Scientific and Ethical Concerns About Russian/British Genetic Engineering Gene Therapies

Dianne N. Irving
Copyright May 7, 2005
Reproduced with Permission

As usual, advances in genetic engineering and other powerful technologies are cast in the media primarily in terms of curing diseases, etc. And hopefully that will be the case, assuming that the means to get there are ethical as well. However, what is usually not mentioned are other uses that the same genetic engineering technologies can be put to that might involve less-than-ethical purposes -- including eugenics.

For example, in the article below the Russian scientist mentions that he "aims to help the company to manufacture competent cells, which are derived from E.coli bacteria, and can reproduce implanted or foreign DNA." (emphasis added) In genetic engineering such "competent cells" are called "vectors"; they transfer "foreign" genes from one place to another. Vectors can be bacteria, viruses, or other living single-cell organisms, and they are used in a process called "recombinant-DNA gene transfer". The "foreign" gene that is natural or itself genetically engineered is inserted into the genome of the vector. The vector, now containing this "foreign" gene, will be transferred to the patient and will duplicate itself (reproduce) inside the host who has been infected with this vector.

That is, first insert the "foreign" gene into a vector cell (like a bacteria or virus, etc.), then infect a patient with this genetically engineered vector that contains the "foreign" gene. When the genetically engineered vector replicates inside the human host, this "foreign" gene will also be replicated along with the vector's original genes -- and thus be transferred to the human host. Hopefully the "diseased" gene in the patient will be "corrected" by, or at least supplement, these disease-causing cells in the patient. This is called "recombinant-DNA somatic cell gene transfer" or therapy, the point being that the targets are the diseased somatic cells of the patient.

Hopefully some genetic-based diseases can be "cured" using such genetic engineering technologies. Yet there has been little discussion of gene therapy and its "pros" and "cons" even among scientists, much less in the public square. Obviously, issues of the "informed consent" of the patient loom large in all such experiments. But three other concerns especially need more widespread discussion: (1) the fact that the science involved in such research is almost entirely hypothetical, and thus the physical effects on patients taking part in the research are almost unknowable and unpredictable; (2) the accidental infection of germ line (reproductive) cells during somatic cell gene therapies; and (3) the use of gene therapies that specifically target germ line cells for eugenic purposes.

The first ethical consideration in any basic or applied scientific research protocol is that the science being used is accurate. Otherwise, the data obtained will be invalid. Yet the scientific and medical worlds have been flooded for many years with a barrage of false science and invalid data, bringing into serious question whether or not some research is being done which is automatically invalid even for purely scientific purposes. There are also serious scientific issues that should be raised concerning the use of human subjects in research that is not already grounded on previous and lengthy animal studies, that is not performed by real academically qualified "experts" in that field who are supposed to have competent knowledge of the science involved, and where the science is still so barely understood or so biologically complicated that the data obtained using human patients would be statistically invalid and the possible injuries or death to the patients would be impossible to calculate or to anticipate. The research discussed in the article below embodies all of these ethical and scientific concerns.

Second, there have been scientific studies documenting the fact that not only the somatic cells but also the germ line cells of the patient can be accidentally infected in the process of using somatic cell gene therapies. That means that the "foreign" gene will be accidentally passed down through successive generations of that patient's progeny. Of even more concern would be the use of somatic cell gene therapies that are purposefully and deceptively used to change the genetic makeup of the patient's future progeny who would continue to carry the "foreign" gene - all done under the guise of treating the somatic cells of a particular patient to "cure" his/her disease.

Second, the same genetic engineering process can be used with germ line cells of the patient as the specific target. That is, "foreign" genes can be purposefully introduced into the germ line (reproductive) cells of the patient by means of such vectors, the reason being to genetically "enhance" or engineer the future progeny of the patient. This is "eugenics" at its genetically engineered best.

Depending on which "ethics" one chooses to justify the use of recombinant-DNA gene transfer, different "ethical" conclusions are reached. Generally, somatic cell gene transfer carries few ethical objections -- assuming all other parameters of the research are ethical as well. But even scientists are increasingly concerned about the accidental contamination of germ line cells in the process, as well as about the specific targeting of germ line cells for eugenic purposes. FYI, here is an example of such concern expressed, e.g., by scientists Strachan and Read in their human molecular genetics textbook:

Section 22.6: The ethics of human gene therapy

All current gene therapy trials involve treatment for somatic tissues (somatic gene therapy). Somatic gene therapy, in principle, has not raised many ethical concerns. Clearly, every effort must be made to ensure the safety of the patients, especially since the technologies being used for somatic gene therapy are still at an undeveloped stage. However, confining the treatment to somatic cells means that the consequences of the treatment are restricted to the individual patient who has consented to this procedure. Many, therefore, view the ethics of somatic gene therapy to be at least as acceptable as, say, organ transplantation, and feel that ethical approval is appropriate for carefully assessed proposals. Patients who are selected for such treatments have severely debilitating, and often life-threatening, disease for which no effective conventional therapy is available. As a result, despite the obvious imperfections of the technology, it may even be considered to be unethical to refuse such treatment. The same technology has the potential, of course, to alter phenotypic characters that are not associated with disease, such as height for instance. Such genetic enhancement, although not currently considered, can be expected to pose greater ethical problems; attempts to produce genetically enhanced animals have not been a success and in some cases have been spectacular failures (Gordon, 1999).

... Germline gene therapy, involving the genetic modification of germline cells (e.g. in the early zygote), is considered to be entirely different [from somatic gene therapy]. It has been successfully practiced on animals (e.g., to correct beta-thalassemia in mice). However, thus far, it has not been sanctioned for the treatment of human disorders, and approval is unlikely to be given in the near future, if ever.

Section 22.6.1: Human germline gene therapy has not been practiced because of ethical concerns and limitations of the technology for germline manipulation

The lack of enthusiasm for the practice of germline gene therapy can be ascribed to three major reasons:

[1] The imperfect technology for genetic modification of the germline

Germline gene therapy requires modification of the genetic material of chromosomes, but vector systems for accomplishing this do not allow accurate control over the integration site or event. In somatic gene therapy, the only major concern about lack of control over the fate of the transferred genes is the prospect that one or more cells undergoes neoplastic transformation. However, in germline gene therapy, genetic modification has implications not just for a single cell: accidental insertion of an introduced gene or DNA fragment could result in a novel inherited pathogenic mutation.

[2] The questionable ethics of germline modification

Genetic modification of human germline cells may have consequences not just for the individual whose cells were originally altered, but also for all individuals who inherit the genetic modification in subsequent generations. Germline gene therapy would inevitably mean denial of the rights of these individuals to any choice about whether their genetic constitution should have been modified in the first place (Wivel and Walters, 1993). Some ethicists, however, have considered that the technology of germline modification will inevitably improve in the future to an acceptably high level and, provided there are adequate regulations and safeguards, there should then be no ethical objections (see, for example, Zimmerman, 1991). At a recent scientific research meeting in the USA some scientists have also come out in support of such a development (Wadman, 1998).

From the ethical point of view, an important consideration is to what extent technologies developed in an attempt to engineer the human germline could subsequently be used not to treat disease but in genetic enhancement. There are powerful arguments as to why germline gene therapy is pointless. There are serious concerns, therefore, that a hidden motive for germline gene therapy is to enable research to be done on germline manipulation with the ultimate aim of germline-based genetic enhancement. The latter could result in positive eugenics programs, whereby planned genetic modification of the germline could involve artificial selection for genes that are thought to confer advantageous traits.

The implications of human genetic enhancement are enormous. Future technological developments may make it possible to make very large alterations to the human germline by, for example, adding many novel genes using human artificial chromosomes (Grimes and Cooke, 1998). Some people consider that this could advance human evolution, possibly paving the way for a new species, homo sapientissimus. To have any impact on evolution, however, genetic enhancement would need to be operated on an unfeasibly large scale (Gordon, 1999).

Even if positive eugenics programs were judged to be acceptable in principle and genetic enhancement were to be practiced on a small scale, there are extremely serious ethical concerns. Who decides what traits are advantageous? Who decides how such programs will be carried out? Will the people selected to have their germlines altered be chosen on their ability to pay? How can we ensure that it will not lead to discrimination against individuals? Previous negative eugenics programs serve as a cautionary reminder. In the recent past, for example, there have been horrifying eugenics programs in Nazi Germany, and also in many states of the USA where compulsory sterilization of individuals adjudged to be feeble-minded was practiced well into the present century.

[3] The questionable need for germline gene therapy

Germline genetic modification may be considered as a possible way of avoiding what would otherwise be the certain inheritance of a known harmful mutation. However, how often does this situation arise and how easy would it be to intervene? A 100% chance of inheriting a harmful mutation could most likely occur in two ways. One is when an affected woman is homoplasmic for a harmful mutation in the mitochondrial genome and wished to have a child. The trouble here is that, because of the multiple mitochondrial DNA molecules involved, gene therapy for such disorders is difficult to devise.

A second situation concerns inheritance of mutations in the nuclear genome. To have a 100% risk of inheriting a harmful mutation would require mating between a man and a woman both of whom have the same recessively inherited disease, an extremely rare occurrence. Instead, the vast majority of mutations in the nuclear genome are inherited with at most a 50% risk (for dominantly inherited disorders) or a 25% risk (for recessively inherited disorders). In vitro fertilization provides the most accessible way of modifying the germline. However, if the chance that any one zygote is normal is as high as 50 or 75%, gene transfer into an unscreened fertilized egg which may well be normal would be unacceptable: the procedure would inevitably carry some risk, even if the safety of the techniques for germline gene transfer improves markedly in the future. Thus, screening using sensitive PCR-based techniques would be required to identify a fertilized egg with the harmful mutation. Inevitably, the same procedure can be used to identify fertilized eggs that lack the harmful mutation. [Tom Strachan and Andrew P. Read, Human Molecular Genetics (New York: Wiley-Liss, 1999), pp. 539-541]

At least in the interest of "balanced reporting", hopefully future media reports will at least acknowledge some of these basic scientific and ethical concerns involving the use of human somatic and germ line gene therapies in human subject research - not just parade before a vulnerable public the "curative" aspects of such controversial research.

Yorkshire Post Today [UK]
May 6, 2005
Greg Wright

Russian joins genetic engineering project

A breakthrough in the battle against cancer, diabetes and heart disease is coming a step closer, through a partnership between a Yorkshire company and a Russian scientist.

Yorkshire Bioscience - YORBIO - has enlisted the help of Dr Igor Granovskiy as it attempts to become the first British company to manufacture a vital tool for genetic engineering.

YORBIO, based in York, has won a £19,000 award from the Department of Trade and Industry Global Watch Secondment Programme, which enables smaller UK firms to get advice from foreign scientists.

YORBIO's award will fund Dr Granovskiy's six-month secondment. He aims to help the company to manufacture competent cells, which are derived from E.coli bacteria, and can reproduce implanted or foreign DNA.

Competent cells form an essential part of genetic research into areas ranging from the development of cures for cancer, diabetes and heart disease, to waste treatment and pollution prevention.

Dr Granovskiy joins YORBIO from the Russian Institute of Biochemistry and Physiology of Microorganisms based at Pushchino, which is 60 miles south of Moscow and considered a world-class centre of excellence.

YORBIO was set up by Russian-born scientist Dr Slava Pavlovets in 2004 to speed up the diagnosis of newly-emerged infectious diseases such as SARS and avian flu. The business got off the ground with a £10,000 loan from the York Innovation Fund.

"This is the sort of opportunity we need in order to encourage crucial high-level technology transfer. Consequently, this is an excellent opportunity not only for YORBIO, but also the wider scientific community", said Carolyn Randall, Business Promoter at Science City York, a partnership between the city's council and university.