BIOETHICS

Pranela Rameshwar, Ph.D.

Dept Medicine-Hematology/Oncology
 2012 Nobel Laureates in Medicine for Cell Reprogrammming

Gurdon, the Gurdon Institute in Cambridge, UK

• First person to demonstrate that cells could be reprogrammed.
•,Published 50 years ago (Gurdon, J. B. J. Embryol. Exp. Morph. 10, 622–640 (1962).

Nature News Oct 8, 2012

Vatican 2013
• ESC and Related SCs
• Timeline
– Today’s guide
• Cloning
• Religious views
• Ethics with adult stem cells
Fischbach GD & Fischbach RL, JCI
 Induced Pluripotent Stem Cells (iPS) (MOUSE)
• Expression of Nanog, Oct4
– Cells are ESC-like
– Retrovirus used to insert the genes
• Retrovirus can induce cancer
• Other methods needed to re-express the endogenous genes.
• Myc is induced subsequent to re-expression of Nanog and
Oct4.
– Myc is an oncogene.

• Caveat:
– Issues with epigenetic and phenotypic stability of
their differentiated cells.
– Rejection issue is circumvented but other issues
remain the same.

David cttrabisju, Tokyo Nat Med 2007;13:766; Stem Cells 2009;27:1-3

 ● PGD is used in IVF to do genetic testing before
implantation (1).
● This is done by extracting blastomere:
● 8-cell stage embryos (1).
● Advance Cell Technology reported derivation of
ESCs by removing two cells from the Morula.
● Proposed that these new lines could be used for federal
grants.
● Later it became known that the embryos were destroyed
(misrepresentation) (2).

1. Chung Y, Klimanskya I et al, Nature (Online, Oct 16, 2005); 2. Klimanskaya I, Chung Y et al, Nature (Online, 23 Aug, 2006)
Constance Holden, Science 2006;313:1869; Stem Cells Online 9/06
Research Cloning vs. Therapeutic
Cloning
• Therapeutic Cloning:
• Implies we are close to cures.

• Research Cloning:
• Implies we are do cloning, only for research
purposes.
• We do not know how far away we are from a cure
for any disease.
International Perspectives
◻ First IVF baby, 1978
◻ Studies began on early human development in
UK
◻ UK government took the initiative with laws.
◻ The Warnock Commission, 1984, the Human
Fertilization and Embryo Act:
⬜ Regulated research with human embryos derived
by IVF
⬜ Legal in UK to do research with human embryos
up to 14 days of fertilization.
◻ US: no laws on IVF
Peter W. Andrews Stem Cells Dev 2009;18:1113
• PROBLEM IN USA:
– REGULATE ESC DERIVED FROM AN
UNREGULATED SYSTEM
 Timeline
◻ 1998: Dr. James Thompson reported on isolation of human ESC.
◻ No federal funding for Dr. Thompson, as the law then in the US (Rep
Jay Dickey, 1995):
⬜ Funded by Geron Co and WARF

◻ 1999: NIH draft guidelines with hESCs (derived in private sector); left
over from fertility clinic with consent; no profit by the clinic.
◻ 2000, Final guidelines, solicited application for research.
⬜ During election, statement by then candidate G.W. Bush against
ESC research, no application.
⬜ Intense lobbying when President Bush was sworn into office on
hESC research.
◻ 2001:
⬜ Protectionist view of the embryo

⬜ Executive order - Federal funding for limited lines (8/9/01).

AAAS-Center for Science, Technology and Congress: www.aaas.org/spp/cste/briefs/ste,cells/

 Immediate opposition
• Lack of genetic diversity
• Genetic mutations
• Animal proteins
• Asks for lines other than those in the registry had to be
studied
 Status of States in the US

Susan Okie, NEJM 2005;353:1

Timeline Events and Issues
● End of 4/05:
● National Research Council and Institute of
Medicine (two branches of the National
Academies, a non-governmental scientific
advisory body):
● Issued new ethics guidelines for ESC.
● Policies welcomed by scientists and politicians.
● Mid 5/05, Korean research team
derived new ESC lines with the
signatures of individuals with type 1
diabetes and SCI.
● End of 5/05, the House of Assembly
passed legislation to expand federal
lines. This was vetoed.
Susan Okie, NEJM 2005;353:1
Domestic Policy Council 1/07/www/whitehouse.gov/stemcell
Domestic Policy Council 1/07/www.whitehouse.gov/stemcell
Loser P et al, Stem Cells 2010;28:240
Loser P et al, Stem Cells 2010;28:240
Before 2001
● 1995:
● Dickey-Wicker Amendment:
● Prohibits federal funding of research in which human
embryos are destroyed or subjected to risk of injury or
death.
● Annual renewal (Nat Med 2009;15:347)

● 1999:
● Human ESC derived:
● Clinton administration argued that research can be
done providing that actual destruction of embryos is
performed with non-federal dollars.
● Research on the resulting lines would be qualified for
federal dollars;
o Reason: ESCs were not direct destruction of the
embryos.
o Contradiction of the above because federal dollars
 Executive Order 13505

• Secretary of Health and Human

Services:
– Via the NIH Director
• May support and conduct responsible,
scientifically worthy human stem cell
research:
– Including hESC research, to the extent of the law.
http://stemcells.nih.gov/policy/2009guidlines.htm
Kirsten Dorans, Nature Med 2009;15:347
Overturn of Obama Policy on Stem
Cell
◻ August 23, 2010:
⬜ Obama policy overturned based on violation of
Dickey Wicker rule.
■ Same could have happened for lines approved by
Bush administration.
■ Bush argued that the decision on life and death was
already made.
Human ESC derived:
Clinton administration argued that research can be done providing that
actual destruction of embryos is performed with non-federal dollars.
Research on the resulting lines would be qualified for federal
dollars;
Reason: ESCs were not direct destruction of the embryos.
Fischbach GD & Fischbach RL, JCI
2004;114:1364
UNITED NATION RESOLUTION
• On Feb 18, 2005 UN passed a resolution
banning therapeutic cloning.
• Votes were as follows:
● 71 favor; 35 against; 43 abstained.
• The resolution is broad and does not make a
distinction between human cloning and
research cloning.

The Chronicle, 2/21/05

Donors of Eggs
● Women (1%) of oocyte donors could
become infertile.
● Some die during harvest.
● The donors do not benefit from the
research.
● The egg donors are anonymous, and are
not being experimented.
◦ Thus federal guidelines do not consider
them as `human subjects’.
WHO OVERSEE ESC RESEARCH?
⦿ Embryonic Stem Cell Research Oversight
(ESCRO) committees.
◼ Provide approval before initiating any hESC
research.
◼ Responsible for registration and auditing
responsibilities of institutions conducting hES
research.
◼ Improve public access to information.
◼ Clarify what is `direct expenses’ for allowable
reimbursements to women donating oocytes.
⦿ Revised guidelines covered iPS and PSC.
ESCRO
• Who are the committee members”
• Should have scientific, medical and ethical expertise
➢ Could be internal to a single institution
➢ Could be established jointly by more than one
institutions.
➢ An institution could use the ESCRO of another
institution or by an independent ESCRO.
➢ Could include:
• Lay personnel
• Developmental or SC biologists
• Ethicist
• Molecular Biologists etc
What is the responsibilities of
ESCRO committee?
• All hESC
➢ Blastocysts (IVF)
➢ Blastocysts for research
➢ Nuclear transfer into oocytes
• Fetal SCs
• EGCs
• ipS from non-embryonic cells:
➢ E.g., spermatogonial SCs
 What is the role of the IRB?

● Should review all new procurements of all gametes,

blastocyts, somatic cells for the purpose of
generating new hES, hPS.
● Procurement via:
○ IVF
○ Oocytes
○ Sperm
○ Somatic cells donated for the development of hESC.
● There should be an informed consent stating the
purpose of the experiments.
● Human adult SCs is governed by the IRB
MEDICAL ADVANCE VS. PROTECTING HUMAN LIFE AND
DIGNITY

⦿ Major quandary:
◼ Is an embryo a human life?
• If so, is it something needed for protection?
⦿ Ques:
◼ How does one match the beginning of life with
the ends of science?
⦿ Outside of the above Ques:
◼ Open the path for manipulations and design a
human.
RELIGIOUS ISSUES
 RELIGION
HOW DOES THE EMBRYO GO FROM
BEING ESSENTIALLY AN `OBJECT’ TO A
PERSON.

WHAT BRINGS ABOUT THIS

TRANSFORMATION?
 General Ethical Discourse

◻ 1998 isolation at UWI- donation from couples.

◻ Indepth ethical discussions.
◻ Scientific reasons:
⬜ Public concern of cloning
⬜ Mixing of human and animal cells
⬜ Modification of human tissue
⬜ Quest for immorality
◻ Ideology/Philosophical:
⬜ Pro-life
■ Believe 5-day old preimplantation embryos have same moral
standing as a living person.
■ Regardless in a Dish or in the body

Insoo Hyun, JCI 2010;120:71

 ARGUMENTS OF
SUPPORTERS
● Not all religions grant moral status to embryos.
● The following religions grant moral status at a
later stage of gestation or after birth:
● Jews, Islam, Hindu, Buddhist, some Christian groups
● Some argue that potentiality of an embryo to a
human is a probability because of defects.
● This argument relates to fertilization in the dish and
by natural method (70-80% are defective and never
implant)
● Argue that the embryo available for research would
have never given a life because the couples who
donated them would have destroyed the excess.
●

Insoo Hyun, JCI 2010;120:71

● Jewish Fate:
● Moral status to a fetus, 40 days of gestation.

● Hinduism
● Believes in reincarnation of the soul rather than death:
● The time of incarnation of the soul into the fetus can be
about 4-7 months.
● Sikh: Life begins at conception
● Islam:
● The Sunni and Shi’s Muslim scholars believe that the ensoulment
takes place about the end of the fourth month (120 days PC).
● Stem cell research and cloning for therapeutic purposes is
permissible with full consideration and all possible precautions in
pre-ensoulment stages of fetal development
● In other views, ensoulment could occur after 40 days.

 
B. Larijani and F. Zahedi, Transplantation Proceedings, 36, 3188–3189 (2004); Evans J, Nature Med 2009;15:4
 Sharî'ah Perspective

● In vitro fertilization is allowed

● No surrogate allowed and no donation of
eggs or sperms
● If the embryo is not in the natural womb it
is not a human.
● Believe its obligatory to save life within the
embryo
● Can only use for research from left over in
vitro fertilization.
● No monetary involvement for donation
● Needs informed consent from donor
http://www.muslimbridges.org (Dr. Muzammil H. Siddiqi)
 JEWISH LAW ON PREIMPLANTATION EMBRYO
Timeline:

• 6 stages of development:
• The preimplantation embryo
• Embryo (from implantation to identifiable organogenesis, 40 days PC
• The fetus (from organogenesis, 40 days PC to 20 or more wks).
• The viable fetus (20 or more wks until onset of labor)
• Dislodged fetus (from the beginning of the second stage of labor until birth
• Neonate

Given the above argument, preimplantation embryo cannot develop into a human.
Thus, the preimplantation embryo does not have the same sacred title to life as
the implanted embryo.

Creation of embryo is allowed if this is used to save life.

Eidelman AI & Halperin M, Nature Med 2009;15:238

 Quran
• "The Quran states that there is a distinction
between the different stages of human
development and Muslim jurists have stated,
this distinction occurs four months (120 days)
after conception. This fact, in conjunction with
the importance of preventing illness and
suffering as expressed in the Quran, means that
stem cell research in Iran involving unborn
embryos is relatively uncontroversial. "
Morrison DWG & Khademhosseini A, Stem Cell Science in Iran
Evans J, Nature Med 2009;15:4
UK – Christian Perspective
• Gradualist Position:
▫ Held by mainstream Church of England
▫ An embryo younger than 14 days cannot be considered
a person.
• Absolutionist:
▫ Held by mainstream Roman Catholic Church
▫ An embryo is a person from the moment of
conception.
▫ Morally wrong to destroy the embryo.
▫ Catholic church never define time of ensoulment.
▫ Evans J, Nature Med 2009;15:4
 Significance of 14 days
● Number of changes at day 14:
● 10-14 days, implantation, the woman knows
she is pregnant
● Physical relationship is established
● Embryo is likely to be born:
● Different before implantation
● Embryo can no longer divide to form twins:
● Individualism is established
● This is key because it is believed that society is
dealing with one or more individuals.
● The argues against individual personhood at
conception because identical twins are not
established.
● In summary: Implantation, Individuation
Interview Series, Stem Cells; 2010;28:177 by Majlinda Lako, Alan Trounson, Susan Daher

and Differentiation
Science, 2010;327:25
 PAYMENT
● Hematopoietic Stem Cells
◦ Registry:
⚫ US
⚫ World Marrow Donor Association (WMDA)
⚫ No payment/Altruism
⚫ 70% of match from another country
● No payment policy in US:
◦ Challenged
◦ Why employee of transplantation services paid?
◦ Why not the donor?
⚫ No loss to donor, still have the salary + reimbursement for lost wages
● Reimbursement:
◦ Payment for cost by donor, e.g, loss of wages, travel
● Renumeration:
◦ Payment above reimbursement.

Boo M…Chapman J et al, Blood 2011;117:21

 Issues with renumeration
● Dignity:
◦ Beyond a value on any part of the body.
● Harm:
◦ Risks, reimbursement for expenses linked to
the harm only.
● Cannot use one population to benefit
another:
◦ Wealthier benefit from poor.

Boo M…Chapman J et al, Blood 2011;117:21

 Problems with reimbursement
● Safety:
◦ Donors may hide medical and psychosocial
problems.
● Deterrent:
◦ Might deter altruistic individuals from
donating.

Boo M…Chapman J et al, Blood 2011;117:21

TOURISM THERAPY
Boutique/Tourist Clinics
● Theatrics:
● Political
● Began with ESC (mostly politically
motivated)
● At the time, the adult stem cells
stayed in the background.
● Not a consideration
● This partly contributed to today’s problems.
Private Clinics
• CLASH BETWEEN ACCEPTABLE MEDICAL PRACTICE
AND ETHICS OF EARLY TREATMENT (unproven
therapy)
• Explanation
• Approved formulations
• Is this practice new in medicine?
• ANALOGY:
• Lessons from transplantation with hematopoietic stem
cell
• Colossal failure
Corrective Action??
• Between a Rock & a Hard Place:
• Stop, make it illegal
• Change the laws
• Neither ideal:
• Go to another country
• E.g., Central America
• Unintended consequence to other areas of medicine
 My Experience
● Parternship between a plastic surgeon and a
Biotechnology Company:
● Site for academic training of fellows:
● Initial response
● Dialogue:
● Led to safety studies
● Stem cell organizations:
● Could be involved:
● Ego needs to be eliminated:
● Work on the motivation of clinics – MONEY
o The clinics are interested in safety