Towards An Ethics of the Human Genome Project

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Towards An Ethics of the Human Genome Project

• Pattle P.Pun,
• Department of Biology,
• Wheaton College,
• Wheaton, IL 60187
• USA

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(No Transcript)
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What does the draft human genome sequence tell
us?
By the Numbers The human genome contains 3164.7
million chemical nucleotide bases (A, C, T, and
G).  The average gene consists of 3000 bases,
but sizes vary greatly, with the largest known
human gene being dystrophin at 2.4 million
bases.   The total number of genes is estimated
at 30,000 to 35,000 much lower than previous
estimates of 80,000 to 140,000 that had been
based on extrapolations from gene-rich areas as
opposed to a composite of gene-rich and gene-poor
areas.   Almost all (99.9) nucleotide bases are
exactly the same in all people.   The functions
are unknown for over 50 of discovered genes.
Human Genome Program, U.S. Department of Energy,
Genomics and Its Impact on Medicine and Society
A 2001 Primer, 2001
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What does the draft human genome sequence tell us?
How It's Arranged The human genome's gene-dense
"urban centers" are predominantly composed of the
DNA building blocks G and C.   In contrast, the
gene-poor "deserts" are rich in the DNA building
blocks A and T. GC- and AT-rich regions usually
can be seen through a microscope as light and
dark bands on chromosomes.   Genes appear to be
concentrated in random areas along the genome,
with vast expanses of noncoding DNA between.  
Stretches of up to 30,000 C and G bases repeating
over and over often occur adjacent to gene-rich
areas, forming a barrier between the genes and
the "junk DNA." These CpG islands are believed to
help regulate gene activity.   Chromosome 1 has
the most genes (2968), and the Y chromosome has
the fewest (231).
Human Genome Program, U.S. Department of Energy,
Genomics and Its Impact on Medicine and Society
A 2001 Primer, 2001
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What does the draft human genome sequence tell
us?
The Wheat from the Chaff Less than 2 of the
genome codes for proteins.   Repeated sequences
that do not code for proteins ("junk DNA") make
up at least 50 of the human genome.  
Repetitive sequences are thought to have no
direct functions, but they shed light on
chromosome structure and dynamics. Over time,
these repeats reshape the genome by rearranging
it, creating entirely new genes, and modifying
and reshuffling existing genes.  
Human Genome Program, U.S. Department of Energy,
Genomics and Its Impact on Medicine and Society
A 2001 Primer, 2001
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What does the draft human genome sequence tell
us?
Variations and Mutations Scientists have
identified about 1.4 million locations where
single-base DNA differences (SNPs) occur in
humans. This information promises to
revolutionize the processes of finding
chromosomal locations for disease-associated
sequences and tracing human history.   The
ratio of germline (sperm or egg cell) mutations
is 21 in males vs females. Researchers point to
several reasons for the higher mutation rate in
the male germline, including the greater number
of cell divisions required for sperm formation
than for eggs.
Human Genome Program, U.S. Department of Energy,
Genomics and Its Impact on Medicine and Society
A 2001 Primer, 2001
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Medicine and the New Genomics

• Gene Testing
• Gene Therapy
• Pharmacogenomics

Anticipated Benefits

• improved diagnosis of disease
• earlier detection of genetic predispositions to
  disease
• rational drug design
• gene therapy and control systems for drugs
• personalized, custom drugs

Human Genome Program, U.S. Department of Energy,
Genomics and Its Impact on Medicine and Society
A 2001 Primer, 2001
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Huntington Disease (HD)and Cystic Fibrosis (CF)

• How are HD and CF inherited? What are the
  patterns of inheritance?
• What is the cause of HD? Of CF? Whats wrong with
  the HD or CF genes?
• What is the predictive reliability of the genetic
  test that determines whether an individual
  carries a gene for HD? For CF?

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What is the clinical course of HD?

• HD is typically a late manifesting autosomal
  dominant neurodegenerative disorder. It is
  characterized by motor disturbances, loss of
  cognitive functions, and psychiatric
  manifestations. HD patients present with loss of
  coordination, worsening gait, constant
  uncontrolled movements (chorea) and personality
  changes.

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• After diagnosis, HD patients require medical
  intervention and as the disease worsens patients
  invariably require specialized care in long-term
  nursing facilities. Death comes within 15 years
  after the initial clinical diagnosis of HD.

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What is the HD gene?

• The HD gene is represented by a segment of DNA
  (approximately 300,000 letters) found on human
  chromosome 4.
• Approximately 3 of the letters of the HD gene
  are expressed as the HD protein, which has been
  named huntingtin.
• Although HD is relatively rare (both inherited
  and de novo case), every human possesses two
  alleles of the HD gene.

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Whats wrong with the HD gene?

• The variant HD alleles which cause HD have a
  molecular abnormality consisting of an expanding
  triplet repeat (CAG).
• The expanding triplet repeat causes extra
  glutamine amino acids to be placed within the
  front end of the huntingtin protein, making
  huntington bigger.

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The genetic test that measures the presence of
the HD disease alleles.

• The original HD test was based on genetic markers
  that were close to the HD gene. These tests were
  about 95 reliable (sometimes crossing over would
  break the linkage).
• The current test is based on the direct
  assessment of the exact size of the expanding
  triplet repeat region of the HD gene. This is a
  much more reliable test, more than 99.5
  accurate.

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The genetic test that measures the presence of
the HD disease alleles.

• Alleles of HD which have between 10 and 35 (CAG)
  repeats never cause HD.
• Alleles of HD which have more than 40 (CAG)
  repeats always cause HD.
• Alleles of HD which have between 36 and 39 (CAG)
  repeats almost always causes HD.

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Clinical Diagnosis of CF

• Typical pulmonary manifestations.
• Typical gastrointestinal manifestations.
• A history of cystic fibrosis in the immediate
  family.
• Sweat chloride concentrations greater than a
  baseline value.
• Identification of pathological CFTR mutations on
  both CFTR alleles.
• Occasionally, CF is uncovered by a discovery of
  male infertility.

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Consequence of CF

• CF patients have greatly shortened life
  expectancy. The mean age of death now is around
  30.
• There is no cure for cystic fibrosis.
• Cystic fibrosis is a fatal disease.

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Inheritance of CF

• Cystic Fibrosis is a autosomal recessive disease.
  It is caused by a single gene defect which is
  inherited in a autosomal recessive mendelian
  fashion. Both alleles of the CF gene must be
  affected to be at risk of CF. Having a single
  allele of the CF gene makes the individual a
  carrier, but does not produce CF.

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Identification of the CF gene

• The CF gene, now called CFTR, was identified in
  1989 by several groups, including Francis
  Collins, the current director of the NIH Human
  Genome Institute.

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Genotype and Phenotype correlation in CF

• Many symptoms are common to all CF patients, such
  as salty sweat.
• There is a reasonably good correlation of
  genotype (particular CF alleles) and pancreatic
  function.
• There is little or no correlation of genotype and
  severity of lung disease or other clinical
  symptoms. Lack of concordance in twin studies.

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Gene therapy for cystic fibrosis

• Gene therapy for cystic fibrosis has been
  evaluated in several human clinical trials.

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Behavior is Multifactorial
Sin?
Environment
Genes
Development
Behavior
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Classical Methods for Studying the Relationship
between Genes and Behavior

• Twins
• Same genes different environments
• Adoptees
• Different genes same environment

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Heritability of Various Psychiatric Diseases,
Personality Traits And Behaviors

• Phenotype Heritability
• Schizophrenia .60
• Bipolar disorder .62
• Major depression .40
• Social phobia .52
• Panic disorder .42
• Generalized anxiety disorder .35
• Neuroticism .52
• Extraversion .38
• Novelty Seeking .45
• Cigarette smoking .60
• Divorce .52
• Religious affiliation .00

Heritability is the fraction of total
variability due to genetic differences. It is
determined by studying twins and adoptees.
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Although many behaviors are partially heritable,
most of the genes are unknown

• For example
• Schizophrenia and Bipolar DisorderDozens of
  loci have been identified by linkage mapping, but
  only a few have been replicated in at least one
  study and none in every study. No specific genes
  have been found.
• Personality traits such as Neuroticism and
  Novelty SeekingSpecific genes have been found,
  but they account for only a few percent of total
  variance.

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Behavior Gene Discovery

• Complications
• Multiple genes
• Environment is important
• Pleiotropy
• Measurement

Mapping Genes To Traits
Mapping Traits To Genes
Trait 1 Gene Trait 2
Trait 3
Gene 1 Trait Gene 2 Gene 3
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The Number of Genes Involved in Particular
Behaviors is Unknown
gene 1
environment
gene 6
or
?
gene1
environment
gene 100
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The Advent of Genomic Medicine

• The science of genomics rests on direct
  experimental access to the entire human genome
  and applies to common conditions, such as breast
  cancer and colorectal cancer, human
  immunodeficiency virus (HIV) infection,
  tuberculosis, Parkinson's disease, and
  Alzheimer's disease. These common disorders are
  also all due to the interactions of multiple
  genes and environmental factors. They are thus
  known as multifactorial disorders. Genetic
  variations in these disorders may have a
  protective or a pathologic role in the expression
  of diseases

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Two case vignettes (I)

• Thirty-four-year-old Kathleen becomes pregnant
  and sees a new physician for her first prenatal
  visit.
• Her medical history is remarkable for an episode
  of deep venous thrombosis five years earlier
  while she was taking oral contraceptives
• her mother had had deep venous thrombosis when
  pregnant with Kathleen.
• Her physician suspects that Kathleen has a
  hereditary thrombophilia and obtains blood tests
  to screen for a genetic predisposition to
  thrombosis.
• Kathleen proves to be among the approximately 4
  percent of Americans who are heterozygous for a
  mutation in factor V known as factor V Leiden
  that increases the risk of thrombotic events.
• On the basis of this knowledge and her history of
  possibly estrogen-related thromboembolism, she is
  treated with prophylactic subcutaneous heparin
  for the balance of her pregnancy. She remains
  asymptomatic and delivers a healthy, term infant.

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Two case vignettes (II)

• Four-year-old John has acute lymphoblastic
  leukemia and tolerates induction and
  consolidation chemotherapy well, with minimal
  side effects.
• As a key part of his maintenance-treatment
  protocol, he begins to receive oral
  mercaptopurine daily, but because a genetic test
  shows that John is homozygous for a mutation in
  the gene that encodes thiopurine
  S-methyltransferase, an enzyme that inactivates
  mercaptopurine, he receives a greatly reduced
  dose.
• Only a few years ago, about 1 in 300 patients had
  serious, sometimes lethal, hematopoietic adverse
  effects during mercaptopurine therapy. Although
  John is in this at-risk minority, a simple
  genetic test, which is now routine for patients
  beginning mercaptopurine therapy, alerts his
  physicians to this genetic predisposition.
• They reduce his dose of mercaptopurine and
  carefully monitor his blood levels, ensuring that
  the drug levels remain therapeutic, rather than
  toxic.
• John subsequently has an uneventful several-year
  maintenance period and achieves complete
  remission.

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The Cypriot ParadigmThe Journal of Medicine and
Philosophy     Volume 23, Number 3 / July 1998  
Pages  274 - 287 Geneticization The Cyprus
Paradigm

• Genetic Testing for Thalassemia for Greek
  Cypriots
• Government and church cooperate in public
  education, counseling and clinical service.
• Small, homogeneous population
• Fairly high living standard
• High literacy rate.
• Within One Generation, disease rate fell from
  1/1000 births to 0 in 1986.
• No more reported case as of 1992.

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Sustained Correction of X-Linked Severe Combined
Immunodeficiency by ex Vivo Gene Therapy, NEJM
3461185-1193 April 18, 2002

• Methods
• CD34 bone marrow cells from five boys with
  X-linked severe combined immunodeficiency were
  transduced ex vivo with the use of a defective
  retroviral vector. Integration and expression of
  the c transgene and development of lymphocyte
  subgroups and their functions were sequentially
  analyzed over a period of up to 2.5 years after
  gene transfer.

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Sustained Correction of X-Linked Severe Combined
Immunodeficiency by ex Vivo Gene Therapy

• Results
• No adverse effects resulted from the procedure.
  Transduced T cells and natural killer cells
  appeared in the blood of four of the five
  patients within four months. The numbers and
  phenotypes of T cells, the repertoire of T-cell
  receptors, and the in vitro proliferative
  responses of T cells to several antigens after
  immunization were nearly normal up to two years
  after treatment. Thymopoiesis was documented by
  the presence of naive T cells and T-cell
  antigen-receptor episomes and the development of
  a normal-sized thymus gland. The frequency of
  transduced B cells was low, but serum
  immunoglobulin levels and antibody production
  after immunization were sufficient to avoid the
  need for intravenous immunoglobulin. Correction
  of the immunodeficiency eradicated established
  infections and allowed patients to have a normal
  life.

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The case of Jesse Gelsinger
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The Case (1)Jesse Gelsinger was born
with an X-linked recessive error of metabolism,
ornithine transcarbamylase deficiency (OTC).
This disease causes a life threatening buildup
of ammonia. Half of the youngsters born with the
disease die within hours of birth. Jesses case
was relatively mild and was controlled with
drugs. Even so, he had experienced one serious
episode of coma.
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Gelsinger (2)When Jesse turned 18, he
volunteered for a gene transfer trial at the
University of Pennsylvania. The bioethics
committee supervising the trial would not accept
affected newborns on the grounds that the parents
would be too distraught to provide informed
consent. Jesse was jubilant on being accepted.
Whats the worst that can happen to me, he
said. I die and its for the babies.
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Gelsinger (3)After two lower dosage
trials on other volunteers, Jesse was
administered the highest dosage level of an
adenovirus vector, with the functional OTC gene
stitched into it. This vector had already been
safely used in over 80 gene therapy trials
involving approximately 1,000 patients.
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Gelsinger (4)Jesse entered the
hospital on September 13, 1999. Seventeen others
in the trial had already been treated and
suffered only minor aches and pains. However,
Jesse soon suffered a high fever. His ammonia
levels skyrocketed and eventually he suffered
lung failure and brain death.
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Gelsinger (5)Doctors later explained
that, because of a previous infection, Jesse had
had an acute immune reaction to the adenovirus.
In the months following his death, FDA and NIH
officials identified a host of procedural
irregularities and problems that contributed to
Jesses death.
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Safety and Consent in GT Research Several
lessons of the Jesse Gelsinger Case

• The risks of this research
• The need for better adverse event reporting and
  fully informed consent

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Therapy
Enhancement
Somatic
Germ Line
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Sources of Concern

• Insertional mutagenesis and the iatrogenic
  creation of genetic disorders
• The enduring nature and proliferating potential
  of such mishaps
• The low level of need prenatal and
  preimplantation selection and egg or sperm
  donation obviate most Germ Line GeneTherapy

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• Can genetic testing be a tool for discrimination
  by social institutions such as the insurance
  industry?
• What is the limitation of genetic technologies?
• By what criteria can we evaluate the use or
  misuse of human genetic information?

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• How far should one pursue to improve the human
  conditions by genetic manipulation?
• How can we prevent the abuse of human genetic
  information?
• Does the presence of the genetic defect doom the
  future of a child's life?
• Do parents have a right not to be subject to
  genetic testing to alleviate anxiety?

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• Are medical professionals obligated to counsel
  patients in making these decisions?
• Should employers or insurance companies be given
  free access to the genetic information of
  potential employees or clients to determine their
  employability or set the insurance rates?

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• What professional standards should be set for a
  physician in regards to the amounts and varieties
  of genetic testing required for his patients by
  which malpractice litigation can be measured?
• Does a person have a right not to know about his
  genetic makeup?
• Will genetics become a weapon for social
  discrimination?

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Purdy

• It can sometimes be immoral to have children when
  we know (or should know) that our offspring may
  have a genetic disease.

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JC Peterson

• Improvement of our genetic heritage is a
  reflection of Gods gracious redemption if done
  properly.

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A. Various Ethical Principles informed by the
Christian Worldview
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1. Divine Law of Aquinas and Augustine

• The Creator has designed purposes and directions
  for His creation. This Divine Law can be
  discovered in Nature. Despite man's sinful
  nature, God still reveals this Law to man through
  the Scripture and the Church. The Divine Law is
  consonant with human nature and can be
  universally applied.

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2. God's Steward in His Creation

• Human's participation in creation as a
  significant part of man's stewardship of God's
  creation demands his respect for nature, not his
  exploitation. Man has to maintain two attitudes
  in exercising his stewardship of nature to be
  grateful towards his Creator, and to be prudent
  towards managing the creation.

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3. The Ethics of Virtue

• A virtuous person is driven to do good deeds not
  by the mores of his institutions, but by his own
  virtuous disposition. The Scriptures define
  virtuous disposition as the internal desire to be
  good and to do good, not only based on ones'
  education and upbringing, but on the freedom from
  the bondage of sin and the fruits of the Holy
  Spirit in a repentant sinner.

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B. Towards a Christian Model of Ethics What
Constitute a Perfect Human Being?

• Therefore you are perfect, as your heavenly
  Father is perfect Mt. 548

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The concept of a Perfect Human Being as defined
by scriptural perspectives should help in the
discussion of the ethics of HGP since it defines
the essence of what is being human as well as the
criteria by which genetic technologies should be
applied particularly in relation to man himself.
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A Perfect Human Being
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1. Creature of God Confined by Finitude

• There is a limit within which human intervention
  to save life can operate since man is doomed to
  die because of our sin. However, advancement in
  medical and genetic technologies can ultimately
  be the instruments that God uses to manifest His
  work in ameliorating the effects of sin and decay

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2. Created to Enjoy and Glorify God

• Health can be defined more holistically as "the
  strength to be human, not to pursue total
  fulfillment. The paradox of the evils in the
  world under the benevolence of the Creator can
  only be solved in the death and resurrection of
  Jesus Christ. While eliminating human suffering
  is a noble cause, there may be a higher purpose
  for some incurable diseases after all human
  efforts are exhausted.

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3. Made Alive by the Direct Involvement of God

• God's direct involvement in human life is evident
  in the act of breathing into the nostrils of man
  in creation. Genetic engineering of germ cells or
  the cloning of adult human beings cross the
  border line of depriving the offspring yet to be
  born of the freedom to choose the direction of
  his/her life, a gift uniquely given only by the
  Creator Himself.

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4. Created to be God's Steward

• As stewards of God's creation, Christians should
  be the salt and light of the world and actively
  provide leadership in establishing ethical
  principles for the HGP, instead of being the
  obscurantists who oppose technological advance
  for the sake of tradition.

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5. Created in His Image Divine Moral Law

• All human beings are created in the Image of God.
  Although the Fall depraved man's divine
  conscience, the church and the social
  institutions have the obligations to uphold God's
  Divine Moral Laws which are meant to bring
  welfare to individuals and to societies. The
  Golden Rule was meant for the survival and
  stability of human society. The genetic
  information of individuals should be guarded as
  one's private property and is to be protected
  against unjustified intrusion.

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6. Creature Representing Creation to God

• The Fall brought about the three fold alienation
  of man (1) with the Creator, (2) with fellow
  creatures, (3) with the creation, resulting in
  the loss of spiritual, social and physical
  health respectively. Man representing the
  creation in reconciliation in each of these 3
  levels through Jesus Christ brings man into
  harmony with God and the creation in the healing
  process. Without the covenantal relationship of
  reconciliation in each of these 3 levels,
  holistic health cannot be achieved

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7. Conformed to the Image of the Incarnate Word.

• Based on the historical fact of Christ's
  resurrection, the redemption of our bodies at
  Christ's second coming is the consummation of all
  creation, which eagerly awaits its liberation
  from its bondage to decay and deliverance into
  the glorious freedom of the children of God. By
  conforming to the image of Christ, man is
  justified and will be glorified when his lowly
  body is transformed to be like His glorious body.
  It is therefore wrong to look for the domination
  of creation including the elimination of human
  suffering outside the lordship of Christ in other
  earthly powers such as those of the state and
  science and technology

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• A Perfect Human Being
• 1. Creature of God Confined by Finitude
• 2. Created to Enjoy and Glorify God
• 3. Made Alive by the Direct Involvement of God
• 4. Created to be God's Steward
• 5. Created in His Image Divine Moral Law
• 6. Creature Representing Creation to God
• 7. Conformed to the Image of the Incarnate Word.

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An Attempt to Solve a Dilemma Genetic
Information Nondiscrimination Act of 2003
(revised 2005)

• http//thomas.loc.gov/cgi-bin/bdquery/z?d108SN010
  53_at__at__at_Lsumm2msummary
• http//www.govtrack.us/congress/bill.xpd?tabsumma
  rybills109-306

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1. Prohibition on Genetic Discrimination in
Employment and Insurance.
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2. Establishing Uniform Rule to Protect Genetic
Privacy (i.e. HIPAA)
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HIPAA Health Insurance Portability and
Accountability Act of 1996

• PROTECTING THE PRIVACY OF PATIENTS' HEALTH
  INFORMATION
• The rule does not restrict the ability of
  doctors, nurses and other providers to share
  information needed to treat their patients. In
  other situations, though, personal health
  information generally may not be used for
  purposes not related to health care, and covered
  entities may use or share only the minimum amount
  of protected information needed for a particular
  purpose. In addition, patients would have to sign
  a specific authorization before a covered entity
  could release their medical information to a life
  insurer, a bank, a marketing firm or another
  outside business for purposes not related to
  their health care.
• http//www.hhs.gov/news/facts/privacy.html