lecture 8: epigenetics and cancer cells

Question 1

What are things that immediately spring to mind when somebody mentions stem cells?

Answer 1

• a lot are about ethical concerns
• destruction of the human embryo
• oppose destructive stem cell research
• you me. everybody. we’re all just grown-up embryos
• use a lot of emotive language
• discovery of pluripotent stem cells that put stem cells on the map
• the boys from brazil: movie where scientists are attempting to clone hitler
• are we playing god?
• cloning - birth of dolly
• raoul - leader of the raliens
• Scifi
• extreme abuse of the technology
• score board

Question 2

Does the australian community think using stem cells to conduct medical research and treat disease is acceptable?

Answer 2

• don’t know: 6%
• no: 5%
• yes: 88%
• according to DIISR: community attitudes to biotechnology (2010)
• but which type of stem cells?
  
  • pluripotent stem cells (embryonic, SCNT, iPS stem cells)
  • tissue stem cells (foetal, cord, adult)

Question 3

Does the australian community think using human embryonic stem cells to conduct medical research and treat disease is acceptable?

Answer 3

• don’t know: 6%
• no: 17%
• yes: 70%
• DIISR - community attitudes to biotechnology (2010)

Question 4

What are issues associated with use of human embryonic stem cells in research?

Answer 4

• it’s a potential life
• usually hyperstimulate
• 12 follicles
• drain out fluid
• pass in a testtube
• surrounded by cumulus mass
• wash and clean eggs
• keep in incubator
• morning
• add aliquot of sperm to well
• next day you you score fertilisation
• some clinics culture them an extra 24 hours, some over a week and then do embryo transfer
• not an exact science
• good scenario: 10 eggs, 8 ferts, some cleave
• start to see different rates of cell division and fragmentation
• that crude measure is how an embryologist will kind of work out what is a good embryo vs a bad one
• sometimes they arrest and don’t cleave at all
• rank them
• usually a couple will only have two embryos max put back
• sometimes only 1
• let’s say they have 5 left: different options
  
  • destroy them
  • many cryopreserve (freeze)
  • have to make a decision according to victorian legislation
  • tough choice
  • give them to someone else (altruistic egg donation)
  • research
• embryo is destroyed in the process of making embryonic stem cells
• concern about the sanctity of life and reproductive technology
  
  • isn’t an embryo a life?
  • why do scientists have to kill IVF embryos to get stem cells?
  • why do we have excess IVF embryos? why do IVF clinics deliberately make more embryos than are required? do they do this to make more money?
  • are IVF couples forced to donate their embryos? if they don’t will their treatment be compromised?
  • concner that IVF embryos are “farmed” for spare parts

Question 5

What are issues associated with use of human embryonic stem cells in research?

Answer 5

• SCNT
  
  • take a nucleus from a donor
  • put it into an enucleated oocyte
  • that drives embryonic development
  • get a blastocyst stage
  • (reproductive cloning would have this blastocyst transferred to a surrogate)
  • if you kept that embryo in the lab and isolated embryonic stem cells from the ICM
  • could create a master bank of stem cells that are genetically equivalent to the original donor
  • that could be differentiated and used for drug discovery, aiding understanding of the disease, theoretically could be put back in the patient
• first proof of concept: named and shamed in the vatican
• public outcry and interest
• can do this in humans
• ethics
  
  • where do these enucleated oocytes come from
  • scientist use SCNT to create life to destroy a life (embryo = life)
  • can SCNT be used to clone humans?
  • concered that women will be exploited by SCNT - forced/able to sell eggs
  • SCNT will be used to create monsters (half human/half animal) if animals eggs are used
• lab tech forced to use her eggs

Question 6

Are iPS cells really the ‘ethical’ alternative?

Answer 6

• meant you didn’t have to go through cloning
• less ethical issues
• equivalence?
• not black and white
• Yamanka told Nature: “We are presenting new ethical issues, maybe worse ones, because many people can do this - and without telling anybody.”
• Cyranoski
• Establishment of iPSC from centenarians for neurodegenerative disease research
• can make sperm from these cells
• what are the boundaries?

Question 7

Are iPSC really just cloning by another name?

Answer 7

• from somatic cell nuclear transfer (SCNT): dolly
• from iPSC: Xiao Xiao / tiny
• tetraploid blastocyst
• can’t make an embryo directly from iPSC
• very inefficient generation:
  
  • 22 births/624 injections (3.5%)
  • 2 births/187 injections (1.1%)
  • nature paper demonstrated gerline transmission

Question 8

How is the use of human embryos regulated in australia?

Answer 8

• use of stem cells is highly regulated
• project by project consideration of:
  
  • how consent will be obtained
  • likelihood of significant advance in knowledge or improvement in technlogies for infertility treatment
  • number of embryos necessary to achieve project goals
• research involving use of human embyos act 2002
• prohibition of human cloning act 2002
• ethics approval and NHMRC licence
• embryo
• stem cells
• research
• national statement on ethical conduct in human research
• SCNT for stem cells allowed following 2006 amendment
• prohibit the transfer of an embryo generated by SCNT to the uterus of a woman or animal
• high community support due to high regulation
• legislation doesn’t cover generation of iPS like it does with others
• but still have to get ethics approval
• if it involved genetic modification would also have to consider the requirements set out by another body: OGTR (office of gene technology regulation)
• not legislative requirements
• cannot pay for or make embryos for research in australia

Question 9

When is it “ethical” to start using stem cells for therapy?

Answer 9

• capturing the imagination:
  
  • grow your own heart
  • grow new breasts
  • lipo fat turns to stem cells
• what do people in the community think we are doing?
• have been using HSCs for a long time (40/50 years
• restricted to use in diseases of the blood and immune system
  
  • AML, ALL, MDS, NHL, other leukaemia, CML, HL
• new uses of stem cells/growth in ‘novel’ applications stem cells
  
  • most frequently used are mesenchymal stem cells (connective tissue)
  • lots of different conditions investigating safety and efficacy of MSCs
  • clinical trials
  • dramatic increase in the number of models

Question 10

What are current clinical trials to evaluate possible treatments?

Answer 10

• mesoblast (ASX) bone marrow → cartilage, bone, heart
• Advanced Cell technology (ACT) → rare type of blindness – Stargardt’s Macular degeneration and macular degeneration

Question 11

What is the right way of translating stem cell science?

Answer 11

• column 1
  
  • demonstrated efficacy and risk assessment in preclinical models
  • peer review
  • clinical trials
  • proven therapy
  • √
• column 2
  
  • rationale and preclinical evidence of efficacy and safety
  • peer review
  • medical innovation, involving few seriously ill patients
  • clinical trials when possible
  • proven therapy
  • √
• column 3
  
  • no rationale or preclincal evidence of efficacy
  • no peer review
  • stop
  • X
  • seeing more and more of it despite objections

Question 12

What are the hazards of unproven stem cell treatments?

Answer 12

• outside clinical trials by non-experts
• lack of proven benefits
• endorsed by patient testimony
• risk of physical harm
• financial exploitation
• diversion from existing proven therapies
• disqualification from future clinical trials

Question 13

At what cost?

Answer 13

• more at risk than “doing your money”
• expected growths
• cosmetic surgery
• stem cell treatment causes nasal growth in woman’s back
• stem cell ‘cure’ boy gets tumour
• deaths