Human gene transfer research (HGTR) involves the deliberate transfer of genetic material (naturally-occurring, genetically-modified, or synthetic DNA or RNA) into human subjects.

Clinical success has come more slowly than was first predicted, but HGTR remains a fundamentally novel approach to medical practice. It may one day enable clinicians to cure genetic disorders at their source, as well as provide oncologists with tools designed to disable or cure specific cancers.

In March 2000 Katherine A. High and Mark A. Kay reported that subjects with hemophilia B experienced an increase in factor IX protein activity for at least six months after the gene transfer.

Yet this long awaited clinical progress has been tempered by setbacks. In December 2002 a subject in the hemophilia-B study developed signs of liver injury, halting the trial.

Gelsinger was affected by ornithine transcarbamylase (OTC) deficiency. Patients with OTC deficiency lack an enzyme needed for processing nitrogen with the result that toxic levels of ammonia accumulate in their bloodstreams, leading to severe mental impairment and even death. But Gelsinger’s symptoms were manageable so that, unlike subjects in other gene transfer trials, he approximated a healthy volunteer.

The viral vector used in this protocol was an adenovirus—a virus that usually causes the common cold. Although used in many protocols prior to Gelsinger’s death, in his case the vector triggered a deadly immune response.

HGTR is overseen in the United States by two agencies within the Department of Health and Human Services: the NIH and the Food and Drug Administration (FDA).

While FDA review is “public” insofar as it involves federal oversight, NIH review through the Recombinant DNA Advisory Committee (RAC) is truly a forum open to the public.

Serious debate about human gene transfer began in the 1960s, when scientists, theologians, and philosophers raised many concerns about genetic engineering, or genetic manipulation. Theoretical concerns evolved into real possibilities in 1972 when scientists discovered how to combine genetic material from different organisms.

One of the most important outcomes of these events was the 1982 publication of Splicing Life, a report on human gene transfer issued by the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. The commission argued that only transfer into somatic tissues to prevent or treat disease could be justified.

Early ethical and social concerns surrounding HGTR were outlined in 1985 in the NIH’s “Points to Consider.”

Since then, broader public and commercial contexts of HGTR have raised additional concerns, especially involving subject recruitment and economic conflicts of interest. These issues become increasingly important as HGTR moves toward new applications and methods.

1. Concern for the well-being of genetically-modified animals should be guaranteed;

2. The effects on the offspring and possible repercussions for the environment should be considered;

3. Such animals should be kept under tight control and should not be released into the general environment;

4. The number of animals used in experiments should be kept to a bare minimum;

5. The removal of organs and/or tissues must take place during a single surgical opera-tion;

6. Every experimental protocol on animals must be evaluated by a competent ethics committee.

Almost 20 years since the first gene-transfer trial was carried out in humans, the field has made significant advances towards clinical application.

Nevertheless, it continues to face numerous unresolved ethical challenges — among them are the question of when to initiate human testing, the acceptability of germline modification and whether the technique should be applied to the enhancement of traits.

.

1) germ-line gene transfer offers a true cure, and not simply palliative or symptomatic treatment;

2) germ-line gene transfer may be the only effective way of addressing some genetic diseases;

3) by preventing the transmission of disease genes, the expense and risk of somatic cell transfer for multiple generations is avoided;

4) medicine should respond to the reproductive health needs of prospective parents at risk for transmitting serious genetic diseases;

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

1) germ-line gene transfer research would involve too much scientific uncertainty and clinical risks, and the long term effects of such research are unknown; 2) such gene transfer research would open the door to attempts at altering human traits not associated with disease, which could exacerbate problems of social discrimination; 3) as germ-line gene transfer involves research on early embryos and effects their offspring, such research essentially creates generations of unconsenting research subjects; 4) gene transfer is very expensive, and would never be costeffective enough to merit high social priority; and 5) germ-line gene transfer would violate the rights of subsequent generations to inherit a genetic endowment that has not been intentionally modified

Other commentators have pointed to the difficulty of following up with patients in long-term clinical research (III. Ledley 1993).

Some are troubled that many gene transfer candidates are children too young to understand the ramifications of gene transfer research.

Others have pointed to potential conflict of interest problems—pitting an individual's reproductive liberties and privacy interests, on the one hand.

Against the interests of insurance companies, or society on the other—not to bear the financial burden of caring for a child with serious genetic defect. Issues of justice and resource allocation have also been raised: in a time of strain on our health care system, can we afford such expensive research?

Progress in molecular biology has enabled us to better understand human genetic disease, and has helped enhance the quality of life. This has been possible with technical developments to detect genetic disease presymptomatically.

Presymptomatic testing would not yield information about the carrier status of an individual but also about other family members. Such information may lead to unreasonable beliefs and could alter social relationships.

The sequencing of the entire genome has already had a profound impact on the wider spectrum of clinical research, as it opens a new horizons for not only treatment of diseases but looking at the most fundamental causes of diseases. Already the genes for many diseases including for example, various cancers, Alzheimer’s disease, and polycystic kidney disease, have been identified.

Genomic sequencing allows rapid and accurate diagnosis for individuals. Initially the sequencing of human genome has led to a shift towards preventive medicine rather than curative, because further research is needed to develop therapies.

One of the ideals of science is freedom for self-understanding. The influence of Human Genome Project on human self-understanding has been heralded as revolutionary. The sequencing of the genome will provide new clues on how we evolved.

It would help us to understand what it means to be a human from different historical perspectives of bioarchealogy, anthropology, evolution, and human migration.

Genetically-Modified Organisms (GMOs) are already a hot topic in agriculture and livestock breeding. GMOs are organisms with genes modified for one or the other trait. We now have plants that are insect resistant, disease resistant, drought and cold resistant.

We have farm animals that are healthier, more productive and disease resistant. Other plants and animals that are genetically modified include ones that incorporate vaccines in an edible form, or deliver hormones.