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Stem cells Flashcards

1
Q

What is moral pluralism?

A

The idea that there are several values which may be equally correct and fundamental, and yet in conflict with each other

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2
Q

What is the sanctity of life view?

A

The embryo has full moral status, e.g. in Christianity

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3
Q

What is the potentiality view?

A

The embryo has time-relevant or event-relevant moral status, e.g. after a certain day, e.g. Islam

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4
Q

What is the discarded-created distinction?

What are the critiques of this?

A

It is permissible to derive and use stem cells from embryos discarded following IVF, but it is impermissible to derive and use stem cells from embryos created solely for the purpose of stem cell research therapy.
Countries that adopt this into their policies: Australia, Denmark, Netherlands, Finland, Estonia, Canada, Switzerland
Based on nothing is lost principle, intention and respect
Critique: surplus embryos are still embryos - no moral difference

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5
Q

What is the use-derivation distinction?

A

It is permissible to use ESCs in research, but it is always impermissible to derive ESCs.
Used in Italy and Germany.
Based on HESCs are not embryos or potential babies - significant moral difference.
Critiques: inconsistency and hypocrisy: benefiting from others wrong doing. Only works if moral status is derived from potential to be a person. Encourages embryo destruction by using them.

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6
Q

State some religious views on ESC research.

A

Catholicism: Pope issued a condemnation of ESC research
Islam: ensoulment of foetus does not occur until 120 days, and it is a societal obligation to perform research on these extra embryos instead of discarding them. However, schools of Sunni law have forbidden abortion before and after ensoulment. Most schools make allowances for circumstances threatening the health or life of another.
Judaism: During first 40 days of gestation, the foetus is ‘as if it were simply water’

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7
Q

What are pathos, logos and ethos?

A

Pathos: passions and emotions, e.g. president Bush using ‘snowflake babies’
Ethos: credibility and trust,
Logos: reason, e.g. religious teachings
These are mobilised in a public debate on medical research and technology.

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8
Q

Name some bogus companies that rip people off.

A

Neuroestoratology; company in China claims they can cause neurological conditions like stroke and cerebral palsy with stem cells
Emcell: Ukraine company claims they can cure cancer, cerebral palsy, ED diabetes etc. with foetal stem cells
XCell centre: German company claimed it could cure cerebral palsy, spinal cord injuries, macular degeneration etc. with stem cells
Medra: recruits US patients and sent them to Dominican republic for foetal stem cell therapy.
In US, around 300 companies sell bogus stem cell therapies.

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9
Q

Who found a way to make mouse skin cells (fibroblasts) into pluripotent SCs?
What were the 4 genes?

A 
Shinya Yamanaka
Oct3/4
Sox2
Klf4
Myc
The cells can be reprogrammed into iPSCs by retroviral transduction of the genes encoding these four reprogramming factors.
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10
Q

What did Clive Svendsen do with iPSCs?

A

Made iPSCs from cells taken from a young boy with spinal muscular atrophy and turned these cells into neurones to enable him to study the differences between diseased and healthy stem cells.

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11
Q

What are the uses of iPSCs?

A

Disease modelling (likely to be more accurate for human disease than mouse tissues)
Drug screening and discovery
Cardiac, neural, liver toxicity tests
Understanding how cells differentiate and acquire specific abilities, e.g. how a nerve cell acquires the ability to transmit impulses

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12
Q

How could iPSCs be used to model cardiac disease?

A

Skin fibroblasts from patient with type 1 long QT syndrome, carrying mutation in potassium channel gene, were reprogrammed into iPS cells. IPSCs were differentiated into cardiomyocytes. The phenotype seen in LQT1 was mimicked by isoprenaline which induced arrhythmic events in these cells. Treatment with propanolol suppressed the arrhythmia.

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13
Q

How could iPSCs be used to model neural disease?

A

Skin fibroblasts from a patient affected by Rett syndrome that carry a mutation in the epigenetic regulator methyl GpC binding protein 2 gene were reprogrammed into iPSCs. These iPSCs were differentiated into glutamatergic neurones. These cells showed reduced gluatmatergic synapse number and reduced size of the soma. Treatment with IGF-1 led to increased glutaminergic synapse number and increased synapse size.

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14
Q

Has cell therapy using iPSCs generated from autologous skin been shown to help treat sickle cell anaemia in a mouse?

A

Yes. It was Jaenisch, 2007.
They used genetically engineered mice to have human alpha and beta globin. In 3/3 transplanted mice, iPS derived cells contributed to 40-70% of peripheral blood cells. Beta A globin was detected in RNA and protein levels and RBC counts and haemoglobin in peripheral blood were significantly raised.

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15
Q

What is Cellular Dynamics International?

A

A FUJIFILM company. The leading developer and manufacturer of ipsc derived human cells used in drug discover, toxicity testing, stem cell banking and cell therapy development.

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16
Q

What are the disadvantages of using iPSCs?

What is the solution?

A

Autologous transplantation is impractical, especially for emergency
Takes a long time to establish iPSC lines, validate and differentiate into target tissue
Very expensive - may introduce bias based on money
Patient may harbour other deleterious material
Solution: use allogeneic transplantation from HLA matched donors. For this we need banks.

17
Q

How do you select stem cell donors?

A

Different for different countries - e.g. Japan has very homogenous population.
Stringent criteria for pre-screening of potential donors to reduce expenses:
- HLA type
- blood type O
- clean medical history
- clean family history: malignancies, hereditary diseases

18
Q

Key advantages of iPSCs derived from cord blood?

A

Avoids accumulation of somatic mutation over lifespan and are less immunologic.

19
Q

Disadvantage of banks?

A

May introduce bias based on privilege and SES, as most minority ethnic backgrounds are less likely to have a good match.

20
Q

Name a method used for quality control of clinical grade iPSCs?

A

Exome sequencing - makes sure they do not harbour dangerous mutations.

21
Q

What was the first clinical trial using autologous hiPSC derived cells?

A

Takahashi generated iPSCs from a 4mm skin biopsy from upper arm, differentiated into RPE cells and prepared as sheets for implantation to treat age related macular degeneration. Trial was halted due to mutations found in iPSCs.

22
Q

Methods to replace RPE cells?

A

Inject a suspension of stem cell derived RPE cells directly into retina. This has worked in animal models, safe in humans, but doubt whether free-floating cells with organise into the layer of RPE cells.
Inject fully formed layer of stem cell derived RPE cells
Inject whole retina - researchers are trying to create these

23
Q

Current ongoing clinical trials for hiPSCs

A

March 2017 - Japanese man received iPSC derived cells to treat macular degeneration
May 2018: sheets of iPSC derived cardiac muscle cells used to treat ischaemic cardiomyopathy
Aug 2018: iPSC derived dopaminergic producing cells to alleviate Parkinson’s disease symptoms
Currently: seeking approval to begin clinical testing iPSC derived platelets to treat aplastic anaemia

24
Q

What is cell passaging?

A

A technique that enables an individual to keep cells alive and growing in cultured conditions for extended periods of time.

25
Q

In terms of cell line culturing, what can be indicative of a transformed culture?

A

Very long teenage phase (period where cells don’t do much in the period between cell thawing and having enough cells for passage) and very quick time to master cell bank stage

26
Q

Do facilities that expand a stem cell bank need a GMP licence?

A

Nope- they’re making the starting material, not the product.

27
Q

Name some requirements of GMP facilities for making stem cell lines.

A
  • 3 stages of entry: 3 clothes changes
  • Reagents come in from a different route – through transfer hatches to avoid accidents
  • Cell bank preparation is done in highest quality areas
  • Waste goes out through a separate exit
  • Cells goes out through another hatch for cryopreservation. Cannot have cryopreservation in clean room environment because it gives off a large number of particles so you cannot keep the air clean.
  • Regular deep cleaning, equipment monitoring, air quality, temperature and pressure is measured regularly
28
Q

What must be validated in a stem cell facility to show that it is reliable and you are creating a reproducible product?

A
  • Facilities: air quality, change control procedure, validation master plan, validation review and statement of suitability
  • Equipment: design, installation, operation, performance
  • Analytical methods: research protocol/publication, qualificaiton, validation protocols
  • Staff training: competency, ongoing professional development
  • Cleaning: removal of cells, DNA and contaminants. Disinfectants must be rotated to prevent resistance.
29
Q

What do you want to test in cell line testing?

A
  1. Identity: cell line cross-contamination and switching
  2. Biomarkers/undifferentiated and differentiated cells
  3. Stability: diploid karyotype, mutations (not all mutations affect the safety), other changes
  4. Microbiology: Bacteria, fingi, mycoplasma, viral screening, prions
30
Q

What are the core requirements for cells intended for clinical use?

A
  1. Traceability: materials and procedures
  2. Risk assessment: identify, assess and control
  3. Control of cell processing: procedures, staff and environment
  4. Testing- Cell quality control, characterisation and safety. Due diligence process: check through all documentation for each cell line
  5. Keep data in a cell line history file: avoid wasted resource and reduce risk to patient and developers
31
Q

What does the European union tissue and cell directive regulate?

A

All human tissues that are prepared or stored for human application, e.g. minimal manipulation.

32
Q

What are the exceptions to the EUTCD regulation?

A

Tissues that are expanded to use in many patients - needs more complex regulation. Regulations:
1. Advanced therapy medicinal products (AMTP): covers clinical trials and then going onto market authorisation
Hospital exemption: stem cell product made in hospital and prescribed for a specific patient
3. ‘Specials’ provisions: product made somewhere else and brought in and prescribed for individual patient

33
Q

What are the different regulatory bodies for stem cells?

A

HFEA: protects donors of gametes and embryos, ensures valid consent (hESCs)
Human Tissue Authority (HTA): used when embryos are disaggregated into stem cell line. protects donors and patients to ensure quality and safety of all cells for human application.
UK Steering Committee: provides ethical oversight of all embryonic stem cell research to reassure public
MHRA: oversees clinical trials through licencing and inspection
EMA: product licensing
UK stem cell bank gives standardisation for hPSC lines, and has connections with HFEA and runs under scrutiny of UK steering committee

34
Q

What 3 qualities are you looking for in standardisation of cell therapy products?

A
  1. Identity
  2. Purity - media components, particles, leachates, excipients, non-therapeutic cells
  3. Potency - biological activity per dose

However, there is a lack of assays predictive of function for Identity and potency, so use surrogate markers.
Non-therapeutic/non-viable cells may influence purity and potency.

35
Q

List some sources of pluripotent stem cells.

A
  1. inner cell mass: hESCs or hNESCs
  2. Embryo: primordial germ cells (slow growing and not amenable for research)
  3. Somatic cells: hiPSCs or somatic cell nuclear transfer (to oocyte)
  4. Tissue based stem cells and progenitor populations, e.g. mesenchymal stem cells
36
Q

What are some ethical issues with hPSC lines?

A
  1. Publication of large data sets with unknown consequences for donors and families
  2. Managing adverse discoveries from cell line data
  3. Loss of anomymity
  4. iPSC reproductive cloning still a possiblity

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