Ethical Issues in Genetics

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Ethical Issues in Genetics

• David T. Rubin, M.D.
• February 2007

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Nature 171, 737-738 (1953) Molecular structure
of Nucleic Acids WATSON, J. D. CRICK, F. H.
C. Medical Research Council Unit for the Study of
Molecular Structure of Biological Systems,
Cavendish Laboratory, Cambridge. A Structure for
Deoxyribose Nucleic Acid

• We wish to suggest a structure for the salt of
  deoxyribose nucleic acid (D.N.A.). This structure
  has novel features which are of considerable
  biological interest.

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Genetic Testing / Genetic Information

• Genetic testing can be done on a small amount of
  blood or on cells swabbed from inside your cheek.
  
• Genetic testing may test for the presence/absence
  or concentration of certain proteins or
  metabolites in your blood sample, or it may
  require the analysis of your genetic material
  (DNA or chromosomes).
• While these tests may not be physically risky,
  they require strict scrutiny because of the type
  of information they may reveal.

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Genetic Testing vs Gene Therapy

• Genetic testing can be performed on healthy
  individuals, at-risk individuals, or
  symptomatic individuals. It can also be
  performed on embryos pre-implantation or the
  in-utero fetus.
• Our ability to test is much further advanced than
  our ability to treat.

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The Range of Genetic Information

• Diagnostic genetic testing
• Predictive genetic testing
• Genetic testing for reproductive risk factors.

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Diagnostic Genetic Testing

• Newborn screening for early-onset treatable
  conditions (e.g., PKU).
• Clinical diagnostic role
• Congenital malformations
• Symptomatic individual
• Pharmacogenetics ability to test whether a drug
  is effective for a particular individual or
  whether an individual can tolerate certain drugs
  at particular levels.

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Predictive Genetic Testing

• Pre-symptomatic testing genetic testing for a
  gene which confers virtual certainty of disease.
• Classic example Huntington Disease (single gene
  disorder)
• Pre-dispositional testing genetic testing to
  determine if an individual is at higher risk than
  the general population for developing a disease.
• Single gene disorder Women with BRCA-1 gene
  have up to an 85 likelihood of developing breast
  cancer by age 70 years compared to an 11 chance
  in the general population.
• Multi-gene disorders Whether individuals have
  genes that increase or decrease the likelihood of
  a multifactorial condition (e.g., cardiac
  disease).

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Why Predictive Genetic Testing is not Necessarily
Predictive Even in Single Gene Disorders
(Genetics as Weatherman)

• PENETRANCE the percentage of individuals with
  the mutant gene who develop the disease. The
  penetrance of genes can vary from 30 to 100.
• EXPRESSIVITY the marked variation in clinical
  features manifested by the same gene, even the
  same mutation, even within the same family.

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Reproductive Use of Genetic Information

• Premarital Counseling and Testing
• Pre-conception Counseling and Testing
• Prenatal Counseling and Testing
• Pre-implantation Genetic Diagnosis (PGD)

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Complex Genetic Disorder

• Multiple gene sequences
• Non-Mendelian inheritance (incomplete penetrance)
• Mistakes may increase disease susceptibility
• Same genotype results in different phenotype
• Same phenotype results from different genotype

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Gene-Environment Interaction
Genetic Susceptibility
High
Risk of Disease
Medium
Low
Environmental exposure
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Genetic Predisposition Testing Is a Multi-Step
Process
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To Test or Not to TestWhat are the Questions?
Jonsen, Siegler, Winslade. Clinical Ethics, 4th
ed. 1998.
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To Test or Not to TestWhat are the Questions?
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Dirk brings his family tree to class.
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Verbal history
Cancer NOS 40s
Ovarian 46
Ovarian 42 Breast 64
Breast 60
Lung 40s
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Ovarian 37
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When Should Genetic Testing Be Considered?
Physician Factors

• Education
• When to test
• Who to test
• How to test counseling, informed consent
  (when?)
• Will results influence medical management- of my
  patient or their family?
• Need to couple studies of accuracy of predictive
  testing with intervention.
• Long lag time
• Balance risks/benefits of the intervention vs.
  disease
• Correct interpretation of results

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Use and interpretation of commercial APC gene
testing for familial adenomatous polyposis

• Patients tested N177
• Clinical features of FAP/at risk for the disease
  83.0
• Appropriate strategy for presymptomatic testing
  79.4 (50 of 63 patients).
• Genetic counseling before the test 18.6 (33 of
  177)
• Written informed consent 16.9 (28 of 166)
• Physicians misinterpreted the test results 31.6

Giardiello, et al. N Engl J Med. 1997 Mar
20336(12)823-7.
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To Test or Not to TestWhat are the Questions?
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Some Factors That Influence Risk Perception

• Family experience with disease
• Personality traits
• Disease perception
• Family relationships
• Educational level
• Cultural, social, and religious factors

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Informed Consent for Genetic Testing

• Information on specific test being performed
• Implications of / -
• Possibility of uninformative results
• Options for risk estimation without genetic
  testing
• Risk of passing on mutation
• Technical accuracy of test

• Fees involved in testing and counseling
• Risks of psychological distress
• Risks of discrimination
• Confidentiality issues
• Options and limitations of medical surveillance
  and screening

ASCO (1996) Statement of the American Society
of Clinical Oncology Genetic testing for cancer
susceptibility. Journal of Clinical Oncology, 14
(5) 1730-1736.
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Inflammatory Bowel Disease Patients Interest in
Genetic Testing
Survey of 115 IBD patients at the University of
Chicago
Konda et al, Inflammatory Bowel Diseases, 2006.
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Patient Interest In Genetic Testing For Adult
Family Members
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To Test or Not to TestWhat are the Questions?
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Psychological Implications

• Benefits
• Removal of uncertainty and doubt
• Permits earlier detection and interventions
• Provides explanation for disease
• Helpful information for family
• Able to plan/be emotionally prepared for future
• Reduces cost of care
• Spares increased surveillance if negative result
  (truly negative)
• Opportunity for participation in cancer control
  research

• Risks
• Increased anxiety, depression, anger
• Survivor/transmission guilt
• Family relationship disruption
• Worry about children and their future
• Stigmatization
• Insurance/employment discrimination
• Uncertainty with ambiguous results
• False sense of security with negative results
• Interference with work, school, life goals

Lessisk et al. (2001) Advances in genetic testing
for cancer risk. Med Surg Nursing, 10 (3)
123-127.
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To Test or Not to TestWhat are the Questions?
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Health Insurance Portability and Accountability
Act (HIPAA)

• Does
• State that genetic information cannot be used to
  determine eligibility
• Prevent insurers from charging different
  individual premiums within a group plan
• State that genetic information cannot be viewed
  as a preexisting condition (in the absence of a
  diagnosis of the condition related to such
  information)

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Health Insurance Portability and Accountability
Act (HIPAA)

• Does not
• Prevent access by insurers to genetic information
  
• Prevent the insurer from demanding genetic
  testing as a condition of coverage
• Protect against group rate hikes
• Provide much protection outside the group market

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Genetic Discrimination Legislation by State and
Type
H health insurance legislation D disability
insurance legislation L life insurance
legislation E employment legislation P
privacy legislation
minimal protection ltd. to group
disability very ltd. From
www.gene-watch.org
de Tar, L., Nedelcu, R.
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A Case-Based Approach
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Case 1 Huntington Disease (HD)

• Autosomal dominant form of dementia (progressive
  cognitive disability) with onset in mid-life.
  Autosomal dominant means if your parent has it,
  you have a 50 chance of being affected.
• Virtually 100 penetrant (meaning if you have the
  gene, you WILL get the disease).
• Frequently there is earlier onset in later
  generations (anticipation).

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The hereditary chorea, as I shall call it, is
confined to certain and fortunately few families,
and has been transmitted to them, an heirloom
from generation away back in the dim past.  It is
spoken of by those in whose veins the seeds of
the disease are known to exist, with a kind of
horror, and not at all allude to except through
dire necessity when it is mentioned as "that
disorder."  -- Huntington, 1872
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Case 1 Huntington Disease (HD)

• What are the risks and benefits of testing once
  symptoms develop?
• What are the risks and benefits of testing
  pre-symptomatically?
• Do I have the right to be tested if my twin
  sister does not want to know her risk status?
• Do I have the right to be tested if my maternal
  grandmother was affected but my mother does not
  want to know her status?
• Do I have the right NOT to be tested if I am
  planning to have children?

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Case 2 BRCA-1 Testing

• Women who carry the BRCA-1 gene have an increased
  risk of breast cancer at a young age. Depending
  on ethnicity and family history, the risk may be
  as high as 85 by age 70 years.
• Much data about risks in the Ashkenazi Jewish
  community.
• Although the gene is autosomal dominant (you only
  need one abnormal gene to get the disease), it is
  not completely penetrant.
• In comparison, in the general population, 1-in-9
  women get breast cancer.

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Case 2 BRCA-1 Testing

• What are the risks and benefits of testing for an
  individual? for a community? (BRCA-1 has a
  higher incidence in the Ashkenazi Jewish
  community)
• How does genetic testing for HD differ from
  genetic testing for BRCA-1?
• Because there are multiple mutations of the
  BRCA-1 gene, breast cancer risk determination
  often requires that an affected family member
  provide genetic material. Do family members have
  an obligation to do so?

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Case 3 FAP Testing

• Familial Adenomatous Polyposis is an autosomal
  dominant syndrome characterized by
• 100 risk of colon cancer by age 45
• Extra-colonic tumors of brain, pancreas,
  duodenum, bone, thyroid, skin
• 1/11000 individuals have the disorder, and 1/3 of
  mutations are de novo
• Genetic testing is available and sequencing of
  the APC gene accurate.
• Once the mutation is identified in a proband, it
  easy to test other family members for the
  specific mutation
• In the absence of testing, the phenotype of the
  disease can be easily detected by looking in the
  rectum and sigmoid colon

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Familial Adenomatous Polyposis
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APC Gene on Chromosome 5
0
2843
1500
? amino acids ?
AAPC
AAPC
CLASSIC POLYPOSIS
CHRPE
GARDNER
Modified from Kinzler and Vogelstein, 1998.
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Case 3 FAP Testing

• Your patient is diagnosed with FAP by phenotype,
  and subsequent genetic testing identifies the
  mutation in chromosome 5
• As part of your counseling, you recommend testing
  first-degree family members
• She agrees to notify her brother of the mutation
  and his risk, but informs you that she has an
  estranged sister and has no interest in notifying
  her.

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Case 3 FAP Testing

• What should you do?
• Do you have a duty to warn her sister?

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Duty to Warn?

• Tarasoff v. Regents of the University of
  California (1976)
• Duty to warn if there is an imminent risk of
  direct and serious danger to another
• Do genetic findings reach the level of prediction
  necessary?
• Siblings have a 50 risk
• There is NO legal duty to rescue. The proband
  does not cause the risk to the sibling the risk
  exists regardless.
• Proband may cause the risk to his/her child.

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Duty to Warn? Duty to Rescue?

• Pate v Threkel, Florida, 1995
• Woman diagnosed with medullary thyroid cancer.
  Her daughter sues the physician for not warning
  her that she too might be at risk.
• Court Doctor did not have a duty to the
  daughter. Had a duty to inform the woman (his
  patient) that her children could be at risk.
• Safer v Estate of Pack, NJ, 1996.
• Physician treats a male patient for CRC. 26
  years after the man has died, his daughter learns
  that she has multiple polyps and cancer. She
  sues the doctor.
• Trial Court No doctor-patient relationship
  Genetic disease not like infectious disease
  the harm is already present within the
  non-patient child as opposed to being introduced
  by a patient.
• Appellate Court There can be a duty to warn.
  Doctor had obligation to the daughter.

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Case 3 FAP Testing

• She notifies her brother, and he comes to see
  you.
• After hearing about this disease, he states that
  he would rather not be tested, and would like
  nature to take its course.
• He has two children, ages 10 and 14.
• Does the fact that he has children change your
  approach to this individual?

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What is a Stem Cell?

• Stem cells are cells that have the ability to
  generate or renew tissues in the human organism.
  They are the precursors that develop into various
  cell types, which are the basis for human organs
  and tissues.
• Stem cells are found in all stages of the
  developing embryo and in the adult human (in
  various organs in all three layers of cells).

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Sources of Human Stem Cells

• Procurement from human tissue (e.g., bone marrow
  aspiration) (Adult Stem Cells AS).
• Umbilical Cord Blood Stem Cells (UC) are
  collected at birth.
• Human fetal tissue following abortion or
  miscarriage (Embryonic Germ Stem Cells EG).
• Embryos created by IVF no longer needed by the
  couple (Embryonic Stem Cells ES).
• Embryos created by IVF expressly for research
  purposes (Embryonic Stem Cells ES).
• Embryos resulting from somatic cell nuclear
  transfer (SCNT) or other cloning techniques
  into a human ovum (Embryonic Stem Cells ES).

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Procuring Stem Cells
UMBILICAL CORD STEM CELLS
ADULT STEM CELLS
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Procuring Embryonic Stem Cells (ES)
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Procuring Embryonic Germ Stem Cells (EG)
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CREATING EMBRYONIC STEM CELLS (ES) via SOMATIC
CELL NUCLEAR TRANSFER (SCNT)
N.B. SNCT is also known as Therapeutic Cloning.
If the blastocyst were to be implanted, it would
result in Reproductive Cloning.
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Why does the source of the stem cell matter?

• Adult Stem Cells
• AS are rare often difficult to identify,
  isolate, and purify.
• No confirmed data that AS are pluripotent,
  although do have some plasticity.
• AS create an immune response when transplanted.
• AS cannot proliferate ex vivo for a long period
  of time.

• Embryonic Stem Cells
• ES are ubiquitous in embryos, but their
  procurement creates a moral debate.
• ES are pluripotent.
• ES are immunologically tolerated by others.
• ES can undergo many replications ex vivo.

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What is the therapeutic potential of stem cells?
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What are the Ethical and Policy Controversies
Surrounding Embryonic Stem Cell Research?
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The Real Moral Issue

• What does it mean to be human?
• Are we talking about a fertilized egg or a
  zygote or an embryo or a fetus or a child-to-be?
• What is the moral status of a fertilized egg or
  a zygote or an embryo or a fetus or a child-to-be?

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What is the moral status of an embryo?

• Embryos are human beings and deserve full moral
  standing.
• Embryos are just a clump of human cells.
• Embryos are potential human persons and must be
  treated with respect, but do not have full moral
  standing.

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Why the moral status matters

• If one believes that embryos are human beings and
  deserve full moral standing, then stem cell
  research should be prohibited.
• Moral arguments
• The use of ES is intrinsically unethical.
• The use of ES, even if within our moral rights as
  a community, may have the negative untoward
  effect of diminishing respect for humanity.
• The Slippery Slope From therapeutic cloning to
  reproductive cloning
• Pragmatic arguments
• Adult stem cells currently show a lot more
  promise than originally thought. We can do AS
  research without offending anyones morality.

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Why the moral status matters

• If one believes that embryos are potential human
  persons and must be treated with respect, but do
  not have full moral standing, then one would
  permit a more liberal policy.
• Moral argument
• We can do it while respecting the embryo as human
  material, albeit not as a moral agent.
• Pragmatic arguments
• We will advance science most quickly.
• Even if we dont allow this research to be done
  here in the U.S., the research will continue. A
  reverse brain drain?
• If we are going to let this research be done,
  then it is better to have it in the public sector
  where there is greater oversight and greater
  transparency than leaving it to the private
  sector.

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Concluding Remarks

• Genetics is forcing us to reconsider our medical
  ethics paradigm which places exclusive focus on
  the doctor-patient relationship in isolation from
  the wider community in which this relationship
  occurs.
• We are all members of many communities which
  sometimes have conflicting interests and needs.
• Not everyone wants to know their genetic make-up
  knowledge may be power but it also may cause
  fear, stigmatization, and/or discrimination.
• Although individuals have final authority about
  when and whether to be tested, individuals ought
  to consider the impact of their decisions on
  various third parties.