Emma Donnay, Javier Howard, Jessica
Martinez, Michael Ostach and Jackie
Viselli
Overview
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What is gene therapy?
Pros and cons
Do genes have a moral status?
Gene therapy in the medical context
Cosmetic gene therapy
FDA and NIH guidelines
WHAT IS GENE THERAPY?
Gene Therapy Defined
• Gene therapy is an approach to treating disease by either modifying the
expression of an individual's genes or by the correction of abnormal genes.
• The goal of gene therapy is the elimination of disease.
http://www.asgct.org/about_gene_therapy/defined.php
A Brief History
• One of the first papers to address gene therapy was published in 1972 in
Science and was titled “Gene therapy for human genetic disease
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• An excerpt from the abstract:
– “In our view, gene therapy may ameliorate some human genetic
diseases in the future. For this reason, we believe that research directed
at the development of techniques for gene therapy should
continue…We …propose that a sustained effort be made to formulate a
complete set of ethicoscientific criteria to guide the development and
clinical application of gene therapy techniques. Such an endeavor could
go a long way toward ensuring that gene therapy is used in humans
only in those instances where it will prove beneficial, and toward
preventing its misuse through premature application.”
Friedmann, T.; Roblin, R. (1972). "Gene Therapy for Human Genetic Disease?". Science 175 (25): 949. doi:10.1126/science.175.4025.949.
A Brief History cont.
• The first “successful” experiment did not take place until 1990.
– 4 year old girl treated for Severe Combined Immunodeficiency (SCID).
• There have been no completely successful applications of gene therapy for
human disease, although considerable progress has been made.
• Many appoaches for gene therapy are currently being evaluated in animal
models of human diseases and in clinical trials.
Two Types of Gene Therapy
Somatic Gene Therapy
Image source: http://www.whyvitamin.com/wp-content/uploads/2009/10/ovum-cell.jpg
Image source: http://www.cell-research.com/20034/Cover-final2.gif
Germline Gene Therapy
Somatic Gene Therapy
• The alteration of somatic cells (non reproductive cells).
• Alterations of somatic are restricted to that individual and will
not be passed onto future generations.
Germline Gene Therapy
• The alteration of germ (sperm & egg) cells.
• The alteration is made during the embryonic stage, such that the genes
altered would be passed down to future generations.
• Germline gene therapy can be done by altering the genes of a pre-embryo
that carries a serious genetic defect before implantation into the mother or
by altering the germ cells of an afflicted adult so that the defect does not get
passed on to their offspring.
• Because of the unknown effects germline therapy has on future
generations, it is the most controversial.
How Does Gene Therapy Work?
• A normal gene may be inserted into a nonspecific location within the
genome to replace a nonfunctional gene. This approach is most common.
• An abnormal gene could be swapped for a normal gene through
homologous recombination.
• The abnormal gene could be repaired through selective reverse mutation,
which returns the gene to its normal function.
• The regulation (the degree to which a gene is turned on or off) of a
particular gene could be altered.
Viral Vectors
• Gene therapy typically uses inactivated viruses to deliver genes throughout
the body.
Image source: http://library.thinkquest.org/28000/media/genetherapy/l_gene.therapy-ms.gif
Issues and Advancements in Gene
Delivery (Vectors)
• Three types of vectors will be discussed:
– Retrovirus vectors
• HIV is a retrovirus.
– Adenovirus vectors
• Known for causing upper respiratory tract infections.
– Liposome vectors
• Imagine a liposome as being similar to a soap bubble.
Retrovirus Vectors
• The normal function of a retrovirus is to insert it's genetic material into the
target cells genome to alter it permanently.
• Scientists remove the viruses genetic material and replace it with the
genetic material they wish to deliver to the defective cells.
• Inactivation of the virus leads to its use in gene therapy.
• Pros
– Retroviruses target very specific cells depending on the type of virus.
• Cons
– Inserting new genes into a cells genome may cause mutations or disrupt
a cell linked to cancer thereby causing cancer to develop
Adenovirus Vectors
• Like retrovirus, uses host cell to replicate.
• Unlike retrovirus does not insert DNA into host cell's genome.
• Pros
– No risk of mutation of cells, or disruption of genome sequences.
• Cons
– Can trigger immune response from the body causing the body to kill off
the altered cells rendering the therapy useless.
– In addition, if the body has already naturally come into contact with an
adenovirus it could have antibodies already formed against the virus
initiating an immune response.
Liposome Vectors
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Uses a fatty cell, a liposome, to carry
healthy human genes into target cell.
The gene to be delivered is "transformed"
into a small circular ring of DNA (a
plasmid), and is then inserted into a
liposome.
Pros
– Safer then modified viruses.
Cons
– Requires a very large number of
infected liposomes to have desired
effect. Has to be directly introduced
to infected cells.
Nose sprays have been developed to
deliver liposomes directly to the lungs of
cystic fibrosis patients.
Image source: http://www.supplementclinic.com/v/vspfiles/assets/images/liposome1c.jpg
Lavorini-Doyle C., Gebremedhin S., Konopka K., Düzgüneş N. 2009. Gene delivery to oral cancer cells by nonviral vectors: why some cells are resistant to transfection. J
Calif Dent Assoc, 37(12):855-8.
PROS AND CONS
Pros
• Potential to cure inheritable genetic disorders such as Cystic Fibrosis,
Parkinson's Disease, and Alzheimer's Disease which currently have no
other permanent cures.
• Medical necessity.
• Parental autonomy: parents can make choices about what is best for their
children.
• Better to prevent a disease rather than just a temporary fix.
Cons
• “Playing god.”
• We don't know the long term effects gene therapy will have on future
generations.
• Slippery slope: if we begin to alter genes for the purpose of curing diseases
it might lead into altering genes for cosmetic purposes.
• Too costly.
• Lack of informed consent because a fetus/embryo cannot consent.
DO GENES HAVE A MORAL
STATUS?
Overview
Arguments for moral status
• "The sacred gene“
– Human DNA has been used as a symbol of individual human identity,
and of the human spirit, soul, or essence.
– Richard Dawkins
• Argues that genes are the true locus of human agency.
Arguments against moral status
– Mary Anne Warren
• The parts argument
• Sentience and consciousness
• Problems with the sacred gene argument
– Environmental factors and epigenetics
A determination of the moral status of a given gene has
implications for deciding if genetic therapy is
ethically appropriate.
Richard Dawkins
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Well known for his work in
evolutionary biology and
creationism.
Argues that genes are the true locus
of human agency.
"Individuals are not stable things,
they are fleeting ... the genes ...
change partners and march on
...they are the replicators and we are
their survival machines. When we
have served our purpose we are cast
aside. But genes are denizens of
geological time; genes are forever."
Dawkins, Richard (1976). The Selfish Gene. New York City: Oxford University Press. ISBN 0-19-286092-5.
Image Source: http://upload.wikimedia.org/wikipedia/commons/7/77/Dawkins_at_UT_Austin.jpg
Arguments Against Moral Status
• Mary Anne Warren
– Argues that genes do not have independent moral status.
– Key components of her position:
• The parts argument
• Sentience and consciousness
• Rebuttal of the "sacred gene" argument
Anne Warren, M. (2008) The Moral Status of the Gene, in A Companion to Genethics (eds J. Burley and J. Harris), Blackwell Publishing Ltd, Oxford, UK. doi:
10.1002/9780470756423.ch11
The Parts of Organisms Do Not
Have Moral Status
• One reason that we regard living organisms as worthy of moral status
is because they are systems of their own that exhibit a purpose. They
are organized to maintain and reproduce themselves, and to interact
with their environments in ways that have evolved because they
tended to serve these ends.
• Parts of organisms (i.e. a foot or an organ) only act in the
manifestation of the entire organisms purpose, and function to
contribute to the survival of the entire organism, and not solely itself.
Consider for a Moment:
• Tissues and organs take on specific forms and functions in a given
organism.
• This is because the traits these components exhibit promote the
reproductive success of the organism.
• The "goals" of a liver, for example, are directed in ways that generally
differ from the goals of the organism (i.e. the liver detoxifies drugs and
stores glycogen).
• Therefore, it is inappropriate to attribute independent moral status to the
parts of organisms.
Sentience and Consciousness
• Sentience: the ability to feel or perceive.
– The experience of pain, pleasure, and other mental state occurs at the
level of the organism.
• One may feel pain in his or her hand, although it is unlikely that the hand
has private pains unfelt by the individual. In other words,
organs/tissues/cells do not have central nervous systems of their own.
Sentience and Consciousness cont.
• We can therefore argue that we have special obligations to organisms, such
as to not cause them pain or suffering.
• This obligation does not translate to parts of organisms, as they do not
experience pain and pleasure.
• A similar argument for consciousness and memory:
– Some organisms have moral agency, meaning that they posses a level
of sophistication allowing them to tell right from wrong, and act in the
pursuit of conscious goals.
– Parts and organs are not moral agents, and do not have the rights that
flow from moral agency.
Warren's Conclusions from the
Previous Arguments
• We can extend the previous arguments to DNA.
• In the context of gene therapy, Warren contests that:
– There is no a priori reason not to permit genetic alterations, provided
that we know enough to avoid the associated risks to current and future
persons.
Problems with the Sacred Gene
Argument
• Warren contests that the empirical evidence is not sufficient to hold genes
in such high regard.
• "DNA is not the sole source and shaper of organisms, and neither is it an
immortal being. It is not an immaterial entity that is eternally reincarnated
in new physical bodies. It is a physical part of living and mortal organisms,
one that has a central but not omnipotent role in the organism's
development, functioning, and reproduction.“
• Key components:
– It takes more than DNA to create a functioning organism. For example,
for a zygote to fully develop there needs to be:
– Nutrients from the environment
– A correct temperature range for biochemical reactions to occur.
• Environmental factors can influence the expression of certain genes.
Epigenetics
• "Above the genes.“
• Modifications that are caused due to environmental factors, among other
things.
• Epigenetic modifications cause certain genes to be unexpressed, although
does not change the sequence of the genes.
– Some individuals may contest that the sequence, or "information,"
contained in ones genome is the most basic, or underlying, element that
acts to create the organism.
• There is evidence that epigenetic "information" can be passed on to
progeny.
http://learn.genetics.utah.edu/content/epigenetics/inheritance/
Jablonka E., Raz G. 2009. Transgenerational epigenetic inheritance: prevalence, mechanisms, and implications for the study of heredity and evolution. The Quarterly Review
of Biology 84(2):131–176.
Epigenetics cont.
• An example of an epigenetic
process is genomic imprinting.
• Genomic imprinting involves
DNA methylation and histone
modifications.
• Involved in the manifestation of
Prader-Willi and Angelman
syndromes.
Image source: http://embryology.med.unsw.edu.au/MolDev/Images/epigenetics.jpg
Prader–Willi Syndrome
• Symptoms:
– Short stature
– Poor motor skills
– Weight gain
– Underdeveloped sex organs
– Mild mental retardation and
learning disabilities
http://www.nlm.nih.gov/medlineplus/praderwillisyndrome.html
Image source: http://medgen.genetics.utah.edu/photographs/diseases/high/420a.gif
Prader–Willi Syndrome cont.
• Caused by genomic imprinting on
a set of genes within chromosome
15.
• Paternal chromosome undergoes
imprinting.
• Most cases of PWS are due to a
spontaneous genetic error that
occurs at or near the time of
conception for unknown reasons.
http://www.pwsausa.org/faq.htm
Image source: http://www.sahha.gov.mt/showdoc.aspx?id=439&filesource=4&file=fig02.jpg
Angelman Syndrome
Image source: http://www.primehealthchannel.com/wp-content/uploads/2010/11/angelman-syndrome-picture.jpg
GENE THERAPY IN THE
MEDICAL CONTEXT
http://www.youtube.com/watch?v=tR6lpbiVPFw
“Bubble Boy” Syndrome
• Also known as Severe Combined
Immunodeficiency.
• The first “successful” gene
therapy experiment was done on
four year old Ashanti DeSilva in
1990 to replace the defective
enzyme adenoside deaminase
(ADA).
• She was not completely cured, as
she still must continue to take a
low dose of PEG-ADA, the
traditional drug treatment for
SCID.
• After her treatment, the field of
gene therapy flourished.
David Vetter lived until the age of 12 with SCID.
http://www.nytimes.com/2005/07/03/books/chapters/0703-1st-naam.html?_r=1
Image Source: http://findmeacure.com/wp-content/uploads/2010/05/bubble-boy-disease-of-David-Vitter.jpg
Jesse Gelsinger
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There have been major setbacks in the
field.
In 1999, 18 year old Jesse Gelsinger
died in a gene therapy trial for
ornithine transcarbamylase
deficiency, a condition in which the
body is unable to metabolize
ammonia.
He died from multiple organ failure
due to a immune response to the
adenovirus vector.
Jesse and his father were not
informed of this complication, as
there were two monkeys that had died
in animal trials due to the same vector
virus.
Hartnett T. 2008. Regulatory and ethical issues in conducting gene therapy research. Research Practitioner, 9(1): 4-10.
Image Source: http://www.jesse-gelsinger.com/images/jesseboxing.jpg
COSMETIC GENE THERAPY
What is Cosmetic Gene Therapy?
• Similar in a sense to plastic therapy
• Uses germline genetic engineering
• Would allow parents to change characteristics of their children (and thus
following generations as well)
• Would be separate from medical gene therapy
What Characteristics Can be
Altered?
• Height - Growth Hormone/Estrogen
• Weight - Altering Leptin
• Memory/Learning - Estrogen/Intracranial Gene Delivery
• Muscle Strength/Buildup - Growth Hormones
• Hair Color/Growth
What Would Gene Therapy Change?
• Appearance
• Mental Capacity
• Intelligence
• Physical ability
• Athletic potential
Reasons Against Cosmetic Gene
Therapy
• Greater class differential (those who can afford vs. those who cannot)
• Preferential coupling between the rich and attractive (pure blood)
• Less sense of purpose and belonging for child
• "Bad" parents predetermining child's future
• More of a materialistic society - children as products
• Increased discrimination
• Constantly new technology, "outdated" by adulthood
Reasons for Cosmetic Gene Therapy
• Technological advance of the human race
• Uses the further knowledge and ability of man
• Can be related to putting the first man on the moon (and atomic bomb
example)
– High risk, high financial investment, could be deemed unnecessary.
• Satisfies the human need for exploration and curiosity
• "Human evolution will be self driven" - Lee Silver
• Would be for the benefit and advancement of man
Ethically Permissible?
• Christopher Columbus example
• Conclusion for the pro cosmetic gene therapy argument:
– It is ethically permissible for humans to follow their
impulse for advancement to improve as a race and the
understanding of the world.
Final Thoughts
• If you could "create" the perfect child based on the physical
and mental qualities available to be altered, which would you
most likely consider actually altering on your future child?
• What are some general qualities that all parents would hope
for their children to have?
• What are more important to you? Physical characteristics or
character traits?
– (i.e. would you rather have a genetically modified genius child that
treats everyone else as inferiors or a mildly smart child by nature who
is kind at heart and treats people fairly?)
• Where do you find that your values lie?
FDA AND NIH GUIDELINES
Gene Therapy Legislation in the U.S.
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Both the National Institute of Health and the Food and Drug Administration serve to protect
Americans by regulating the use of gene therapy.
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NIH and the RAC
– The National Institute of Health established the Recombinant DNA Advisory Committee
(RAC) on October 7, 1974. This committee serves to aid the U.S. government in
developing comprehensive legislation in the gene therapy field. NIH uses the RAC in
order to have a critical forum for the discussion of the issues we face with recombinant
DNA technology and it’s applications in our society. This forum not only looks at the
scientific challenges, but also the ethical and legal repercussions of a greater use of the
technology.
– The main job of the RAC is the review of human gene transfer research. They analyze all
of the studies involving recombinant DNA technology and then report back to the NIH
about their findings and give recommendations for legislation regarding the technology.
All human gene therapy trials that take place at institutions which receive federal funding
from the NIH are reviewed by the Recombinant DNA Advisory Committee.
– RAC reports are posted to the online so the public is able to stay informed about
developments in the gene therapy field.
Gene Therapy Legislation cont.
• FDA & CBER
– The U.S. Food and Drug Administration is a U.S. government agency
put in place to protect the health of our citizens by making sure that
drugs, medicine and other products are safe and effective before they
are put in use. This includes the regulation of clinical trials testing
controversial treatments, like gene therapy.
– The FDA’s Center for Biologics Evaluation and Research (CBER)
regulates human gene therapy because if falls under the legal definition
of a “biologic," which is a biological product, like a vaccine, used in
medicine.
CBER Requirements for Gene
Therapy Research
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Manufacturers of gene therapy products must go through extensive tests and meet
requirements put out by the FDA before they can even test a product in a lab.
If lab results are successful, they can test the gene therapy treatment on animals.
At this point, they must receive a special exemption, an Investigational New Drug
Application (IND), from the FDA in order to test their product on humans. In an
IND, the manufacturer of the product explains their previous research and how they
plan to conduct the study, gives the possible risks to patients and lists the steps it
will take in order to protect those who participate in the study.
They also must get approval from an institutional review board, which is a
committee of advisors, specializing in science and medicine, and consumers.
In addition, the researchers conducting the study must receive consent from
participants, informing them of potential risks and benefits.
If they are successful in all of these aspects, the FDA can approve of the sale of the
gene therapy product. This has yet to happen. The FDA has not yet approved for
sale ANY human gene therapy product.
Bleijs, D.A., comp. Gene Therapy Legislation in the United States of America. Issue brief. Gene Therapy Net, 2010. Web. 1 Dec. 2010.
<http://www.genetherapynet.com/united-states-of-america.html>.
Gene Therapy Legislation Around
the World
• China
– In 2003, Gendicine, the first commercial gene therapy medicine,
became available on the Chinese market. This cancer drug was
approved by the Chinese authorities after it gave promising results in
clinical trials. It’s success is virtually unnoticed outside of China.
– In 2005, China put another gene therapy drug on the market. Oncorine,
an oncolytic (tumor destroying) adenovirus, is meant to be used
alongside chemotherapy in order to treat patients with a late stage
nasopharyngeal cancer. This is the first oncolytic viral therapy
approved by any government agency in the world.
Bleijs, D.A., comp. Gene Therapy Legislation in China. Issue brief. Gene Therapy Net, 2010. Web. 1 Dec. 2010. <http://www.genetherapynet.com/asia/china.html>.
Gene Therapy Legislation Around
the World cont.
• Europe
– There are many discrepancies across Europe and scientists are calling
for a ‘best practice philosophy’ across the European Union.
– There isn’t much progress being made in the U.K. Many attribute the
lack of success to the stringent laws that restrict research in gene
therapy.
– Many scientists working in Britain believe that they are behind
compared to European and U.S. colleagues. Gene therapy research
regulations in Britain is said to be the most strict in Europe and
significantly more strict than U.S. regulations.
John Illman. Gene Therapy in Europe: New Initiatives Seek Streamlined Debate. J Natl Cancer Inst 2000 92: 188-190. http://jnci.oxfordjournals.org/content/92/3/188.full
DISCUSSION
Class Discussion
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Could the widespread use of gene therapy make society less accepting of people
who are different?
Should people be allowed to use gene therapy to enhance basic human traits such
as height, intelligence, or athletic ability?
Do you believe that genes have independent moral status? Why or why not?
Does the information pertaining to Prader–Willi and Angelman syndromes lead
you to agree that genes are not morally absolute? Perhaps genes do contain some
level of moral status, although are not omnipotent.
Consider the information about David Vetter (the boy who lived in a bubble) and
the first successful case of gene therapy that treated the 4 year old girl with SCID.
Do these cases change or strengthen your views about gene therapy? Think back
to the beginning of the semester and evaluate these cases from both a
consequentialism standpoint and a deontology (non-consequentialism) standpoint.