Ethical and Policy Challenges to
Clinical Application of Advanced
Genetic Screening Technology
Edward RB McCabe, MD, PhD
Physician-in-Chief, Mattel Children’s Hospital at UCLA
Professor, Departments of Pediatrics and Human Genetics
Director, UCLA Center for Society, the Individual and Genetics
http://www.arc2.ucla.edu/csig/
Genomic Medicine
• Anticipatory, not reactive
• Predictive and preventive
• Knowledge from genomics and derivative
disciplines
• Screening of individuals and populations
• New analytical technologies and
bioinformatic approaches
Genomic Medicine: Challenges
• Requires change in culture
– Practitioners
• Preventive medicine approach
• Less independence
– Population
• Lifestyle
• Participation in large clinical trials
Genomic Medicine: Challenges
• Requires change in medical data analysis
– Driven by lab data not knowledge (at least
initially) of pathogenesis
– Huge amount of information
– Pattern recognition
Genomic Medicine: Challenges
• Requires change in diagnostic approach
– Trust in unseen algorithms
– Evaluation of matrices and dynamic
complex systems, not linear pathways
– Less hypothesis-driven and increasing
reliance on protocols
Genomic Medicine:
Consequences
• Balance between art and science will shift
toward the science, at least in the
predictive screening and diagnostic areas
• Cannot lose the art of medicine, because
that will be essential for successful
implementation of preventive and
therapeutic measures
Genomic Medicine:
Consequences
• Reduction of the burden of chronic illness
• Decrease in the prevalence of common
complex diseases
• Increase in health disparities between
those with and without access to genomic
medicine
• Technological spin-offs in other areas of
medicine including infectious diseases
How Have We Gotten Here and
What Have We Already
Learned?
Watson and Crick, May 1953
From Olby, The Path to the Double Helix, 1974
Human Genome Project
• Initiated 1990
• Completion originally planned for 2005
• Finished sequence anticipated Spring,
2003, to commemorate the 50th
Anniversary of Watson and Crick
publication (Nature 171: 737-738, April
25, 1953)
Human Genome Project
• Results
– Complete sequencing of the Human Genome
– New branch of science and medicine –
Genomics
What Is a Genome?
• Genome: All of the DNA for an organism
• Human Genome
– Nucleus: 3.2 billion base pairs packaged into
chromosomes
– Mitochondrion: 16,600 base pairs packaged
in one circular chromosome
Genomics: Derivative Disciplines
• Transcriptomics
– Transcript is an RNA copy of a gene
– Transcriptome is all RNA gene copies
in a cell, tissue or individual
• Proteomics
– Proteome is all proteins in a cell, tissue
or individual
Genomics: Derivative Disciplines
• Metabolomics
– Metabolome is all of the small molecule
components of a cell, tissue or
individual that are produced by the
proteins of the proteome
Thorough Understanding of
Genomics
Will generate
the complete parts lists and
the parts’ assembly directions
for fully functioning organisms
What have we already learned
from genetics and genomics?
We are not the center of the
biosphere!
Galileo Galilei. Dialogo… Tolemaico, e
Copernicano…
Florence, 1632
Aristotle, Ptolemy, and Copernicus
Homeobox Genes
There is No Biological Basis for
the Concept of Race!
• There is more genetic variation within
ethno-cultural groups than there is
between them
• Therefore, even the terminology “race” is
erroneous conceptually
• Corollary:
– There is no biological basis for racism
Even Our Ethno-Cultural
Identity May Be Challenged by
Genetics/Genomics
• For many of us, our knowledge of our heritage
is quite limited
– Three-generation pedigrees
– Surnames
– Family lore
• Therefore, we may be open for surprises if
genetic/genomic technologies ever allow
accurate evaluation of biological inheritance
Even the Concept of Two Sexes
Lacks Biological Rigor!
• The dichotomous (male/female) concept
of gender denies modern genetic and
social observations
• An individual’s sex may be defined in
various ways, and they may not all be
synchronous for a specific individual
Modern Concepts of
Sex/Gender
•
•
•
•
•
•
Sex of rearing
Genital sex
Chromosomal sex
Genetic sex
Legal sex
Gender identity
Modern Concepts of
Sex/Gender
• Even biological concepts of sex/gender indicate
a continuum and not a dichotomy
• There may be a conflict in sexual assignments
even when using biological criteria, e.g.:
– 46,XY female: SRY– 46,XX male: SRY+
– 46,XY(SRY+) female: DAX1 duplication
What have we already learned
from genetics and genomics?
• Fundamental and well-accepted concepts
are not supported by the lessons from
modern genetics and genomics
• If we must re-think our position in the
biosphere, and our ethno-cultural and
sexual identities, then how else will
genomics and genetics influence our
concepts of self?
Influence of Genetics/Genomics
on Concepts of Disease
• All disease has one or more genetic
components
• Therefore, we are all at risk for genetic
diseases
• If we accept these statements, then there
is no basis for genetic discrimination,
since we are all in the same risk pool
• But the insurance industry is based on the
ability to discriminate and assign risk
Influence of Genetics/Genomics
on Concepts of Disease
• At this point in the evolution of our knowledge,
we have the information to permit us to identify
predisposition to certain relatively rare genetic
diseases, e.g., CF, Huntington disease, etc.
• The burden of genetic disease, however, is
among all of us with predisposition to common,
complex genetic disease, e.g., cancer,
cardiovascular disease, diabetes mellitus, etc.
Manhattan Project of Biology
• “We have just come through the
Manhattan project of biology. Let’s get it
right this time!” Al Carnesale,
Chancellor, UCLA
– Ethical, Legal and Social Issues (ELSI)
Program, NIH
– UCLA Center for Society, the Individual and
Genetics
– US DHHS Secretary’s Advisory Committee
on Genetic Testing (SACGT) and Secretary’s
Advisory Committee on Genetics, Health
and Society (SACGHS)
Small Businesses and
Health Insurance
A patient who works for a small selfinsured company has a positive family
history for emphysema on both her
mother’s and her father’s sides. Her
physician recommends that she have a
number of tests performed, including
one for 1-antitrypsin (1AT).
Small Businesses and
Health Insurance
When the 1AT test is reported to be
abnormal, he tells her that this may
explain the emphysema in her family
and places her at very high risk for this
lung disease. Her physician reports the
results of his evaluation to her
insurance company as required.
Several days later she is called into
the office of her employer and fired.
Small Businesses and
Health Insurance
• Actual case: Patient had symptoms at time of
testing
• Commissioner Paul Miller, EEOC, argued this
case under ADA
• Settled in favor of employee
• Remains to be determined whether an
abnormal test result in the absence of physical
signs and symptoms would be covered by ADA
Invasion of Genetic Privacy
Workers for Burlington Northern Railroad gave
blood sample as part of company physical
examination. Portion of sample sent to a
private laboratory for PMP22 (Peripheral
Myelin Protein-22) deletion testing. This
deletion is associated with HNPP (Hereditary
Neuropathy with liability to Pressure Palsies), a
slowly progressive neuropathy that may
present with carpal tunnel syndrome.
Invasion of Genetic Privacy
Workers did not know genetic testing for
HNPP was being done and did not
provide consent for testing. Union
brought suit against BNRR and testing
was stopped.
Invasion of Genetic Privacy
• Informed consent has been recommended
for all genetic testing
• There needs to be a firm evidence-base
for any genetic test to move into the
clinical arena
• Therefore, “labeling” of genetic tests is
essential for health professionals and
their patients
Direct-to-Consumer Marketing
of Genetic Testing
A 25 y.o. with a very strong positive
family history of breast cancer (mother,
maternal aunt, maternal great aunt, all
with presentation before age 40) sees a
DTC ad for BRCA1 and BRCA2 testing.
Testing was not performed on her
mother, who died in 1987. This woman is
one of three sisters.
Direct-to-Consumer Marketing
of Genetic Testing
The cost of testing these two genes is
$2,800 without a known mutation. She
elects to pay this out-of-pocket to avoid
informing her primary care physician
and insurance company of the testing.
Direct-to-Consumer Marketing
of Genetic Testing
• If a mutation is identified:
– Consideration of interventions
– Discussions with sisters and other relatives
– Impact on health insurance
• If no mutation is identified:
– Influence on medical decision-making
– Discussions with sisters and other relatives
– Impact on health insurance
Direct-to-Consumer Marketing
of Genetic Testing
Zitner, LA Times, Sunday, August 11, 2002
• DTC genetic testing for:
– Drug metabolizing enzymes
– Vitamin mix selection
– Personalized health and nutritional advice
(e.g., MTHFR)
– Hereditary hemochromatosis
– Cystic fibrosis
– Factor V Leiden
Direct-to-Consumer Marketing
of Genetic Testing
• Home genetic testing
– Equipment under development by several
companies
– Determining market at this time
• What will be role of health care provider
in test interpretation?
GeneFluidics’ Solution
Biofluidic chip
Biological agent
1.2 inches
4 inches
Genetic material
Proteins, Ions
DNA micro sensor array
The $1,000 Genome
• Acquisition
– Error rate
• Interpretation
– Lack of evidence-base
• Privacy
– Information storage
• Discrimination
– Abnormality vs. normal variation
Storefront Genome
UCLA
January 26, 2003
9 am – 5 pm
Sunset Village Conference Center
http://www.arc2.ucla.edu/csig/
Changing Clinics
A family has a 5 yo who has a rare
genetic disease and has been followed in
the same clinic since she was diagnosed in
the neonatal period. They move to a new
state and are told that the care will be
altered significantly because this new
clinic has a different approach to
management.
Reasons for Differing Clinical
Practices in Medical Genetics
• Practice of medicine
– “An art not a science”
– Practitioner-based
– Not subject to regulation
• Case series for most rare genetic diseases
– Quite small
– Not organized for iterative improvement
Collaborative, Multi-Institutional,
Protocol-Driven Clinical Studies
• An approach to make progress toward a
sound evidence-base when individual
patients are rare
• Example from genetic disease
– Double blinded study of the value of
penicillin prophylaxis for Sickle Cell Disease
(Gaston et al, NEJM 1986)
Collaborative, Multi-Institutional,
Protocol-Driven Clinical Studies
• Children’s Oncology Group: Most
successful example
– At least 85% of children with cancer
enrolled in research protocols
– Permits an iterative approach to
interventional changes
– Credited with success of pediatric cancer
outcomes
Multitude of Genotypes Even for
“Common Disease” Phenotypes
• Since complexity is the rule for “simple”
Mendelian traits as well as “common”
disorders
• Therefore, the rare and common disorders will
both be composed of individuals with rare
composite genotypes
• Consequence: We can develop similar
approaches for acquisition of an evidence-base
across genetic diseases
Collaborative, Multi-Institutional,
Protocol-Driven Clinical Studies
• The highly individualistic approach that
provides the medical geneticist with
management autonomy delays progress
unnecessarily
• An organized national approach will require
– Buy-in by the medical genetics community
– Resources to support protocols
Participation of Normal
Individuals in Large Studies
You are asked to enroll in a genetic
predisposition study. It will include those
who agree to participate from at least
500,000 individuals who have been
selected randomly. Participants will
answer a detailed questionnaire and will
have mutation analysis performed for the
gene of interest.
Participation of Normal
Individuals in Large Studies
Participants will be followed throughout
their lives to determine whether or not
they develop this or any related diseases.
Large Clinical Studies
• Population
– Representative?
– Biased?
• Data release
– Participants?
– Health care providers?
– Insurance providers?
Large Clinical Studies
• Monetary
– Source of support for trial?
– Payment for medical care?
• Uniformity
– Diagnostic criteria?
– Practitioner training?
– Ongoing data collection?
Large Clinical Studies
• Hemochromatosis study
• Cystic fibrosis newborn screening studies
– Colorado
– Wisconsin
• California tandem mass spectrometry
pilot
Genetic Census: UK Biobank
Kinkead, NY Times: Dec 31, 2002
• Planning initiated 1999
• Will begin in 2003
• Goal over next 10-20 yrs
– To investigate role of genes and environment
in common diseases
– Planned in anticipation of time when
individuals will be able to sequence their
genomes and will want to know the
implications for their disease risk
Genetic Census: UK Biobank
Kinkead, NY Times: Dec 31, 2002
• Project cost
– $120M
– Financed by UK government, the Wellcome
Trust, and Medical Research Council
Genetic Census: UK Biobank
Kinkead, NY Times: Dec 31, 2002
• 1.2M healthy individuals ages 45-69 yrs will
contribute blood specimens
– DNA will be prepared and frozen
• 500,000 individuals will be chosen to be
followed for 10 yrs through NHS records
• At intake
– 10 page comprehensive questionnaire
– 10 day diet diary
– Brief health exam
Genetic Census: UK Biobank
Kinkead, NY Times: Dec 31, 2002
• Data separate from NHS record
– Anonymous but not completely
– Updates possible from physicians and new
questionnaires
• Anticipate by 2014
– 40,175 will have cancer, diabetes, heart
disease or stroke
– 6,200 will have dementia, hip fractures,
Parkinson disease or rheumatoid arthritis
Genetic Census: UK Biobank
Kinkead, NY Times: Dec 31, 2002
• Single nucleotide polymorphisms (SNPs)
will be analyzed
• Will compare SNPs with epidemiologic
information
• Milburn, UK Health Secretary:
– “…flagship project on molecular
epidemiology for the new century.”
Genetic Census: UK Biobank
Kinkead, NY Times: Dec 31, 2002
• Has been slow to start because of ethical
concerns
• Critics:
– Individuals will be exploited
– Privacy will be invaded
– Access by courts and pharmaceutical
companies
– Studies to be permitted not fully defined
Other Genetic Database Projects
Kinkead, NY Times: Dec 31, 2002
• 1970’s
– Nurse’s Health 121,701
• 1980’s
– Sweden 80,000
– Framingham, MA >4,000
– Am Cancer Society 110,000
Other Genetic Database Projects
Kinkead, NY Times: Dec 31, 2002
• 1992
– Epic (10 European countries) 520,000
• 2002
– Marshfield, WI (Personalized Medicine
Project) 42,000
• 2003-2005
– 7 projects planned with 50,000 to 1M each
Cloning Humans
On December 27, 2002, at a press
conference at a Holiday Inn in
Hollywood, FL, the birth of a healthy 7 lb
baby girl on December 26, 2002, was
announced. Nicknamed Eve, the baby
was born at an undisclosed location
outside of the USA to a 31 yo American
woman from whom Eve was cloned.
Cloning Humans
The announcement of the birth of the
first cloned human was made by Dr.
Brigitte Boisselier, a chemist and the head
of a private company, Clonaid. She said
that four other women were pregnant
with Clonaid-created clones, and 20 more
women were scheduled for implantation
of cloned fetuses in January, 2003.
Cloning Humans
Clonaid was founded by Claude Vorilhon,
a former race car driver. He also formed
the Raëlians, a worldwide “atheistic
religion” of 55,000 followers. They
believe that memories and consciousness
transfer from an individual to their clone,
and therefore cloning is the path to
eternal life.
Cloning Humans
• Two additional groups have claimed that
they they are close to creating human
clones
• No other primate has been cloned
• Health risks well documented for other
mammals
– Clones
– Mothers
Cloning Humans
• IOM committee report
– Reproductive cloning should be banned with
criminal penalties because of risks
– Therapeutic cloning should be encouraged
– The issue of cloning and the data from other
mammals should be re-evaluated in 3-5
years
Summary
• Genomic Medicine
– Offers great promise
– Also significant challenges
• Will require significant changes by
– Practitioners
– Public
Summary
• Genomic medicine will foster significant
tension between the art and science of
medicine
• Incredibly complex technology will
require Medical Genetics expertise
– Analogy with Radiology and imaging
technologies: Used by all areas of medicine
but need specialists knowledgeable in the
technological fine points