Most groups do not have official positionsMost groups do not have official positions Most common positions:Most common positions:

JudaismJudaism - supportive since it serves a - supportive since it serves a common good (fighting disease)common good (fighting disease)

MuslimMuslim - abortion is wrong but life begins - abortion is wrong but life begins when fertilized egg touches wombwhen fertilized egg touches womb

Presbyterian, UCC Presbyterian, UCC - “generally supportive” - “generally supportive”

State ResponseState Response

California voters approve California voters approve Proposition 71 which provides $3 Proposition 71 which provides $3 Billion for stem cell research (2004)Billion for stem cell research (2004)

Other states approve similar Other states approve similar measures measures (Connecticut, Florida, Illinois, (Connecticut, Florida, Illinois, Massachusetts, Missouri, New Hampshire, Massachusetts, Missouri, New Hampshire, New York, Pennsylvania, Texas, New York, Pennsylvania, Texas, Washington, Wisconsin) Washington, Wisconsin)

Stem Cell Research Enhancement Stem Cell Research Enhancement ActAct

Would allow use of surplus Would allow use of surplus in vitroin vitro fertilization embryos with donor permission fertilization embryos with donor permission (2005)(2005) Passed House of Representatives (238-194) and Passed House of Representatives (238-194) and

Senate (63-37)Senate (63-37) Vetoed by George Bush (2006)Vetoed by George Bush (2006)

Stem Cell Therapeutic and Research Act of Stem Cell Therapeutic and Research Act of 2005 (enacted)2005 (enacted) Provides funds for adult stem cell therapies and Provides funds for adult stem cell therapies and

umbilical cord stem cellsumbilical cord stem cells

Current SituationCurrent Situation

Barack Obama executive order allows Barack Obama executive order allows research with new stem cell lines (2009)research with new stem cell lines (2009)

BUT Dickey Amendment to 1995 BUT Dickey Amendment to 1995 Appropriations Bill bans funds for Appropriations Bill bans funds for human cloning or any research that human cloning or any research that voluntarily destroys embryos.voluntarily destroys embryos.

RESULTRESULT Research Labs using state Research Labs using state funds to create stem cell lines and funds to create stem cell lines and federal funds to work with the cellsfederal funds to work with the cells

Alternatives to hES CellsAlternatives to hES Cells

Umbilical cord bloodUmbilical cord blood Contains hematopoietic and Contains hematopoietic and

mesenchymal stem cells (lower mesenchymal stem cells (lower potency than hES)potency than hES)

Patient specificPatient specific Cord blood banksCord blood banks

$2000 collection and $125/year storage $2000 collection and $125/year storage feesfees

Some public banks for donated cellsSome public banks for donated cells

Alternatives to hES CellsAlternatives to hES Cells Induced Pluripotent Stem Cells (iPS) Induced Pluripotent Stem Cells (iPS)

Alternatives to hES CellsAlternatives to hES Cells

Induced Pluripotent Stem Cells (iPS)Induced Pluripotent Stem Cells (iPS) Uses Oct4, Sox2, Klf4 and c-Myc genesUses Oct4, Sox2, Klf4 and c-Myc genes Show higher potency than cord cellsShow higher potency than cord cells Low efficiency (recent improvements)Low efficiency (recent improvements) Other problemsOther problems

Abnormal agingAbnormal aging Tumor productionTumor production Incomplete reprogrammingIncomplete reprogramming

Alternatives to hES CellsAlternatives to hES Cells

Direct Cell Reprogramming - 2011Direct Cell Reprogramming - 2011 Turns one cell directly into anotherTurns one cell directly into another

(ex. Skin cell (ex. Skin cell Neuron) Neuron) Uses mRNA, no viral vectorUses mRNA, no viral vector Eliminates need for stem cellsEliminates need for stem cells Potential and problems are uncertainPotential and problems are uncertain

Autologous Stem Cell Autologous Stem Cell TherapiesTherapies

Self-donation of mesenchymal stem cellsSelf-donation of mesenchymal stem cells Injected (with or without chemical Injected (with or without chemical

treatment) into injury sitetreatment) into injury site Not FDA approvedNot FDA approved

Clinical trials underway (heart attack, spinal Clinical trials underway (heart attack, spinal cord injury, etc.)cord injury, etc.)

Many Americans seek overseas optionsMany Americans seek overseas options No proven effectivenessNo proven effectiveness CostlyCostly High pressure sales tacticsHigh pressure sales tactics

Questions?Questions?

The United States has been criticized by some for The United States has been criticized by some for being too restrictive to stem cell-based research and being too restrictive to stem cell-based research and therapies. Should U.S. laws be relaxed to be more therapies. Should U.S. laws be relaxed to be more accommodating to those wishing treatment?accommodating to those wishing treatment?

A recent study by Duke University predicted that by A recent study by Duke University predicted that by the year 2050, regenerative procedures based on the year 2050, regenerative procedures based on stem cell and other biotechnologies could extend an stem cell and other biotechnologies could extend an average human life span by up to 100 years. Is this a average human life span by up to 100 years. Is this a desirable goal?desirable goal?

Many biotechnologies are vastly expensive, yet much Many biotechnologies are vastly expensive, yet much of the basic research supporting these developments of the basic research supporting these developments is paid for by taxpayers. Who should benefit?is paid for by taxpayers. Who should benefit?