Transcript Wrestling with Behavioral Genetics.

“Whenever man takes a new step towards subduing nature
through the art of organisation and technology, he should
previously have taken two steps within himself in order to
deepen his ethical thinking”
(Friedrich von Hardenberg, 18th. century)
GEN-ETHICS
2013
Marek Vácha
 The doctor diagnoses the 44year patient with
Huntington's disease. Female is begging the
doctor not to communicate this information
at any cost to members of her family. The
patient has 3 daughters, ages 16, 21 and 26
years. 26 year-old daughter is shortly before
the marriage. Doctor
 a. must not succumb to the pressure and tell the information to her
husband and two adult children. It is a 50% probability that the
children inherited the affected allele. With this information,
children have the right to adjust their reproductive choices.
 b. The physician has no obligation, however, at his discretion, has
the right to to tell the information to the husband and to both adult
children. It is a 50% probability that the children inherited the
affected allele. With this information, children have the right to
adjust their reproductive choices. Doctor may, at its discretion
disclose this information also to upcoming husband of the eldest
daughter.
 c. The patient has a legal duty to disclose information by
herself to her husband and to her adult children.
Argument is the expected adjustment of reproductive
strategies.
 d. The physician must respect medical confidentiality
and can not disclose anything to adult family members,
despite the fact that neither the oldest daughter, who is
just about to get married, nor her husband coming will
be able to reflect on their reproductive strategy.
Nonetheless, the paternalistic approach can be used.
Solution



a. must not succumb to the pressure and tell the information to her husband and two adult children. It is a 50%
probability that the children inherited the affected allele. With this information, children have the right to adjust their
reproductive choices.
b. The physician has no obligation, however, at his discretion, has the right to to tell the information to the husband and
to both adult children. It is a 50% probability that the children inherited the affected allele. With this information,
children have the right to adjust their reproductive choices. Doctor may, at its discretion disclose this information also
to upcoming husband of the eldest daughter.
c. The patient has a legal duty to disclose information by herself to her husband and to her adult children. Argument is
the expected adjustment of reproductive strategies.
 d. The physician must respect medical confidentiality and
can not disclose anything to adult family members, despite
the fact that neither the oldest daughter, who is just about
to get married, nor her husband coming will be able to
reflect on their reproductive strategy. Nonetheless, the
paternalistic approach can be used.

Case 7
Fischer, C., (2006) USMLE Medical Ethics: The 100 Cases You Are Most Likely to See on the Exam. Kaplan Publishing, New York.


Your patient has just recently been diagnosed
with familial adenomatous polyposis (FAP).
This disorder is chronic, progressive, and fatal.
There is a genetic test test that can tell
whether children of parents with the disease
will develop it. The test is very accurate. The
patient has become divorced and refuses to
give you his consent to inform his ex-wife who
now has custody of their three children. He
threatens to sue you if you reveal elements of
his medical care to his ex-wife.
What should you do?






a. Respect the patient´s right to
confidentiality.
b. Transfer tha patient´s care to another
physician as long as the patient agrees.
c. Ask the health department to inform the
patient´s ex-wife about the disease risk.
d. Seekn a court order to inform the
patient´s ex-wife.
e. Inform the patient´s ex-wife of the risk to
the children
f. Inform the ex-wife´s doctor
Solution






a. Respect the patient´s right to
confidentiality.
b. Transfer tha patient´s care to another
physician as long as the patient agrees.
c. Ask the health department to inform the
patient´s ex-wife about the disease risk.
d. Seekn a court order to inform the
patient´s ex-wife.
e. Inform the patient´s ex-wife of the risk to
the children
f. Inform the ex-wife´s doctor
Solution




The patient´s right to confidentiality ends where it
comes into conflict with the safety of other people.
The most important element is that screening for
polyps should begin at the age of 12 with screening
sigmoidoscopy every year. Colectomy needs to be
done if polyps are found.
The right to ones pesrson´s to privacy is not as
important as the right of another porson to safety.
The mother can successfully pursue a legal action
stating you, the physician, did not inform her that hed
children were at risk of the „injury“ of the gentic
disease.
John Sulstone against genetic
discrimination
 "A hundred years ago, there was no
equitable treatment for women; they didn't
even have the vote. There was no
equitable treatment for people of different
races. We've established both of those,
and now we need to do it across the board
for all genetics.„

http://www.guardian.co.uk/science/2004/may/15/genetics.academicexperts
GENES
GENES
...AND CRIMINALITY
 In 1991 Stephen Mobley shot a Georgia pizza
parlor employee in the back of the head and
bragged about the shooting to his friends. Later,
Mobley appealed his conviction to the state's
Supreme Court. His new defense: my genes
made me do it.

Pointing to a long family history of genetic
illness and criminal behavior, Mobley's attorneys
argue that a range of genetic factors made it
almost inevitable that he would eventually come
to lead a life of crime. The Mobley case stands at
the center of the age-old "nature versus nurture"
debate in the development of human behavior.

H.G.Brunner
H.G.Brunner
 only males
 50 % of males
 X chromosome
Abdelmalek Bayout
 Abdelmalek Bayout, an Algerian citizen who has lived in Italy
since 1993, admitted in 2007 to stabbing and killing Walter
Felipe Novoa Perez on 10 March. Perez, a Colombian living
in Italy, had, according to Bayout's testimony, insulted him
over the kohl eye make-up the Algerian was wearing.
Bayout, a Muslim, claims he wore the make-up for religious
reasons.
 During the trial, Bayout's lawyer, Tania Cattarossi, asked the
court to take into account that her client may have been
mentally ill at the time of the murder. After considering three
psychiatric reports, the judge, Paolo Alessio Vernì, partially
agreed that Bayout's psychiatric illness was a mitigating
factor and sentenced him to 9 years and 2 months in prison
— around three years less than Bayout would have received
had he been deemed to be of sound mind.
Abdelmalek Bayout

But at an appeal hearing in May this year, Pier Valerio Reinotti, a
judge of the Court of Appeal in Trieste, asked forensic scientists for
a new independent psychiatric report to decide whether he should
commute the sentence further.
 For the new report, Pietro Pietrini, a molecular neuroscientist at
Italy's University of Pisa, and Giuseppe Sartori, a cognitive
neuroscientist at the University of Padova, conducted a series of
tests and found abnormalities in brain-imaging scans and in five
genes that have been linked to violent behaviour — including the
gene encoding the neurotransmitter-metabolizing enzyme
monoamine oxidase A (MAOA).
 A 2002 study led by Terrie Moffitt, a geneticist at the Institute of
Psychiatry, King's College, London, had found low levels of MAOA
expression to be associated with aggressiveness and criminal
conduct of young boys raised in abusive environments1.
Abdelmalek Bayout
 In the report, Pietrini and Sartori concluded that
Bayout's genes would make him more prone to
behaving violently if provoked. "There's increasing
evidence that some genes together with a particular
environmental insult may predispose people to certain
behaviour," says Pietrini.
 On the basis of the genetic tests, Judge Reinotti
docked a further year off the defendant's sentence,
arguing that the defendant's genes "would make him
particularly aggressive in stressful situations". Giving
his verdict, Reinotti said he had found the MAOA
evidence particularly compelling.
 Reinotti made the decision in September 2009
Abdelmalek Bayout






But forensic scientists and geneticists contacted by Nature question
whether the scientific evidence supports the conclusions reached in the
psychiatric report presented to Judge Reinotti.
"We don't know how the whole genome functions and the [possible]
protective effects of other genes," says Giuseppe Novelli, a forensic
scientist and geneticist at the University Tor Vergata in Rome. Tests for
single genes such as MAOA are "useless and expensive", he adds.
One problem is that the effects of the MAOA gene are known to vary
between different ethnic groups, Moffit says. A 2006 study in the United
States found that former victims of child abuse with high levels of MAOA
were less likely to commit violent crimes — but only if they were white. The
effect was not evident in non-white children.
"If the defendant has any African ancestry, this could bring up a question of
how well the genotype of that particular gene could relate to his personal
behaviour," Moffitt says.
Pietrini and Sartori, however, did not test Bayout for his ethnicity.
"The ethnicity of the defendant is irrelevant" in this case, Pietrini told
Nature. He argues that the defendent does not belong to any of the nonwhite ethnic groups considered in the 2006 study. "Besides, MAOA is just
one of the candidate genes we analysed," he added.
Abdelmalek Bayout




Cattarossi argues that all evidence that has a bearing on her client's
mental health should be considered by the court. "My client is clearly an ill
person and everything that allows the judge to better evaluate the case
and to decide the right sentence should be investigated," she says.
Since the 1994 Stephen Mobley case in the United States — the first case
in the world in which the defence asked to have their client tested for
MAOA deficiency — lawyers have increasingly been trying to bring MAOA
deficits and similar genetic evidence into courtrooms worldwide. According
to Farahany, who updates a personal database on sentences passed in
the United States, in the past five years there have been at least 200
cases where lawyers have attempted to use genetic evidence to support
the idea their clients' were predisposed to violent behaviour, depression or
drug or alcohol abuse. In Britain, there have been at least 20 such cases
in the past five years.
Up to now most such efforts have been unsuccessful in court — although
a few have influenced sentencing in the United States. Judges have
tended to reject the idea that a person has no control over their choices
because of their genes, says Farahany.
Some fear that such cases could lead to the acceptance of genetic
determinism — the idea that genes determine the behaviour of an
organism — in criminal cases.
Abdelmalek Bayout
 "90% of all murders are committed by people
with a Y chromosome — males. Should we
always give males a shorter sentence?" says
Steve Jones, a geneticist at University
College London. "I have low MAOA activity
but I don't go around attacking people."
 Farahany points out that prosecutors could
use the same genetic evidence to argue for
tougher sentences by suggesting people with
such genes are inherently 'bad'.
 "The question is where do you stop," Jones
adds.

http://www.nature.com/news/2009/091030/full/news.2009.1050.html
Behavioral Genetics and Moral Responsibility
 if some people are identified as violent because of a
diagnosable conditions, and receive special allowances
because of it, then others who are violent might wonder
what really distinguishes them from the „genetically
violent“
 if some violent behavior can be put down to physical
causes, then other violent behavior seems likely to
have the same sort of explanation
 if all behavior has biochemical and eventually genetic
substrata, why should anyone ever be held morally
responsible?

(Kaebnick, G.E., (2006) Behavioral Genetics and Moral Responsibility. in Parens, E., Chapman, A.R.,
Press, N., (eds.) Wrestling with Behavioral Genetics. John Hopkins University Press, Baltimore, p.221)
Genes and Behaviour
 60 per cent of murders in America is carried
out by African-Americans, though they
constitute 12 per cent of the population.
 But before we label blacks particularly
murderous, we should note that murder rates
in Caribbean countries or African countries
are no higher than in other countries.
 Therefore we must look to environmental factors,
rather some innate genetic characteristic, to
explain the extraordinarily high murder rate.
Genes „For“ Criminal Behaviour
 Crime = an act or the comission of activity
that is forbidden
 Criminal behaviour
 can be a one-time phenomenon
 can be a profession




shoplifting x pickpocketing
leaving lethal nerve gas on a subway station
shooting a doctor working in an abortion clinic
„white collar crime“
 = there is not such thing as „a crime“
Genes and Behaviour
The Question of Responsibility
 How much should the fact that one was abused as a
child, sexually molested by a religious leader, or
were currently attempting to give up a smoking
mitigate in a criminal case?
Criminality
 in USA there is proportionally 7x more
murders than in Great Britain
 …is it a proof that Americans have more
„genes for aggressive behaviour“?
 ...almost certainly not, because not long ago
it was one single population (of Britons)
 Australia was long time a convict colony for
prisoners from Great Britain
 nowadays there is no higher criminality than in the
rest of the world
Criminality
 half of our population carries a specific
genetic variant that makes them sixteen
times more likely to end up in jail than the
other half
 it is Y chromosome carried by males
XYY males
 Are XYY males more likely to be found in
prison than are XY males?
 1965, Edinburgh: while all of the 197 males in the
account of prison hospital inmates were described
as „dangerously violent“, seven had the XYY
karyotype
 The seven males constituted about 3,5 % of the
total.
 But since estimates are that only about 1,3 % of all
males have the XYY chromosomal makeup, the
authors of the study posited that the 3,5 % rate
found in the prison population might be 20 times
higher than the frequency in the normal population
XYY males
 They then generalized from that meager
data to claim that men with 47
chromosomes were mentally subnormal
and had a tendency to hyperaggressivity
and violence
XYY males
 Recent evaluation do not find this body of
work credible.
XYY males
 XYY individuals have been shown to be





no more aggressive than average
may be taller
may be less intelligent
hyperactive
more impulsive
 Nevertheless, the claims made managed to
stigmatize a generation of XYY males and
apparently led to the abortion of a significant
number of fetuses with that karyotype.

(Duster, T., (2006) Behavioral Genetics and Explanations of the Link between
Crime, Violence, and Race. in Parens, E., Chapman, A.R., Press, N., Wrestling
with Behavioral Genetics. Johns Hopkins University Press, Baltimore. p. 157)
GENES
...AND RESPONSIBILITY
Incarceration of African Americans x
European Americans
 1933: blacks were incarcerated at a rate
approximately twice that of whites
 1950: four times
 1970: six times
 mid 1990s: blacks are incarcerated seven times
that of whites
 there is no genetic explanation
 these incarceration rates are a function of
social, economic, and political factors

(Duster, T., (2006) Behavioral Genetics and Explanations of the Link between Crime,
Violence, and Race. in Parens, E., Chapman, A.R., Press, N., Wrestling with Behavioral
Genetics. Johns Hopkins University Press, Baltimore. p. 158)
GENES INFLUENCE
BEHAVIOUS
Artificial selection
Behaviour
 terriers are aggressive scrappers
 spaniels are nonaggressive and people
oriented
 there are behavioral breed differences in
the development of social relationship,
emotionality, trainabiliity, as well as many
other behaviors
 scolding that would be brushed off by a terrier
could traumatize a sheepdog
Mice in an open field
Mice in an
open field
Mice in an open field
 the difference between the high and low
lines steadily increases each generation
 this outcome is a typical finding from selection
studies of behavioral traits and strongly
suggests that many genes contribute to
variation in behaivor
ENVIRONMENT
Environment
 prenatal environmental effects
 nutritional balance and hormone fluctuation
during pregnancy
 exposure to drugs, chemicals, toxins etc.
 postnatal environmental effects
 parenting, sibling interactions, peer
relationship, education etc.
 physical illness, psychological stress, cultural
experiences, birth order etc.
Environment
behaviorism:
 give me a dozen healthy infants, well-formed,
and my own specified world to bring them up
in and I´ll guarantee to take anyone at random
and train him to become any type of specialist
I might select – doctor, lawyer, artist,
merchant-chief and, yes, even beggar-man
and thief, regardless of his talents, penchants,
tendencies, abilities,vocations, and race of his
ancestors.
Behaviorism
A man is nothing but a piece of plasticine...
FREEDOM
Animisms
There is no difference
between
1. person and thing
2. living and non-living
3. spiritual and material
World of children and world of science
Being is being alive
Science
Animism
René Descartes
Panmechanismus
 from this picture of the world stem the
horror of man – after all, this raw and
crude material – that´s me!
 „in reality, there is nothing but atoms and
emptiness“ (Demokritos)
Francis Crick:
The Scientific Search
for the Soul
Francis Crick : the soul was not
discovered...
1470
1994
Replicators and Vehicles
 Now (the replicators) they swarm in huge
colonies, safe inside gigantic lumbering
robots, sealed off from the outside world,
communicating with it by tortuous indirect
routes, manipulating it by remote control.
They are in you and me; they created us,
body and mind; and their preservation is the
ultimate rational for our existence. They have
come a long way, those replicators. Now they
go by the name of genes, and we are their
survival machines.
 (Richard Dawkins: The Selfish Gene)
We are… the computers
 Viewed in this light, the question that is sometimes
asked — can computers think? — is somewhat ironic.
Here of course I mean the computers that we ourselves
make out of inorganic materials. What on earth do
those who ask such a question think they themselves
are? Simply computers, but vastly more complicated
ones than anything we have yet learned to make.
Remember that our man-made computer industry is a
mere two or three decades old, whereas we ourselves
are the products of an evolution that has operated over
hundreds of millions of years.
 Fred Hoyle, 1964
 The genetic engineering is nothing that
„revolution of robots“!
GENETIC DISORDERS
Unique characteristics of genetic
disorders
 Genetic disordres strike families, not only
individuals. Knowledge about genetic
disease in one family member may have
important implications for the health
prospects of other family members; the
„patient“ may be an entire family rather that
just single person
 in order to counsel one member of a family it
may be necessary to have detailed
information about several other family
members
Unique characteristics of genetic
disorders
 Inherited disorders may affect more than one
generation. Thus, genetic disease may have
serious consequences for people in generations
yet unborn
 there is a strong need for long term storage
(over many generations) of information about
genetic disease and for the data protection
 genetic diseases also differ from non-genetic
diseases in the sense that it is to an increasing
degree becoming possible to predict disease risk
in people who today are healthy and even
people who are not yet born
Unique characteristics of genetic
disorders
 The need for knowledge about disease
risk is to an extent in conflict with the right
to privacy of the persons whose disorder
is the reason why the risk situation is
known. It is necessary to find a suitable
balance between one person´s need for
knowledge, and the relative´s right to
privacy.
Genetic counseling
 There are over six thousands genetic
conditions, chromosome diorders, and
birth abnormalities, that can result in
miscarriage, stillbirth, death early in life or
problems in childhood or adulthood
Genetic counseling
 nondirectiveness;
 informed consent;
 confidentiality
Genetic counseling
This process involves an attempt by one or more appropriately
trained persons to help the individual or family to
 (1) comprehend the medical facts, including
the diagnosis, probable course of the
disorder, and the available management
 (2) appreciate the way heredity contributes to
the disorder, and the risk of recurrence in
specified relatives
 (3) understand the alternatives for dealing
with the risk of recurrence
Genetic counseling
 (4) choose the course of action which seems
to them appropriate in view of their risk, their
family goals, and their ethical and religious
standards, and to act in accordance with that
decision
 (5) to make the best possible adjustment to
the disorder in an affected family member
and/or to the risk of recurrence of that
disorder.
Genetic counseling
 Test results may be deeply troubling for those
who receive a diagnosis of a genetic disorder
or carrier status, raising fundamental questions
of medical vulnerability, as well as personal
and social image and identity.
 Individuals may perceive that they are
"flawed," "imperfect," "defective," "inadequate,"
or "abnormal," or may have concerns that
others will perceive them or their progeny in
these terms
Genetic Counseling- Problems
 even the most complete family history in
an era of relatively small families may not
reveal all of the risk factors
Medical geneticists confront ethical
dilemmas:
croos-cultural comparisons among 18 nations
by J.Fletcher and D. Wertz
 Fletcher and Wertz studied responses of
medical geneticists in 18 countries. Of 1053
asked to participate, 677 (64%) responded in
1988 and 1990.
 The majority (92-94%) regarded nondirective
approaches as appropriate
Medical geneticists confront ethical
dilemmas:
 Greater than 75% consensus
 disclosure of conflicting diagnostic finding
 disclosure of ambiguous results
 disclosure of controversial interpretations
 protection of mother´s confidentiality in
cases of false paternity
Medical geneticists confront ethical
dilemmas:
 A majority (51-60%) would
 disclose the diagnosis to relatives at risk
for Huntington disease against the
patient´s wishes
 disclose which parent carries a
translocation causing Down syndrome
 disclose XY genotyp in a female
Case Report
 Catherine is a 14 year old girl who in the course of her
evaluation for primary amenorrhea is found to have complete
androgen insensitivity syndrome (CAIS). This syndrome,
previously called testicular feminization syndrome, is a
genetic disorder in which an XY fetus is insensitive to
androgens (male hormones) and is therefore born looking
externally like a normal girl. However, internally, there is no
uterus, fallopian tubes or ovaries but testes are present
either in the abdomen or the inguinal canal. Individuals with
the syndrome have no pubic or axillary hair, are sterile and
cannot bear children. The syndrome is usually detected at
puberty when a girl should but does not begin to menstruate.
The testes need to be removed and patients subsequently
require estrogen replacement therapy.
Case Report
 Should a physician respect the parents’
request not to disclose a diagnosis of
“androgen insensitivity syndrome” to their
adolescent daughter Catherine is a very
good athlete and is very much involved in
hockey. Her coach has sponsored her to try
out for the Olympics hockey team. The
physician talks to the parents regarding the
disclosure of the information to Catherine but
the parents request that the doctor does not
disclose the diagnosis.
DIRECT-TO-CONSUMER
DTC
Direct To Consumer
 individuals obtain direct analysis of their
genome for prediction of future medical
risks, without the involvement of a health
provider.
Direct To Consumer
 it is a natural next step, in the same way
that pregnancy tests had left the confines
of the physician´s office and found their
way onto the pharmacy shelves
 (see the lecture Human Genome Project)
 23andMe
 Navigenics
 deCODE
https://www.23andme.com/
http://www.navigenics.com/
http://www.decode.com/
Story of…
 Jeffrey Gulcher (48, excellent health)
 chief scientific officer of deCODE he decided
to undergo the DNA test
 prediction of a 1,9-fold increased risk of
prostate cancer
 after biopsy, 3 from the 12 biopsies showed
prostate cancer
Direct marketing of genetic tests to the public
(DTC)
 A development with important ethical
implications is the marketing of genetic tests
directly to the public. Such tests are designed
to detect differences in DNA, genes or
chromosomes that are not provided as part
of a medical consultation.
 Direct marketing might be seen as a positive
step, as individuals take increasing
responsibility for their own health and, armed
with information about their susceptibility to
particular disease conditions, makes lifestyle
changes to promote their health
Direct marketing of genetic tests to the
public
 ...but there are at least two potential harms:
 the impact on individuals of misinterpreted or
erroneous predictive health information that
overstates the role of genetics in causing common
diseases, and which might result in delays in
proper medical advice being sought, or in
expensive and unproven dietary or lifestyle
changes
 the possibility of people performing inappropriate
genetic tests on children or other adults without
proper consent
Direct marketing of genetic tests to the
public
 for complex disorders such as high blood
pressure, genetic factors may only
account for a few percent of the risk,
whereas changing habits in relation to
diet, exercise, smoking and
antihypertensive drug treatment could
reduce the risk of a heart attack by up to
80 %.
Questions and problems with DTC
 the risk factors detectable by DTC tests are
modest in their quantitative contribution to
disease
 for most conditions an individual´s risk will bechanged
only slightly by the result of the test
 the testing does not incorporate an assessment
of family history
 DTC tests do not detect the less common but
highly significant genetic mutations that carry a
high risk for disease
 BRCA1/2, Huntington´s disease, fragile X syndrome
Questions and problems with DTC
 a substantial fraction of the heritability for
most common disease has not been
discovered yet.
 the possibility of laboratory mistakes
 the company´s interpretation of the DNA
test results is not entirely trivial
 most of the current data about risk
prediction from DNA testing are based
upon studies done on individuals of
northern European background
Questions and problems with DTC
 consumers who are provided risk
information should be skeptical of claims
about interventions
 is it really necessary to pay hundreds of
dollars for a DNA test to be told that you
should eat a balanced diet, engage in regular
exercise, and maintain a normal weight?
 infomations may cause anxiety, and may
require to beconsulted with experts
AUTOSOMAL DOMINANT
INHERINTANCE
Huntington´s
disease
autosomal
dominant
inheritance
Huntington´s Disease
 = degenerative neuropsychiatric disorder,
affecting the basal ganglia but also affecting
widespread areas of centra nervous systém
 it is inherited as an autosomal dominant:
 P:
Aa x aa
 F1:
Aa aa

1 : 1
 = each offspring of an affected parent has
50% risk of inheriting HD gene
Huntington´s Disease
 Signs and symptoms usually develop in middle
age. Younger people with Huntington's disease
often have a more severe case, and their
symptoms may progress more quickly. Rarely,
children may develop this condition.
 Also called Huntington's chorea, Huntington's
disease was documented in 1872 by American
physician George Huntington. The name
"chorea" comes from the Greek word for "dance"
and refers to the incessant quick, jerky,
involuntary movements that are characteristic of
this condition.
Huntington´s Disease
Symptoms
 personality changes and decreased cognitive
abilities.








irritability
anger
depression
difficulty of making decisions
learning new information
answering questions
remembering important information.
The family and friends may notice these changes
before the patients become aware of them.
Huntington´s Disease
Symptoms
 Early physical signs and symptoms of
Huntington's disease may include mild balance
problems, clumsiness and involuntary facial
movements, such as grimacing. As the disease
progresses, you may develop these other
Huntington's disease symptoms:
 Sudden jerky, involuntary movements (chorea)





throughout your body
Severe problems with balance and coordination
Difficulty shifting your gaze without moving your head
Hesitant, halting or slurred speech
Swallowing problems
Dementia
Huntington´s Disease
 Symptoms begin insiduously, between
ages 35 and 50
 though onset may occur at any time from
childhood to old age
 death occurs an average of 15 years
after symptoms first appear
 it is a late-onset disease, the symptoms
generally not appearing until after the
person has begun to have children
Huntington´s Disease
 1983 - gene for HD was localized to the
short arm of chromosome four
 1993 - gene was isolated
 the defect is an abnormally long repeated
seqence of three DNA base pairs (CAG)
Huntington´s Disease
 The discovery of the HD gene in 1993 resulted in
a direct genetic test to make or confirm a
diagnosis of HD in an individual who is exhibiting
HD-like symptoms. Using a blood sample, the
genetic test analyzes DNA for the HD mutation
by counting the number of repeats in the HD
gene region
 therapeutic options are not yet available
 request to have a DNA test conducted is often
based on a desire to take the test result into
consideration in family planning and other
planning for life.
Huntington´s Disease
 Individuals who do not have HD usually
have 28 or fewer CAG repeats.
 Individuals with HD usually have 40 or
more repeats.
 A small percentage of individuals,
however, have a number of repeats that
fall within a borderline region. (30 - 40)
Huntington´s
disease
Note: Dr. Michael McCormack cited a case where a woman had one
more repeat than her mother and she was symptomatic at 40, while
her mother still showed no signs at 70. Beyond age of onset, we know
very little about the variation in the progression of symptoms, for
some individuals decline quite rapidly, while others experience a
much more gradual deterioration.
Huntington´s Disease
clinical features
 Emotional, cognitive and motor disturbances
 the most common disturbances in emotions
are depressive diorders, irritability and
apathy, aggressive outbursts, impulsiveness,
social withdrawal
 disturbances of cognition: loss of cognitive
speed and flexibility. In the workplace patient
is unable to keep pace with the work
Huntington´s Disease
clinical features
 motor disorder: voluntary and involuntary
movements, especially chorea. Patients develop
diminished manual dexterity, slurred speech,
swallowing difficulties, ultimately become rigid and
unable to initiate any movement voluntarily. Patients
who survive to the advanced state become confined
to bed and area unable to participate in their selfcare
Huntington´s Disease
 A positive gene test without neurological
signs indicates the presence of the HD
gene, but not disease onset
Huntington´s Disease
Therapy
 In 2006, researchers discovered that the protein
expressed by the Huntington's gene interacts with
another protein to disturb the way that cholesterol
accumulates in the brain.
 Cholesterol is essential for healthy brain cells and the
network among those brain cells — but the cholesterol
needs to be in proper levels and in the proper locations.
 When the network of brain cells is disrupted, motor
skills, cognitive skills and speech can be affected.
 If scientists can figure out a way to disrupt this
interaction between the proteins, they may eventually
be able to develop a targeted drug therapy.
Huntington´s Disease
Varlam Shalamov
(1907 - 1982)
Huntington´s Disease
ethical issues
Huntington´s Disease
ethical issues
Informational self
– determination
•right to know
•right to not know
Case Study
 Sue is an 19-year-old college student. Desperate for a little
extra spending money, Sue responds to an ad in the local
paper and volunteers to donate a blood sample to a
company setting up a genetic database. On her follow-up
visit, Sue is shocked to learn that she carries the gene for
Huntington's Disease. As she researches the disease, she
realizes that one of her parents must also express the
Huntington's gene and that they will most likely become
symptomatic in the next ten years. She is baffled however,
when she notes that all of her grandparents, both maternal
and paternal, have entered their 60s without symptoms. As
she begins to research the genetics of the disease, she
realizes that one of her grandparents may have had the
gene, but never expressed the phenotypic disease. How is
that possible?
Huntington´s Disease
Predictive testing

Predictive testing should be performed according to the
international guidelines proposed by the World Federation of
Neurology (WFN), in which ample pre-test genetic counseling and
neuropsychological testing are provided together with posttestb
psychotherapeutic support . This is partly intended to reduce the
likelihood of serious consequences.
 An international collaborative study revealed that out of 4527
participants in predictive testing protocols, 44 (0.97%) had a
catastrophic event:



five committed suicide,
21 made suicide attempts and
18 had to be hospitalized for psychiatric disturbances.

All of the suicides happened in individuals who had become symptomatic,
11 out of 18 attempted suicides and eight out of 18 hospitalized individuals
had also begun to show manifestations of the disease. This means that
catastrophic consequences often occur when symptoms begin, which may
be a long time after the test result is conferred
Right to not know
Huntington´s disease
Some quotations:
„I'm a person who thinks life would be very dull if you had a
crystal ball ... that's my way of looking at things ... I'd sooner not
know what's going to come up in the future ... I'd sooner live day
to day
why don't you just live everyday as it comes ... live for today and
not for tomorrow ... what are you going to achieve by finding
out? ... why burden yourself with all that because if you're going
to get it [HD] ... you're going to get it ... you could put yourself
all through the test and even learn you are gene-positive and you
could die with cancer or heart attack long before Huntington's
hits you …“
Right to know
Huntington´s disease
 Choosing not to know would be ethically
questionable if the choice to remain ignorant
could have serious consequences for a third
party, such as spouse.
 A decision to inform one´s spouse (or
potential spouse) about a known risk of a
serious disorder has to be made by the risk
persons themselves
 the moral duty to have an open
communication with one´s spouse about the
risk may not be included in a law
Diskriminace
http://www.genetichealth.com/ELSI_Genetic_Discrimination_Myth_or_Reality.shtml
 A woman with a family history of Huntington's
disease tried to apply for health insurance. The
company wanted her to prove she didn't have the
mutation, but she didn't want to know. She couldn't
get coverage without the test.
 Another woman's mother had Huntington's. When
her employer found out about her plans to get tested,
he fired her because of the potential costs of
employing someone with the disease.
Discrimination
http://www.genetichealth.com/ELSI_Genetic_Discrimination_Myth_or_Reality.shtml
 Terri Seargent was identified as having Alpha-1, a
genetic disorder that can affect the lungs and/or liver.
When her employer received a bill for her first
preventive treatment, he abruptly fired her, despite
having always referred to her job performance as
exemplary. Someone with the gene for Alpha -1 will
not necessarily become symptomatic. Nevertheless,
according to the Alpha-1 Association, at least 30
people have been denied private health or life
insurance because of their genetic status.
Familial hypercholesterolemia
 Persons with genetic predispositions will not
necessarily contract the disease
 risk predictions at the practical level will
became available wit respect to certain
cancers, allergies, psychoses an other
common diseases
 knowledge of one´s disease risk may be
experienced as a challenge and a stimilus to
positive action, such as changing life style,
diet etc.
Convention on Human Rights and
Biomedicine (Oviedo Convention)
1997
Article 12 – Predictive genetic tests
 Tests which are predictive of genetic
diseases or which serve either to identify
the subject as a carrier of a gene
responsible for a disease or to detect a
genetic predisposition or susceptibility to a
disease may be performed only for health
purposes or for scientific research linked
to health purposes, and subject to
appropriate genetic counselling.
AUTOSOMAL RECESSIVE
INHERINTANCE
Sickle cell disease
 about one in ten African-American is a
carrier
 sickle-cell anemia affects about one in 400
African-American babies.

Collins, F., (2010) The Language of Life. Profile Books LTD. London, GB. p. 97
 in 1933, Diggs and collegues estimated that
about 7,5 % of the African population had at
least one copy of the HbS allele
 it was found that P. falciparum infection
increased the rate of sickling and dehydration of
blood cells containing a mixture of HbS and HbA
proteins. This led to destruction of the blood
cells – and the parasite within it.
 thus it seems that the red blood cells of
heterozygotes are not as good incubators for
Plasmodium larvae as are normal erythrocytes.

(Gilbert, S.F., Epel, D., (2009) Ecological Developmental Biology. Sinauer Associates, Inc. Sunderland, MA. p. 314-315)
 Allison found that different African tribes
had very different frequencies of the HbS
allele.
 In some tribes, as many as 40 % of the
population was heterozygous faor the HbA
allele, while in others almost no one
carried HbS
 It was found, that the HbS allele has
evolved at least five separate times!

(Gilbert, S.F., Epel, D., (2009) Ecological Developmental Biology. Sinauer Associates, Inc. Sunderland,
MA. p. 314-315)
 we still have no genetic therapy for sickle cell anemia
 one of the reasons is that sickle cell anemia is a gain-of-
function mutation
 „sticky“ proteins form cables that give the mutant blood cell
its sickled shape and limit its flexibility, eventually resulting in
clogged blood vessels and early death.
 It is easier to cure a loss-of-function mutation, in which the
functioning gene is simply missing.
 in loss-of-function, one can add a functioning gene where
there was no functioning gene; in treating gain-of-function,
you have to get rid of the mutant gene and then substitute
the wild-type, functioning gene

(Gilbert, S.C., Tyler, A.L., Zackin, E.J., (2005) Bioethics and the New Embryology. Sinauer Associates, Inc. W.H. Freeman &
comp. Sunderland, MA U.S.A. p. 193)
Sickle cell disease
 The disease results
from an altered
hemoglobin, in
which the
aminoacid valin
substitutes for
glutamic acid at
position 6 in the βglobin chain.
Sickle cell disease
The early 1970s saw the establishment of a sickle cell
anemia screening program in the US, which probably
provides an example of all the mistakes that need to be
avoided in such a program.
 It focused on African Americans, referring to the disorder as
a communicable disease. The State laws were scientifically
inaccurate because they did not reflect a clear
understanding of human genetics and the screening tool
they were using, with the results that carriers of the sickle
cell treat were stigmatized.
 This included not only attempts to prevent marriage, they
were also denied health and life insurance. Employment
opportunities were denied, including acceptance into the
US Airforce Academy
X-linked Diseases
Jewish Perspective: genetic testing
 the Talmud advises a man not to marry into a
family where leprosy or epilepsy has
appeared in at least three people.
 it is generally not permissible to screen
specifically for gender just because one
wants a boy or girl or to screen for any
characteristic other than disease (e.g., height
or intelligence)
 screening for gender is thus only acceptable
when there is a family history of genderrelated diseases linked to the chromosome
for the child´s gender
Tay-Sachs Disease: Jewish
Perspective
 there is an effort to have couples undergo
genetic testing before marriage or shortly
thereafter so that they know whether they
need to have any future fetus of theirs tested
for the disease
 an abortion of a fetus afflicted with Tay-Sachs
would be warranted
 if parents allow the fetus to be born, no active
measures may then be taken to hasten its
death, and both the child and the parents
must just wait out the ravage of the disease
Tay-Sachs Disease: Jewish
Perspective
 palliative care must be administred to
make the child as comfortable as possible,
but aggresively treating the child with
medications, machines, or surgery to
prolong life is neither necessary nor wise.
 by analyzing the expressions of many genes
in breast cancer patients, researchers
carrying out one genome-wide association
study were able to identify 70 genes whose
expression pattern could be correlated with
the likelihood that the cancer would recur.
 Given that low-risk patients have a 96%
survival rate over a ten-year period with no
treatment, gene expression analysis allows
doctors and patients access to valuable
information when they are considereing
treatment options

(Reece, J.B., Urry, L.A., (2011) Campbell Biology. 9th. ed. Pearson Publication, Inc. , New York. p. 464)
TESTING



preimplantation genetic
diagnosis
prenatal diagnosis
predictive genetic testing
RECEIVING INFORMATIONS



before pregnancy
during pregnancy
after birth
 Genetic
Screening = programs designed
to identify persons in a subpopulation
whose genotypes suggest that they or
their offspring are at higher risk for a
genetic disease or condition
 Genetic testing = medical procedures tat
determine the presence or absence of a
disease, condition, or marker in
individual patients.
Innocence Project
STRs
 short tandem repeats
 = tandemly repeated units of 2 - 5 base
sequences in specific regions of tahe
genome.
 The number of repeats present in these
regions is highly variable from person to
person (polymorphic) and for one
individual, the two alleles of an STR may
even differ from each other
STRs
 f.e. one individual may have the sequence
ACAT repeated 30 times at one genome
locus and 15 times at the same locus on
the other homolog,
 whereas another individual may have 18
repeats at his locus on each homolog.
DNA Database
The use of DNA in postconviction cases to determine
whether or not there was a wrongful conviction, the
kind of situation that would help to free the innocent
2. The collection of DNA of „suspects“ or arrestees in
pretrial circumstances to increase the DNA database,
which in turn is designed to help law enforcement to
determine if there is „match“ with tissue sample left at
some unsolved crime – the net to catch the guilty
3. The advocacy of increasing the collection of DNA from
a wider and wider band of felons in the postconviction
period, so that there is a record on file in the event of
recidivism
1.
(Duster, T., (2006) Behavioral Genetics and Explanations of the Link between Crime, Violence,
and Race. in Parens, E., Chapman, A.R., Press, N., Wrestling with Behavioral Genetics. Johns
Hopkins University Press, Baltimore. p. 162)
Innocence Project
 nonprofit organization dedicataed ato
overaturning wrongful convications, uses
STR analysis of archived samples from
crime scenes ato revisit old cases.
 As of 2010, more than 250 innocent
people had been released from prison as
a result of forensic and legal work by this
group
Innocence Project
 In 1984, Earl Washington was convicted
and sentenced to death for the 1982 rape
and murder of Rebecca Williams.
 His sentence was commuted to life in
prison in 1993 due to new doubts about
he evidence.
 In 2000, STR analysis by forensic
scientists associated with The Innocence
Project showed conclusively that he was
innocent
 in forensic cases using STR analysis with
13 markers, the probability of two people
having identical DNA profiles is
somewhere between one chance in 10
billion and one in several trillion
THE TUSKEGEE SYPHILIS
STUDY
THE TUSKEGEE SYPHILIS STUDY
 For forty years, from 1932 to 1972, 399
Afroamerican males were denied
treatment for syphilis and deceived by
officials of the United States Public Health
Service
 as a part of a study, sharecroppers were
told that they were being treated for „bad
blood“.
THE TUSKEGEE SYPHILIS STUDY
 At the start of the study, there was no proven
treatment for syphilis. But even after penicillin
became a standard cure for the disease in
1947, the medicine was withheld from the
men. The Tuskegee scientists wanted to
continue to study how the disease spreads
and kills. The experiment lasted four
decades, until public health workers leaked
the story to the media.
THE TUSKEGEE SYPHILIS
STUDY
 Researches used various offers to
stimulate and sustain the subjects´interest
in continued participation.
 these offers included free burial assistance
and insurance, free transportation to and from
the examinations, and a free stop in town on
the return trip
 subjects received free medicines and free hot
meals on the days of examination
THE TUSKEGEE
 In fact, the physicians in charge of the
study ensured that these men went
untreated
 By then, dozens of the men had died, and
many wives and children had been
infected.
The Presidential Apology
 " No power on Earth can give you back
the lives lost, the pain suffered, the
years of internal torment and anguish.
"What was done cannot be undone. But
we can end the silence. We can stop
turning our heads away. We can look at
you in the eye and finally say, on behalf
of the American people: what the United
States government did was shameful.
"And I am sorry."
Herman Shaw, Tuskegee Study participant, after the White
House ceremony.
"We were treated unfairly, to some extent like guinea pigs,"
THE TUSKEGEE
 16 May, 1997 president Clinton
apologized on behalf of the United States
government to the surviving participants of
the study. These men were invited to the
White House to witness the apology
 The study has become a powerful symbol
of racism in medicine, ethical misconduct
in human research and government abuse
of the vulnerable
Discrimination
 We are not responsible for the genes we
are equipped with
 it cannot be accepted that society adds
stigmatisation to at risk persons´ burden
 a persons´genes shoul be considered as
the individual´s own property
Discrimination
 Kare Berg:
I would like to see a system where it is
explicitly forbidden for third parties
 to request genetic tests
 to ask if genetic tests have been conducted
 or if there is a genetic disease in the family
The „third parties“: the employment or insurance market
Convention on Human Rights and
Biomedicine (Oviedo Convention)
1997
Article 11 – Non-discrimination
 Any form of discrimination against a
person on grounds of his or her genetic
heritage is prohibited.
Nancy Wexler
(president of Hereditary Disease Foundation):
I´ve heard people say – including people in the Congress and
even some scientists – that the public can be hurt by genetic
information. It´s true that in the past that information has been
used against people. But genetic information itself is not
going to hurt the public; what could hurt the public is existing
social structures, policies and prejudices against which
information can ricochet. We need genetic information right
now in order to make better choices so we can live better lives.
We need the improved treatments that will eventually be
developed using genetic information. So I think the answer is
certainly not to slow down the advancing science, but to try,
somehow, to make the social system more accomodating to
the new knowledge.
REPRODUCTIVE RIGHTS
Reproductive decision-making
 potential parents who know they have, or
might be carriers of, genetic disorders are
faced with difficult decisions about whether to
have children of their own, The options are:
 to proceed with a planned pregnancy
 not to have children
 to adopt children
 to use donor eggs, sperm or embryos to avoid the
risk of the child being born with the genetic
disorder
Some comments...

"I find it interesting how some people so quickly reduce a disabled
or ill person's life to a 'life of misery', and therefore a life that
shouldn't be if at all possible. I would want to know how many
disabled people those who hold such opinions actually know. It is
possible to live a full life with disabilities - just more challenging."
 "I am 32 and still suffering from my father's hereditary disability and
I can tell you that I hate him for that. He knew he will pass it on to
any child of his and yet that wasn't bad enough. I regret his selfish
attitude and I haven't spoken to or seen him in many years
because of this. You are right to ask you some questions: make
sure you find the right answers not just the ones that suits you."
 "The assumption that the less-abled live exclusively painful,
distressing lives is troubling. Yes, it is hard and difficult. Are many
of you really suggesting they are better of dead, or not existing at
all? Perhaps you should ask a few disabled people. Yes, they
suffer but few want to die, and those that do, require more care
and love, not to hear that science should eradicate their very
existence"
http://www.nytimes.com/1999/04/25/nyregion/disabled-marriedtheir-own-mount-kisco-couple-are-among-those-withhandicaps.html