Gene Therapy Policy Statement

Bushelle E, Hertz E, Hubbard D, Saylor K, Slyker A





I.  Technology of Gene Therapy:


The objective of gene therapy is to rescue mutant phenotypes by providing deficient cells with a normally functioning copy of the gene associated with the disease.  In such rescues the mutant cells are complemented[1] by the rescuing gene and reverted to wildtype function.  This paradigm for gene therapy is only be useful in treating diseases caused by recessive mutations such as cystic fibrosis in which in a single functional copy of the gene is sufficient for the viability of the individual.  Diseases caused by dominant alleles such as Huntington’s disease would most likely not be cured under this scheme because the presence of the mutant gene product from a single allele is lethal.

The current paradigm for treating recessive genetic disorders has two primary dimensions: The first is a genetic construct, which is simply a normal copy of the gene or the information required to synthesize it in the cellular environment.  The second dimension is a delivery system capable of injecting the construct into the mutant cells.  This delivery system is called a vector.   As such, somatic cell therapy is restricted by the ability to target specific cells, the delivery efficiency of vectors, the expression and durability of the inserted constructs, and safety (Lundstrom, 2003).


Genetic Constructs:


There are two basic types of genetic constructs that could be used for therapeutic applications.  They are characterized by an essential difference between them in that one type of construct needs to be inserted into the host organism’s genome in order to be replicated and expressed properly while the other type functions essentially as an additional chromosome.

The type of construct that must be inserted into the host genome comes in two varieties.  The first is a segment of DNA containing the desired gene that has been cut from the genome of a wildtype cell using restriction enzymes.  The second type is an mRNA transcript of the functional wildtype gene that will be reverse transcribed into cDNA[2] in vivo.  Both varieties require the action of special enzymes in order to be incorporated into the host genome.  The information required to synthesize these enzymes is included as part of the genetic construct.  This incorporation is necessary for the inserted DNA is to remain in the recipient organism for a long duration because unincorporated DNA is quickly lost.

The second type of construct is called a Human Artificial Chromosome (HAC).  This construct is essentially a mini-chromosome that, once inserted, is able to function, replicate and segregate just like normal chromosomes (Larin, 2002).  This is less likely to disrupt the existing genetic material of the cell.  The key structural features of these constructs are regions of telomeric DNA which allow HACs to be properly replicated during synthesis and centromeric DNA which allow them to be properly segregated at mitosis (Larin, 2002).



Liposome-mediated transfer:


Liposome-mediated transfer involves delivering the rescuing genetic construct by means of an artificially created lipid bilayer called a liposome (Lundstrom, 2003).  In this method, the liposome is coated with proteins that are recognized by specific receptors on the surface of the targeted cell type.  The binding of the coating proteins to the receptors initiates the uptake of the liposome by the target cell, releasing the contents of the liposome into the cytoplasm of the cell.  For example, inserting a genetic construct containing a functional copy of the CFTR gene into a liposome that is targeted to the cell surface receptors pulmonary cells would be a way to deliver the rescuing genes to the tissues where they are needed in a patient suffering from Cystic Fibrosis.


Figure 1:  Liposome-mediated transfer.  A liposome containing a genetic construct recognizes proteins on the surface of the targeted cell type.  The binding of proteins on the surface of the liposome to those on the surface of the cell initiates fusion of the liposome to the plasma membrane, effectively delivering the rescuing genetic construct into the cytoplasm of the cell.  (Drawing obtained from the Davidson College Biology Department website.)








Viral vectors:


Viral vector technology co-opts the machinery of viruses to insert rescuing genes into mutant cells.  Viruses perpetuate themselves by a process in which they successfully recognize and bind to the surface of a specific cell type, inject a piece of DNA or RNA into the cell, and exploit the cell's replication and translational[3] machinery to produce new virion particles.  The viral machinery exploited in this technology are empty virion particles used to package genetic constructs as well as viral genes the code for enzymes reverse transcriptase[4] and integrase[5].  These enzymes are responsible for the ultimate incorporation of the gene into the recipient cell’s genome.  There are several different types of viral vectors that may be appropriate for gene therapy and they vary according to the maximum genetic load, their ability to target different cell types, and their degradation rate.  It is important to note that safety concerns demand that any virus used as a vector must have its replication capabilities disabled.





The risks posed by gene therapy are associated mainly with the vector systems employed.  Viral vectors in particular carry an assortment of risks.  Viral vectors that are not properly targeted may infect a broader range of cells than are intended.  Furthermore, instances where the genes mediating viral replication are not completely deactivated.  Beyond the risks associated with viral infection, the non-specific action of gene integration via integrase enzymes presents the possibility of disrupting gene regulation in the host genome potentially leading to cancer.

If these vectors reach germline cells, then the modified genes will be heritable.  This has been demonstrated with HACs in mice, which passed the trait through three generations.  Such inheritable genetic modifications present serious ethical dilemmas that will be discussed at length below.  One means of avoiding inheritable genetic modifications is to use degradable constructs, although this would require re-administration in the lifetime of the recipient.


II. Ethical Concerns


            The ethical issues associated with gene therapy center around humankind’s ability to control the destiny and direction of our species.  Arguments against gene therapy frame it as the latest incarnation of the eugenics movement, viewing gene manipulation as a potential instrument for oppression and genetic apartheid.  Arguments for gene therapy view it as a possible cure for many serious diseases.  Ethical concerns differ according to the nature of gene therapy: somatic or germ-line.


Somatic Therapy Concerns


            There is less controversy regarding somatic gene therapy.  Somatic gene manipulations only target pathologically relevant cells of specific tissues, which means that genetic manipulations will not be inherited.  Therefore, somatic gene therapy does not raise the central ethical issue of genetic engineering as a source for genetic improvement of mankind.  There are, nonetheless, some considerable ethical issues.

            Critics argue that the use of somatic gene therapy is like a “slippery slope”. They wonder if it is possible to distinguish between “good” and “bad” uses of the gene modification techniques, and whether the potential for harmful abuse of the technology should keep us from developing more techniques. It is thought that somatic gene therapy is still a dangerous technology with unpredictable outcomes.  Genes are carried by viral vectors that could lead to infection of non-target cells.  Moreover, the transfer gene could integrate at an undesired position in the genome and cause unknown effects.

            Proponents argue treatments of any disease always incur unknown risks.  Chemotherapy, for example, can successfully cure cancer, but is well-known for inducing severe side-effects.  Thus, somatic gene therapy does not differ in principle from cancer treatments.  The central argument in favor of gene therapy is that it can be used to treat desperately ill patients, or to prevent the onset of horrible illnesses. Furthermore, proponents also argue that the medical profession has a moral obligation to administer and further the most efficacious treatments.


Germ-line Gene Therapy Concerns


            The ethics of germ-line gene therapy are considerably more controversial because the genetic corrections would be inherited through generations.  Thus, germ-line gene therapy has larger ethical implications of man’s “God-like” control of human structure and modifications. 

            Critics often begin their argument by asserting that germ-line gene therapy is not likely to be a valuable treatment of genetic diseases and is not capable of correcting a gene in future generations.  They believe that current germ-line gene therapy experiments involve too much scientific uncertainty and clinical risks.  Second, critics believe that gene therapy of genuine diseases would open up a “slippery slope” where future treatments would target the enhancement of traits not correlated with disease.  Princeton geneticist Lee M. Silver envisions a world where germ-line gene therapy creates a genetic apartheid of the “GenRich” and “GenPoor.”  Silver in Remaking Eden: Cloning and Beyond in a Brave New World, predicts that in 2350:

            “The GenRich who account for the 10 percent of the American population all carry synthetic genes. Genes that were created in the laboratory...The GenRich are a modern-day hereditary class of genetic aristocrats...All aspects of the economy, the media, the entertainment industry, and the knowledge industry are controlled by members of the GenRich.”  (Silver 1997)

            Third, critics view research on early embryos as research on unconsenting individuals.  Finally, germ-line gene therapy is viewed as permanently tainting a genetic pool for future generations. 

            Proponents of gene therapy view it as a treatment that can be used to cure terminal disease or a prevention of genetic diseases.   Germ-line therapy offers a true cure, and not simply a palliative or symptomatic treatment.   It may be the only effective way of addressing some genetic diseases, such as, hemophilia and cystic fibrosis.  It is also a technique that can prevent the transmission of disease genes to further generations, thus the expense and risk of somatic cell therapy for multiple generations is avoided.  Medicine should also respond well to the reproductive health needs of prospective parents at risk for transmitting serious genetic diseases.  It is also important to note that the scientific community has a right to free inquiry, within the bounds of acceptable inquiry, within the bounds of acceptable human research. 


            It is uncertain as to whether the disadvantages outweigh the advantages, but to some people it may be their only chance to live.  Mankind is still in need of more information surrounding this topic. We can assume that it will not provide us with a revolution of medicine by overcoming genetic diseases. We can rather hope that it will offer some additional symptomatic but nevertheless useful therapeutic options.


Somatic Gene Therapy



It can be used to treat desperately ill patients, or to prevent the onset of horrible illnesses


Moral obligation of health professions to use best available treatment methods.


Freedom of scientific inquiry and intrinsic value of knowledge.



Unavoidable risks, irreversible mistakes.


Availability of alternative strategies for preventing genetic diseases.  These include selective abortion and nutritional therapies.


May be used for the enhancement or modification of human capabilities that are not disease related.



Germ-line Gene Therapy



Germ-line gene therapy may be the only effective way of addressing some genetic diseases.


Germ-line therapy offers a true cure, and not simply palliative or symptomatic treatment.


By preventing the transmission of disease genes, the expense and risk of somatic cell therapy for multiple generations is avoided.


Medicine should respond to the reproductive health needs of prospective parents at risk for transmitting serious genetic diseases.


The scientific community has a right to free inquiry, within the bounds of acceptable human research. 


Parental autonomy and access to available technologies for purposes of having a healthy child.


More efficient and cost-effective than somatic cell gene therapy.





Expensive intervention with limited applicability, given that genetic defects are seen in only 2 % of live births and that money for health programs might be better spent elsewhere.


Inevitable pressures to use germ-line gene modification for enhancement.  Although recombinant human growth hormone is supposed to be used to alleviate some forms of dwarfism, it is also used to enhance height of individuals who are not suffering from this condition but who are only short.


Germ-line therapies would involve too much scientific uncertainty and clinical risks, and the long term effects of such therapy are unknown.


Such gene therapy would open the door to attempts at altering human traits not associated with disease, which could exacerbate problems of social discrimination.


As germ-line gene therapy involves research on early embryos and affects their offspring, such research essentially creates generations of unconsenting research subjects.


Gene therapy is very expensive, and will be cost effective enough to merit high social priority.


Germ-line gene therapy would violate the rights of subsequent generations to inherit a genetic endowment that has not been intentionally modified.



III. Recommendations


            The first step toward proper oversight of gene therapy would be to create a single, centralized regulatory body in place of the current system, in which the powers of oversight are divided among a number of different organizations (NIH, FDA, OHRP).  This new office would regulate clinical trials, techniques of gene therapy, and the application of government funds to research. 

            We also recommend that a standard patient consent form be drafted, in order to inform potential subjects of the basic principles and risks of gene therapy.  This document could be modified to fit individual research programs, so patients would be aware of the details of their particular treatment.  Submission of this addendum to the oversight body described above would be a prerequisite for government funding.

            On the larger ethical and legal scale, we recommend legislation banning human trials of somatic cell gene therapy for all cases but those involving near-term lethality until gene therapy technology is better understood.  The risks to patients are not well known, and until techniques improve, such as the successful targeting of individual tissues, the dangers are too high for patients whose diseases can be regulated by other means.  Only in cases where the patients are facing death do the potential benefits outweigh the risks.  While clinical tests are a question of informed consent, we believe that legislation is a choice superior to the mere withdrawal of funding, as cases of poor science and unnecessary risk leading to the death of a patient, such as the Jesse Gelsinger incident, will malign gene therapy as a whole and lead to public outcry against future and ultimately beneficial incarnations.

            We believe that human germ-line gene therapy and research therein should be outlawed for the present.  The effects on organisms and the prospect of modification heritability are not yet well studied, and the ethical concerns are too serious to be dismissed.  Simply cutting government funding would lead to the privatization of the technology and do nothing to prevent its future misapplication.  Animal research would still be legal and receive government funding.






Lundstrom, K. (2003)  Latest development in viral vectors for gene therapy.  Trends in Biotechnology. 21, 117-122


Larin, Z. and Mejia, J.E. (2002)  Advances in human artificial chromosome technology.  Trends in Genetics. 18, 313-319

[1] Complementation refers to

[2] cDNA is DNA that is synthesized from an RNA molecule by the enzyme reverse transcriptase.  Unlike normal eukaryotic DNA it does not contain the untranslated regions within genes called introns.

[3] Translation refers to the process in cells whereby proteins are synthesized from RNA transcripts.

[4] Enzyme first discovered in retroviruses, that can construct double stranded DNA molecules from the single stranded RNA templates of their genomes. (CancerWeb On-line Medical Dictionary.)

[5] Enzyme responsible for inserting a foreign gene (say from virus) into the genome of a host organism.