Molecular Biotechnology: Principles and Applications - Glick, B., & Pasternak, J. 2002

Regulation of Molecular Biotechnology Research and Patenting of Biotechnological Inventions
Control of the Application of Biotechnological Methods
Human Gene Therapy

Human Gene Therapy in a broad sense involves the Introduction of functionally active gene(s) into Cells to correct a genetic defect. There are two potential approaches to treating Hereditary diseases. In the first approach, somatic cells (non-germline cells) undergo genetic transformation. Consequently, the correction of the genetic defect remains confined to a specific organ or tissue. In the second approach, the genotype of germline cells (sperm or egg cells) or fertilized eggs (zygotes) is modified so that all Cells of the resulting individual carry the "corrected" genes. As a result of germline gene therapy, genetic modifications are transmitted from generation to generation.

Policy on Somatic Cell Gene Therapy

In 1980, Representatives of the American Catholic, Protestant, and Jewish communities addressed an open letter to the President outlining their Perspectives on human Genetic Engineering. To evaluate the ethical and social dimensions of this issue, a Presidential Commission and a congressional commission were established. These were crucial initiatives, as public-interest programs in the United States are frequently implemented based on recommendations from such panels. The final reports of both commissions drew a clear distinction between somatic cell gene therapy and germline gene therapy. Somatic cell gene therapy was classified as a standard medical intervention, comparable to organ transplantation. In contrast, germline gene therapy was deemed too technologically complex and ethically problematic to warrant immediate Structure/182.html">Practical Application. It was concluded that clear regulations governing somatic cell gene therapy research were necessary, while drafting similar documents for germline gene therapy was considered premature. To curb any unlawful activities, a decision was made to halt all experiments involving germline gene therapy.

By 1985, the NIH had drafted a document titled "Guidelines for Protocol Development and Submission for Somatic Cell Gene Therapy Experiments." It provided comprehensive information on the data required in Applications for human somatic cell gene therapy trials. The regulations governing recombinant DNA laboratory research served as the foundation, merely adapted for biomedical purposes.

Biomedical legislation was revised and expanded in the 1970s in response to the 1972 disclosure of a 40-year experiment conducted by the U.S. Public Health Service in Alabama involving 400 illiterate African American men suffering from Syphilis. The study was designed to observe the natural progression of this sexually transmitted disease without providing any Treatment. News of this appalling experiment on uninformed human subjects shocked many across the U.S. Congress immediately terminated the study and enacted legislation prohibiting similar research ever again.

Among the questions posed to applicants seeking approval for somatic cell gene therapy experiments were the following:

✵ What is The Nature of the disease intended for treatment?

✵ How severe is the condition?

✵ Are alternative treatments available?

✵ What are the risks of the proposed treatment to the patients?

✵ What is the probability of treatment success?

✵ How will patients be selected for clinical trials?

✵ Will this Selection process be impartial and representative?

✵ How will patients be informed about the trials?

✵ What specific information should be disclosed to them?

✵ How will their consent be obtained?

✵ How will the confidentiality of patient data and research Procedures be guaranteed?

In the early days of gene therapy experiments, the majority of clinical trial proposals were initially reviewed by the institutional ethics committee of the host research facility before being forwarded to the NIH Human Gene Therapy Subcommittee (NIH-RAC). The latter evaluated applications based on their scientific and medical significance, compliance with current regulations, and the validity of the rationale. If an application was rejected, it was returned with necessary feedback. The authors could then revise and resubmit their proposal. Upon approval, the NIH-RAC discussed the application in open public sessions using the same criteria. Following approval at this level, the NIH Director endorsed the proposal and signed the clinical trial authorization, without which trials could not commence. Furthermore, because testing somatic cell gene therapy Methods involved novel genetic constructs, the application was also reviewed by the FDA. In the latter case, particular attention was paid to the manufacturing process, quality control methods for purity, and the preclinical trials conducted to ensure product safety.

However, as the number of applications grew over time and gene therapy evolved into what one commentator called a "golden ticket in medicine," the initial approval process proved overly cumbersome and redundant. Consequently, after 1997, the NIH was removed from the regulatory bodies overseeing human gene therapy research. Should the NIH-RAC continue to exist, it will likely serve as a forum for discussing the ethical issues surrounding human gene therapy. Meanwhile, the requirement for all gene therapy applications to undergo public Discussion has been lifted. The FDA, responsible for regulating the production and use of biological products, conducts all necessary evaluations confidentially to protect the developers' proprietary rights. Today, human gene therapy is considered a safe medical Procedure, albeit not a particularly effective one. Earlier fears have dissipated, and it has become one of the mainstream approaches for treating human diseases.

Most experts view the approval process for human somatic cell gene therapy trials in the United States as entirely adequate; it guarantees impartial patient selection and informed consent, as well as the proper execution of all procedures without harming individual patients or the human population as a whole. Other countries are currently developing their own regulations for gene therapy trials as well. In the U.S., this was achieved through careful deliberation of every proposal. As Dr. LeRoy Walters, Director of the Kennedy Institute of Ethics at Georgetown University in Washington, D.C., remarked during hearings organized by the NIH-RAC in January 1989: "I know of no other biomedical science or technology that has been subjected to such thorough scrutiny as gene therapy."

Accumulation of Defective Genes in Future Generations

It is sometimes argued that treating Genetic Disorders via somatic cell gene therapy will inevitably lead to a deterioration of the human gene pool. This view is based on the assumption that the frequency of the defective gene in the population will rise from generation to generation, because gene therapy will enable individuals who were previously unable to reproduce or survive to reproductive age to pass mutant genes on to their offspring. However, this hypothesis has proven incorrect. According to Population Genetics, significantly increasing the frequency of a deleterious or lethal gene through effective treatment requires thousands of years. For example, if a rare genetic disorder occurs in 1 out of 100,000 viable newborns, it would take approximately 2,000 years after the widespread use of effective gene therapy for the incidence of that disorder to double to 1 in 50,000.

Aside from the fact that the frequency of lethal genes barely increases across generations, long-term treatment of all those in need also leaves the genotypes of individual humans unchanged. This principle can be illustrated by an evolutionary example. Primates, including humans, cannot synthesize essential Vitamin C and must obtain it from external sources. Thus, we are all genetically deficient in the gene responsible for producing this vital substance. In contrast, amphibians, reptiles, birds, and non-primate mammals do synthesize vitamin C. Yet, the genetic defect causing the inability to biosynthesize vitamin C has not hindered the successful evolution of primates over millions of years. Similarly, the correction of other genetic defects will not result in a significant accumulation of "unhealthy" genes in future generations.

Germline Gene Therapy. Human germline gene therapy experiments are currently strictly prohibited, though it must be acknowledged that certain genetic diseases can only be cured via this approach. The methodology for human germline gene therapy is not yet sufficiently developed. Nevertheless, there is no doubt that with advancements in animal genetic manipulation techniques and preimplantation embryo diagnostic testing, this gap will be bridged. Furthermore, as somatic cell gene therapy becomes increasingly routine, public attitudes toward human germline gene therapy will shift, eventually necessitating its clinical testing. One can only hope that by that time, all issues associated with the Practical Applications OF human germline gene therapy—including Social and biological implications—will have been resolved.

It is believed that human gene therapy can help treat severe diseases. Indeed, it has the potential to correct a range of physical and mental disorders, though it remains unclear whether society will deem such applications acceptable. Like any emerging medical field, human germline gene therapy raises numerous questions, namely:

✵ What is the cost of developing and implementing human germline gene therapy methods?

✵ Should the government establish priorities for medical research?

✵ Will the priority development of germline gene therapy lead to a reduction in efforts to find other treatments?

✵ Will it be possible to reach all patients in need of such care?

✵ Will an individual or a company be able to obtain exclusive rights to treat specific diseases using gene therapy?

Human Cloning

Public interest in the possibility of human cloning arose in the 1960s following successful experiments on frogs and toads. These studies demonstrated that The Nucleus of a fertilized egg could be replaced with the nucleus of an undifferentiated cell, allowing the embryo to develop normally. Thus, in principle, it is possible to isolate nuclei from undifferentiated cells of an Organism, introduce them into fertilized eggs of the same organism, and obtain offspring with the same genotype as the parent. In other words, each descendant organism can be considered a genetic clone of the original donor organism. In the 1960s, despite the lack of technical capabilities, it seemed effortless to extrapolate frog cloning results to humans. Numerous articles on the subject appeared in the press, and even science fiction works were written. One story focused on cloning the assassinated US President John F. Kennedy, though cloning villains was a more popular theme. Works about human cloning were not only implausible but also promoted the flawed and highly dangerous idea that a person's personality, character, and other traits are determined exclusively by their genotype. In reality, an individual's personality is shaped by the interplay of both genes and environmental factors, including cultural traditions. For instance, the virulent racism preached by Hitler is an acquired behavioral trait not determined by any single gene or combination thereof. In a different environment with distinct cultural characteristics, a "cloned Hitler" would not necessarily develop into a person resembling the historical Hitler. Similarly, a "clone of Mother Teresa" would not necessarily become a woman who dedicated her life to helping the poor and sick in Calcutta.

As methods in mammalian reproductive biology advanced and various Transgenic Animals were created, it became increasingly clear that human cloning was no longer a distant future. This assumption became reality in 1997 with the cloning of a sheep named Dolly, which utilized the nucleus of a differentiated cell from an adult donor ewe. The methodological approach used in "creating" Dolly is, in principle, applicable to producing clones of any mammal, including humans. Even if it proves ineffective for other mammalian species, it presumably will not require excessive experimentation to develop a suitable method. Consequently, human cloning instantly becomes a central topic in any discussion touching upon the ethical issues of genetics and biomedicine.

Undoubtedly, human cloning is a complex and controversial issue. For some, the very thought of creating a copy of an existing individual through experimental manipulation is unacceptable. Others argue that a cloned individual is essentially equivalent to an identical twin, despite the age difference, and therefore cloning is not inherently malicious, even if perhaps unnecessary. Cloning could yield positive medical and social benefits that justify its use in exceptional cases. For example, it might prove vital for parents of a sick child. Responsibility for human cloning experiments is regulated by legislation in many countries, with all research related to human cloning strictly prohibited. Such restrictions are sufficient to rule out the possibility of human cloning; nevertheless, the question of its inevitability will inevitably arise.