Stem cell latest applications 2016 (ethical issues laws in india)

Battles over human embryos
Stem cell research & therapy

Can ethics cope up with science ?
The duty to prevent
/alleviate suffering
The duty to respect t
he value of human life

Stem cells
• How powerful is a stem cell in terms of
differentiation ?
• Can we use stem cells to produce human
organs and implant them ?
• How about in animals ?

Scientists Grow Full-Sized, Beating
Human Hearts From Stem Cells
http://circres.ahajournals.org/cont
ent/118/1/56
adult skin cells 
Massachusetts General Hospital
Harvard Medical School (USA)
January 8, 2016

ionic detergent, sodium dodecyl sulfate (SDS)
Recellularization
intramyocardial injection 

https://stemcells.nih.gov/info/2001report/chapter9.htm

spontaneously contracting activity
alpha-actinin, desmin, antinaturietic protein, and cardiac
troponin

• http://onlinelibrary.wiley.com/doi/10.5966/sctm.2015-
0270/abstract;jsessionid=24AA90D86251207DE4602C86F9569080.f03t04?systemMessage=
Wiley+Online+Library+will+be+unavailable+on+Saturday+12th+August+at+3%3A00+EDT+%2
F+8%3A00+BST+%2F+12%3A30+IST+%2F+15%3A00+SGT+for+4+hours+for+essential+mainte
nance.+Apologies+for+the+inconvenience.
Grafted Subventricular Zone Neural Stem Cells Display
Robust Engraftment and Similar Differentiation Properties
and Form New Neurogenic Niches in the Young and Aged
Hippocampus
Researchers took neural stem cells and implanted them into the
hippocampus—(important in new memories & emotions) —
essentially enabling them to regenerate tissue.

Objective - (TPM ?)
• Totipotent = entire baby + placenta and
umbilical cord
• Pluripotent = Any cell in body (except placenta
& UC)
• Multipotent = any lineage (eg. Hematopoietic
stem cells )

Where does the stem cells come from ?

But why ? What makes them special ?

• number of chemical and physical signals
- secreted chemicals (neighbour cells)
- direct communication
- cell-cell contact
- et ….

• Gene expression
• distinct sets of transcription regulators
- determine the cell types.
• The interaction of signals during
differentiation causes the cell's DNA to
acquire epigenetic marks that restrict DNA
expression in the cell

How Do Different Cells Express the Genes
They Need?

More n more regulators
less and less potency to
form other cells

So how do we make them, the one we
wish ??
• Growth Factors
• Cell Culture Substrate
• Co-culture Environments
• Three-dimensional Culture: you culture them in 3d.
create mechanical stimulation and cell contact.
• Which will make them express/inhibit certain genes

When does totipotency starts and ends ?
• As soon as the fusion of male and female pro
nuclei (n + n = 2n)
• Ends wn
Blastocyst forms

What s e t ?
• Where totipotent cells are used ?
• Inspite of their ability why aren't they used ?
Discuss the ethical issues in their usage.
• Go to the next potencies
pleuri n multi ( currently under use)

• Most of the stem cell therapies uses the
pleuripotent stem cells and adult stem cells .
Qn – Totipotent stem cells has more capability
and why aren't they being used , for stem cell
therapy ? – still under research.
NOT USED - therapies
But, data shows totipotent stem cells are
used for various reasons

• Savior Sibling
• Designer babies
• Preimplantation genetic diagnosis
legal in India
Philippines ? ( no law which regulates )
but there are many medical centers
which do PGD

In case of preimplantaion genetic
diag osis ,…
3rd day – 8 cell stage
(totipotent)
In this stage, the cells are still totipotent -not yet compacting.
- up to a quarter of a human embryo can be removed without
disrupting its development.

27 June 2017
Human embryos edited for
first time in the US using
CRISPR

India, a designer baby factory?
• "India is becoming a baby factory. Last year (2012 )
over 25,000 babies were born out of IVF and
surrogacy in India. Rich people in the country can
afford desig er a ies o
• Exploiting women
ovarian stimulation (25 cycles IVF)
implanted with 4 (foetal reduction)
Importance for fetus
Abandoned
http://www.firstpost.com/living/india-a-designer-baby-factory-327471.html

Ethical issues
• Playing God
• OHSS (discussed later) – exploiting women ?
• Killing unwanted embryos
• Will healthy children soon be a marker of
wealth?
• Superiority
http://fertility.ivf1.com/blog/pgd-testing-costs

INDIA
IVF + PGD – 5-6 Lakhs (480 thousand) $9,500
USA
IVF + PGD - $ 20,000 - $25,000 (USA) 1.2 M P
Designer baby - $ 50,000 (USA) 2.5 M P
Philippines
Php280,000 to Php300,000 ($ 5800)

World s 1st - Savior sibling
• Molly Nash - Fanconi
anemia
• Adam (SS)
• bone marrow failure,
(genetic)
• decreased blood cells.

The couples thought they
would never have more children until
Dr. Wagner told (BMT)
• (IVF) to produce several embryos,
genetic test (Fanconi anemia & HLA)
Jack & Lisa
MHC 1

Cultured on Petri dish and harvested

Question
• Will taking a cell to test from an uncompacted
8 cell stage (morula) impairs development ?

Human preimplantation development
in vitro is not adversely affected by
biopsy at the 8-cell stage.
• https://www.ncbi.nlm.nih.gov/pubmed/2254
404. 1990 Aug;5(6)

What we learnt from previous slides ?
• 8 cell stage can be used to PGD and when
isolating 1 or 2 cells it will not harm the
embryo
• 8 cell is totipotent
• So h do t e use the i ste ell
therapy?

• 15% of IVF embryos arrest during mitosis
(during cell division) at the 2- cell cleavage
stage
• Mostly before blastocyst stage
1) Sub-optimal culture conditions
2) Chromosomal abnormalities
3) Fail to activate embryonic genome
4) Mitochondrial defects

• o l after 8 ell stage e r o s ge o e gets
activated
http://dev.biologists.org/content/139/5/829

• Can we use such stem cells directly ?
no, teratomas (risk)

PGD – ethical issues
• hu a reprodu tio = gift
Sele tio = a ufa ture
(Kass ; Preside t s Bioethi s Cou il - US)
• Gender selection
• deserve special respect as the first stage
toward a new person
• Designer babies

Savior child - Ethical issue
• SS is born is because they happened to be a
tissue match for their ill brother or sister; if
the had t ha e ee a at h the ould
have been discarded
• potential adverse psychological effects
• the destruction of all embryos that lack the
match (murder )
• using its stem cells to save an older sibling is
commodification of life

http://www.thehindu.com/seta/2004/07/29/stories/200407290
0151600.htm
• e ause to do so tur s the hild i to a
object "
• HEFA (UK)
• It will be permitted only when the disease is
very serious and life threatening, and when
there is no other way to treat the child.

How does it feel to know that you were
brought into existence not purely because
your parents wanted an addition to their
family, but because they were desperate
to cure your older sibling?
For her entire life, Anna has undergone
countless transfusions and surgeries to give
Kate the transplants she needs to fight her
disease. However when asked to donate a
kidney, Anna decides to sue her parents for
medical emancipation - mature minor
doctrine (right to give her consent)

INDIA
• "The Pre-Conception and Prenatal Diagnostic
Techniques (Prohibition of Sex Selection) Act,
1994".
• Prohibits sex determination for any reason
• Savior sibling ??

No pre-natal diagnostic techniques shall be
conducted except for the purposes of
detection of
(i) chromosomal abnormalities;
(ii) genetic metabolic diseases;
(iii) Haemo globinopathies;
(iv) sex-linked genetic diseases;
(v) congenital anomalies;
(vi) any other abnormalities or diseases as may
be specified by the Central Supervisory Board

• So far we discussed the totipotent stem cell
uses and their applicability (PGD) and their
legal issues …..
• Now let us proceed with pleuripotent which
are mostly called the embryonic stem cells

Which one to use ?
• True embryonic stem cell (ES cells)
• ES somatic cell nuclear transfer (ntES cells)
• ES cells from unfertilized eggs (pES cells)
• Induced pluripotent cell (iPS cells)

Where does pluripotency starts ?
• Blastocyst - 5th day
• Pluripotency is lost – 16th day

ES cell lines - immortal (self-renewing)
• This is why scientist are curious to research
and SC therapy mostly uses them.
Why adult cell cannot but they can ?
• Three transcription factors
• Oct4 , SOX 2, and Nanog
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405859/

So will embryos die if I isolate the cells
from ICM ?
• GJIC plays an important role in blastocyst
formation

Why embryos die ?
• a system of chemical communication and
surface recognition integrates the cells of the
developing organism.
• If an embryo is deprived of the necessary
internal signals, irreversible arrest of cleavage
can result.
• Hippo pathway - restraining cell proliferation
promoting apoptosis.

Here o es the Bioethi s……
• So is it ethical to kill an embryo ?
Do embryos have dignity ?

• All humans come from embryos
• They have all the potential  human
• It is alive

The concept of organismic death for
the human embryo
• But how can one determine organismic death
at the earliest stages of a human life, at a time
still weeks from the conception even the CNS
not developed ?
• cell division, growth, and differentiation.
(Human) (Embryo)

• Approximately 60% of IVF embryos fail to
meet criteria for viability and are rejected for
uterine transfer
• These are the cells which are used for stem
cell research and therapy
• Do t justif that life starts at o or at 14
days after fertilization.
• non viability = dead

Stem cells - scientifically promising
ethically challenging
• Ovarian hyper stimulation syndrome ?
https://www.nap.edu/re
ad/11832/chapter/4#26

Nausea
Vomiting
Ascites
Dyspnea
kidney failure

http://dxline.info/diseases/ovarian-hyperstimulation-
syndrome

• Toxicity and the risk of tumorigenicity must
be assessed for all stem cell-based products
• good animal models are often unavailable or
inadequate to predict effects in humans
• First, risks cannot be reliably evaluated;
indeed, the aim of these trials is risk
assessment due to the absence of drugs
similar in mode of action

• Second, research participants are not
expected to gain any direct benefit in early
phase trials .
• inducing pluripotency in somatic cells 
Genetic aberrations in the DNA  Neoplasm
• Cost is a standard distributive justice concern
http://www.tour2india4health.com/Stem-Cell-Therapy-in-India.html

https://stemcellres.biomedcentral.com/articles/
10.1186/scrt474
many people have a moral problem with
embryonic stem cell research because creation
of the cells entails destruction of human
embryos. For that reason,

• 1995 - Dickey–Wicker Amendment
• August 9, 2001 – President Bush  only for
the existing cell lines , prohibiting NIH funding
for the derivation or use of additional
embryonic stem cell lines
60 hESC lines
22 hESC lines
January 2009

Bill Gates contributes to California
stem cell campaign
$400,000

• Obama - January 2009
• NIH fu di g for s ie tifi all orth hu a
stem cell research, including hESR

2009 NIH guidelines – update
• Pay for the embryo ? X
• Research using hESCs derived from other
sources, including somatic cell nuclear
transfer, parthenogenesis, and/or IVF embryos
created for research purposes, is not eligible
for NIH funding.

Women underwent IVF(excess)
Voluntary consent for the Donation
consent for Research use
hESC lines approved
NIH funding
Approvalprocess

Super Man’s Stem cell hope
• Horse riding – 1995,May
• shattering - 1st & 2nd
vertebrae
• Embryonic stem cell Rx
- Israel (2003)
• hoped to receive stem cell
• not advanced enough
at the time of his death

October 10,
2004 (aged 52)
Pressure ulcer
Sepsis
Cardiac arrest

Esc made by SCNT
(therapeutic cloning ) ntESc

• Stem cells  destruct clone embryo
therapeutic cloning
• genetically matched the donor – No rejection
• But, SCNT is limited bcz cells fail to progress
past the eight cell stage of development
• Embryonic genome is not activated
Lomax, G. P.; Dewitt, N. D. (2013). "Somatic cell nuclear transfer in Oregon: Expanding
the pluripotent space and informing research ethics". Stem Cells and Development. 22
Suppl 1: 25–8. PMID 24304071. doi:10.1089/scd.2013.0402

Uses of SCNT in stem cell research
• SCNT - first disease-specific embryonic stem
cell line from a patient with type-1 diabetes.
• potentially be used to develop personalized
cell therapies
https://www.nature.com/nature/journal/v510/n750
6/full/nature13287.html

Therapeutic cloning used to treat brain
disease
• Matched neural stem cell - exhibited
neurological improvement.

https://www.mskcc.org/press-releases/therapeutic-
cloning-treats-parkinson-disease-mice
• But when these neurons were grafted into
mice that did not genetically match the
transplanted cells, the cells did not survive
well and the mice did not recover.
• Genetic match – important
possible by SCNT

Limitations
was born after
277 eggs were used for SCNT,
which created 29 viable embryos.
Only 3 of these embryos survived until birth,
and only 1 survived to adulthood.

Ethical issues
• Kills embryo
• Oocyte donation – Research
• Violates person right to genetic individuality
• Eugenic selection (Select imp person)
• Risk of cancer, developmental anomalies, less
life span
• Diminish respect of human life

• however that the recent development of iPS
cells will supersede the use of somatic nuclear
transfer as it is technically easier
• does not require the use of eggs, avoiding
ethical issues with human egg procurement.

Parthenogenetic Embryonic stem cells

Parthenogenetic Embryonic stem cells
• would "match" the tissue of the egg donor
• "universal" donors bcz one set of the MHC
a tige s HLA protei s ould e "i herited
https://www.ncbi.nlm.nih.gov/pubmed/18092905

easier to match stem cells with fewer HLA
combinations to the various tissue types of
patients

• But should parthenogenic embryos be
considered human embryos?
Fewer ethical concerns
• would not complete gestation
• lack of paternal "imprinting" of genes

• Few ethical concern
parthenogenic embryos are not normal
human embryos
because cannot complete gestation
nor be born as live offspring.

International Stem Cell Corporation
Receives Approval to Start Second Patient
Cohort i Cli i al Trial for Parki so s
Disease
• Estimated Enrollment : 12 (3groups , 4 each)
• Study Start Date : March 2016
• Es Study Completion Date : March 2019
• Es Primary Completion Date : March 2018
https://parkinsonsnewstoday.com/2017/05/10/international-stem-cells-trial-in-
parkinsons-disease-can-continue-board-says/

• The motor symptoms of Parkinson's disease
result from the death of dopamine-generating
cells in the substantia nigra, a region of the
midbrain.
• Moderate stage – patients chosen

Human parthenogenetic neural stem cells

• 1st group – 30 million neuron cells
goal - assess the safety of Rx (completed)
• 2nd group – 50 million neuron cells
(started - May 09, 2017)
• 3rd group – 70 million neuron cells

Induced pluripotent stem cells iPSCs
• Somatic cell  pluripotent stem cell
• Transfection
• (viral .v)

• Yamanaka - human fibroblasts
into iPSCs
• OCT4, SOX2, KLF4, and C-MYC,
using a retroviral system

Advantages
getting a perfect match
with NO destruction of
embryos
(surpassed SCNT )

• Age-related macular degeneration 
breakdown of retinal epithelium.
• A Japanese woman (70s) is the first person to
receive tissue derived from induced
pluripotent stem cells. (2014)

• 28 March,2017 - 1st person to receive cells
derived from (iPS) cells donated by another
person.
https://www.ncbi.nlm.nih
.gov/pubmed/18063756

iPSCs in Research
• iCell® Cardiomyocytes
• human cardiomyocytes derived from induced
pluripotent stem (iPS)

Ethical issues
• abnormal reprogramming occurs in stem cells
• generate tumors in the process of stem cell
therapy.
• Consent for genetic modifications
• Patenting scientific discoveries and developing
commercial tests and therapies, with no
sharing of royalties with donors
• Sharing cell line
https://www.ncbi.nlm.nih.gov/pmc
/articles/PMC2726839/

NIH guidelines 2009 update
• No funding for
iPSCs that are introduced into non-
human primate blastocysts.

Multipotent stemcells
• Adult stem cells
• Cord cells
• Fetal cells

Adult stem cells
• Undifferentiated
• Regenerate damaged tissues
• AK somatic stem cells
• Plasticity -
blood stem cells (derived from mesoderm)
may be able to generate both skeletal muscle
(also derived from mesoderm) and neurons
(derived from ectoderm).

Do you know which is the most studied
and most applied adult stem cell ?

https://www.sciencedaily.com/releases/2016/04/160404180
956.htm

• Feb 21, 2017 Ixmyelocel-T
1st therapy to Receive (RMAT)
designation from US FDA for Dilated
cardiomyopathy
• Ixmyelocel-T in Phase 2b trail - May 10, 2017
the RMAT Designation for Rx of a Serious CVDs
http://adisinsight.springer.com/drugs/800018660

largest double-blind, placebo-controlled stem
cell trial for treatment of heart failure

expanded MSCs and alternatively activated
macrophages promote long-term tissue repair of
ischemic tissue
http://vcel.com/treatment-overview/

Allogeneic (HUCT)-derived
mesenchymal stem cells
• MSCs are favored in stem cell therapy for the
following reasons:
Easy availability
No rejection
can proliferate more rapidly and
extensively than adult BMSCs

Spinal cord injury

They are amazing
immunomodulators!
• Graft vs host disease
• Croh s Ds
the father of the mesenchymal ste ell . – Dr. Caplan

immunosuppressive properties + restorative
functions = better outcome

Embryonic stem cells
Advantages
• Availabity (IVF), immortal, Flexible.
Disadvantages
• Immunogenic, tumorigenic, destructive,
diffcut to differentiate, morally objectionable.

Adult stem cells
Advantages
• non immunogenic, non destructive , Flexible
(few),non tumorogenic,, easy harvest (few),
morally acceptable.
Disadvantages
• Less flexible, finite.

Success rates
• The study assessed 38,000 (SCT)
over a period of 12 years.
• The outcomes were heartening: 100 days after
the transplant
• survival rates Acute Myeloid Leukaemia
(AML), Acute Lymphoblastic Leukaemia (ALL)
and Myelodisplastic Syndrome (MDS) were all
in the range of 65% and above, with related
and unrelated donor transplants

Other Ds with inc success rate
• Cancer (leukemia)
• Anaplastic anemia
• Parki so s Ds
• Type 1 diabetes
• Retinal Ds
http://www.explorestemcells.co.uk/WhyPerformStemCellTransplant.html

INDIA
• There is about a 60% to 80% overall success
rate in the use of stem cell therapy in both
India and around the world.
• Depends - disease being treated, the institute
conducting the procedures, and the condition
of the patient.
http://stemcellsmumbai.com/175-louboutin-sandals-size.html

INDIA
2013 – National guidelines for stem
cell research and therapy update.
• prohibit stem cell therapy and consider its use
for any other purpose outside the domain of
clinical trial unethical in the country.
• Other than hematopoietic stem cell
transplantation/ therapy (HSCT) nothing else
is approved
• Cord blood SC banking, cryopreservation of
embryo permissible

2013 – National guidelines for stem cell research
and therapy update
• embryonic stem cells requires very close
monitoring - lower caste exploited.(W n poor)
- Health and Safety of Donors (IC)
- Quality Assurance of Stem Cell
Products .
- Advertising standards council of India

and therapy update
• Creation of a human zygote by IVF, SCNT or
any other method with the specific aim of
deriving a hES-cell line for any purpose is
restricted.
• Research involving introduction of hES-/hEG-
/iPS-/hSS-cells into animals restricted
• There should be no commodification of
human oocyte, human sperm or human
embryo by way of payment or services

and therapy update
• Any research related to human germ line
genetic engineering or reproductive cloning is
prohibited
• Any in-vitro culture of intact human embryo
beyond 14 days is prohibited.
• Animal trial before clinical translation is must.
• implantation of human embryo into uterus
after in vitro manipulation, at any stage of
development is prohibited

How they monitor ?
• an additional layer of oversight, besides the
institutional Ethics Committee (IEC)
National apex committee for stem cell
research and therapy (NAC-SCRT)
institutional Committee for stem cell
research (IC-SCR)
• Review, Approve, monitor.

How much allocated ? ICMR – 3 crores
24 M Php
1 research – 8 lakhs (642 thousand PHP)

Shashank S Tiwari, (2014) Go er i g ste
cell therapy in India: regulatory vacuum or
jurisdi tio al a iguit ? J New genetics and
society, 33(4), 413–433
Many Ad clinical trials as therapy

• It is unfortunate that India currently do not
have a definite system or law for stem cell
therapy practises
• case
• Samir Padhiyar, a 20-year-old choreographer,
was paralysed waist down due to spinal injury
in a road accident in 2011.
• A hospital in Ahmedabad promised him
absolute cure through stem cell therapy.

case
• I was told I could walk as before with just three
stem cell injections at 3-6 months interval. I
signed the consent form and paid them Rupees
800,000 (about $13000)," he says.
• "But there was no follow-up during the whole
treatment that lasted for a year and there has
been absolutely no change in my health condition
even after two years. When I complained and
asked for refund, they offered another stem cell
treatment at a lower cost which I refused."

• Under the new rule, stem cells cannot be
offered to patients as 'therapy'. They can be
used only in "clinical trials" after approval
from the Drugs Controller General of India
(DCGI).
• http://health.economictimes.indiatimes.com/health-
files/governing-the-stem-cell-usage-in-india/678

Hinduism
All life is God’s creation and
therefore all life must be respected

Homicide
interrupts
Reincarnation

Christianity
Bi le tea hes that
human beings are
made in the image
a d like ess of god
(Gen.1:27; 9:6) &
protectable human
life begins at
conception

Muslim
E soulment of the
fetus does not occur
until the end of
fourth month of
preg a a d
considered pre
human stage

• If ethical standards of embryonic rights and
beginning of life remain undefined or debated, it
will remain difficult to establish sufficient
guidelines to regulate new scientific medical
technology.
• A final justice consideration that is , heightened in
the stem cell context is the simple reality , that
• important work dedicated to improving the health
of the public takes place in a market system with
its attendant pressures of competition and
commercialization. The attempt to ensure that
hope does not become hype and that hype does
not become fraud is a matter of justice.

• Want updates ?
http://www.isscr.org/
https://www.ncbi.nlm.nih.gov/labs/journals/cur
r-stem-cell-res-ther/

Stem cell latest applications 2016 (ethical issues laws in india)

Stem cell latest applications 2016 (ethical issues laws in india)

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