Selected annotated bibliography on genetic, reproductive and cybernetic technologies.

Gene Therapy: Dyer AR. The ethics of human genetic intervention: a postmodern perspective. Exp Neurol 1997;144:168-172.

The possibility of genetic therapy and engineering invite discussion of ourselves as individuals, our culture and the value that we place on life. The ethical issues which apply to gene therapy are the same as those for other diseases. These ethical principles are as follows:

1. Autonomy: the right of the autonomous individual for self-determination, as understood in the need for informed consent.

2. Nonmalfeasance: the principle of doing no harm, as understood in the need for safety.

3. Beneficence: efficacy of treatment.

4. Justice: generally seen in the allocation of resources.

The author traces the historical emphases which have been placed upon these principles, and concludes that modern medical ethics is focused on the individual and that the principle of autonomy is now at the center of bioethics. Gene therapy may help shift concern from the health of the individual to the health of the population.

Genetic technology is considered to be a postmodern technology in the sense that it may have a significant impact upon future generations. Such technology may impact the ethical balance for better or for worse. In this technically sophisticated age, the physician, who has traditionally worked to alleviate suffering within an ethical tradition, is often threatened with becoming a trained technician dispensing goods and services in the marketplace. There is also the added fear of an authoritarian society dictating the use of those technologies for political ends.

In anticipating the postmodern future, the author looks to post-modern art and architecture for inspiration, and hopes that a graceful, symbiotic relationship among past, present and future will emerge.

Juengst ET. Can enhancement be distinguished from prevention in genetic medicine? J Med Philos 1997;22:125-142.

The author argues that the distinction between preventive and enhancement uses of medicine's emerging gene transfer techniques depends upon an understanding of disease as an entity, complete with its recognizable constellation of subjective symptoms, physical signs and causes. Legitimate preventive genetic health care should be aimed at preventing and curing robust pathological entities, not to change bodies for the purposes of evading social injustices. It follows that proper medical practice in general should be used to address only those human problems associated with a diagnosable disease entity.

An understanding of disease ontology will help to improve the boundaries of medical practice, permitting healthcare professionals to commit both to prevention and to cure in genetic medicine without fear of "slipping" into illegitimate enhancements. Furthermore, by making disease the pivotal issue rather than comparative norms, the responsibility for setting the limits of practice through the discovery and delineation of new disease entities is kept in the medical domain.

While the author points to a number of implications, he does not pursue them in any great detail. The limitations of the "Normal Function" model of health needs are assessed.

Torres JM. On the limits of enhancement in human gene transfer: drawing the line. J Med Phil 1997;22:43-53.

In determining the ethical permissibility of using human gene transfer or engineering, the intended purpose plays a crucial role in the procedure's classification and appraisement. Human gene engineering, which aims to improve the patient's health, is generally acceptable, although, by strict definition, it may fall into the category of "enhancement." Gene engineering, which aims to enhance the individual in ways other than by disease prevention, however, are generally considered to be unethical by the author. Three relevant points are made:

1. Gene technology involves significant risks of toxicity, cancer, or generalized infections.

2. Implementing gene technology in such a manner risks furthering the socioeconomic differences among members of the human species.

3. In The Declaration of Inuyama (1990), gene transfers "unrelated to any recognized human disease" are prohibited, while implicitly condoning gene medicine that is "related to" a disease.

Looking to society and science at large, the author remarks that somatic-line gene transfer, when carried out for medical purposes (that is, practices that are therapeutic, preventive or aligned to research), does not present any new ethical problem that can be based on questions of principles. Moreover, preventive gene medicine that seeks to address the problems associated by severe diseases, or where there is a reasonable risk of a severe disease appearing, is not considered to raise fundamental ethical problems. On the other hand, human gene transfer performed for reasons of enhancement or for eugenic purposes is generally considered by the scientific community and society at large to be unethical and, therefore, impermissible. However, the author believes that there may be certain circumstances that would make human gene transfer for enhancement purposes ethically permissible; one such example is multidrug resistance (MDR).

In the case of the MDR protocol, the aim is to increase a natural trait through the insertion of an additional MDR gene. Such intervention is generally what is meant by enhancement within the framework of human genetic engineering. Based on this example, the author states that the appropriation and implantation of the MDR protocol should be considered ethically permissible. Consequently, where the patient's health is concerned, the author contends that human genetic engineering is indeed ethical. Where the final purpose of the gene transfer is not the patient's health, however, the author agrees with the universal refusal to permit cell enhancement.

Hoose B. Gene therapy: where to draw the line. Hum Gene Ther 1990;1:299-306.

Ethical boundaries should not be permanently drawn; rather, they should be placed at the point which is "most appropriate" for the given situation, with the understanding that as the knowledge base increases, so will the line accordingly be moved. As such, any such line would be drawn with the understanding that it is only a temporary demarcation.

Given the present state of knowledge concerning each of the four classifications of genetic manipulation (somatic cell gene therapy, germ-line gene therapy, enhancement genetic engineering, and eugenic genetic engineering), the author concludes that the line presently should be drawn broadly at not carrying out any form of gene therapy; the exception would be in specific cases which already have been carefully evaluated.

Although this logic is applied to gene therapy in particular, the underlying logic should be applied to therapies in general; the various difficulties encountered being generally ones of proportion. Moreover, potential treatments should not be prejudged based on emotive terms, such as "enhancement genetic engineering" or "eugenics."

The point of delineation should be where one can be "reasonably sure" that a particular form of therapy will be more beneficial than damaging; such a point is subjective, and, so, there are no hard and fast points of demarcation in drawing such lines. However, given the present lack of knowledge, the great complexity of the issue and the field, and the potential dangers, researchers should proceed with extreme care and caution with regard to all forms of genetic therapy. Moreover, it is important to note that future developments may not always call for advancing the line; it is possible that the line may have to be drawn at a less permissive point simply because the increased knowledge base indicates the existence of unforeseen complications and dangers.

Selection of Embryo Characteristics:

Savulescu J, Dahl E. Sex selection and preimplantation diagnosis: a response to the Ethics Committee of the American Society of Reproductive Medicine. Hum Reprod 2000;15:1879-1880.

The Ethics Committee of the American Society of Reproductive Medicine concluded that it is ethically appropriate to use new reproductive technoloiges to avoid the birth of children suffering from X-linked genetic disorders. The Committee objects, however, to the use of sex selection for nonmedical purposes. It rests its case upon four claims, each of which is refuted by the authors:

1. It identifies "gender as a reason to value one person over another."

The majority of couples who seek the services of Gender Clinics base their decision to have a child of a certain sex not upon sexist notions of superiority but rather upon the desire to achieve gender balance in their family: typically, such couples already have two or three children of one sex.

2. It may "contribute to a society's gender stereotyping and gender discrimination."

As couples who seek to select the sex of their child invariably do so to achieve a gender balance, it seems unreasonable to conclude that their choices will contribute to a society's gender discrimination. If such was indeed the concern, then sex selection could be limited to balancing family sex, and only after the first child.

3. It is "unreasonable for individuals who do not otherwise need IVF to undertake its burdens and expense solely to select the gender of their offspring."

This objection, smelling of medical paternalism, fails to appreciate that it is the woman's body and decision, and, as such, she may choose to accept whatever "burdens" she wishes. A woman who is informed of the physical and psychological costs to herself but feels that having a child of a certain sex is worth the trouble is entitled to make such an autonomous decision.

4. It represents a "misallocation of limited medical resources."

As it is the individual, and not the state (i.e., tax payer) who pays for the service, there is no misallocation of resources: in no instance does the service deprive the community of scare medical resources. The authors remark that individuals who spend their own money on cosmetic surgery are not vilified; nor should those couples who seek a child of a particular sex be vilified for how they spend their money.

In addition to addressing the four claims upon which the Committee has based its case, the authors also address two more claims: firstly, the speculative objection that sex selection will invariably lead to a serious distortion of the sex ratio (as in India or China, where in some places the male to female ratio is nearly 1:2); such has not been found to be the case in the West. Secondly, the "slippery slope" argument that permitting sex selection will inevitably lead to eugenics, which is simply invalid.

Berkowitz JM, Snyder JW. Racism and sexism in medically assisted conception. Bioethics 1998;12:25-44.

With the exception of preventing disabling disease, reproductive technologies should not be employed to predetermine either the race or sex of children. New legislation should be implemented which curtails the utilization of Medically Assisted Conception (MAC).

In selecting the sex or race or their children, parents belie an underlying (at best) parental sexism and/or racism by placing greater value on one sex or race. Furthermore, those physicians who assist in sex or race selection provide de facto support and implicitly legitimize sexism and/or racism, as determined by the particular case.

According to the authors, the use of MAC to decide sex or race implicitly endorses the use of such technology to manipulate physical, emotional, and intellectual characteristics of offspring.

Ten CL. The use of reproductive technologies in selecting the sexual orientation, the race, and the sex of children. Bioethics 1998;12:45-48.

The interests of the unborn child should remain the deciding factor when individuals wish to select in advance the sexual orientation, race or sex of their children. While there is the need both to guard reproductive liberties and to protect nonheterosexuals from unjust treatment, the primary ethical consideration in making such decisions must be the child's best interests.

Furthermore, if the focus is on the best interests of the children, then whether the traits are intrinsically or nonintrinsically undesirable is irrelevant, as quality of life may be reduced. The crucial issue in making such a decision is the degree to which individuals are adversely affected by their genetic disorders or by their unjust treatment in society.

The question on which the debate continues to return is how to compare existence (with a serious disorder or social prejudice) with nonexistence. Whatever reason is used to say that it is not in the best interest of the child to be born with a serious genetic disorder may also be used to argue that it is not in the best interest for a nonheterosexual child to be born into a deeply prejudiced world.

Liao SM. The ethics of using genetic engineering for sex selection. J Med Ethics 2005;31:116-118.

The author concludes that it would be unethical to use genetic engineering to alter the sex of an embryo, even if genetic engineering should provide the means. In comparing this decision with the powers typically granted to parents over their children, such powers are not in fact total, and should not be given where "non-health related irreversible decisions" are involved. Furthermore, this conclusion is independent of claims that the embryo should be considered a person, as the embryo would have developed to become a person of a particular sex were it not for this medical procedure. The fact that the harm to the embryo takes places only at a future date does not reduce or alter the fact that harm has been done. This harm is compared with the following example: "Suppose I planted a bomb now that will explode 100 years from now and kill a certain number of people. I will have committed a harm now to these people, even though they do not yet exist."

Surrogacy:

Steinbock B. Surrogate motherhood as prenatal adoption. Law Med Health Care 1988;16:44-50.

While restrictions on surrogate contracts are justified, an outright ban is not justified and is, in fact, an infringement upon the liberty of citizens. While surrogacy is fraught with many problems, it is an individual decision which should be respected.

The first half of the article is spent discussing the details of "Baby M." In this case, the biological mother, Mary Beth Whitehead, agreed to be inseminated with the sperm of William Stern and to relinquish the child to him for a fee of $10,000. Following birth, Ms. Whitehead attempted to keep the child, and, in dramatic fashion, the case was eventually brought to court.

In discussing the case, it is clear that regulation of surrogate contracts is necessary. The emotional and psychological state of Ms. Whitehead, for example, should have ruled her out as a potential surrogate. The arguments for an outright ban, however, prove to be less substantial. In the essay, the author addresses the four major concerns, explaining why regulation may minimize the more problematic aspects of this practice:

1. Paternalistic Arguments: Although surrogacy is a choice that may later be regretted, the surrogate does not relinquish autonomy over herself, and the individual freedom to make choices that one may later regret needs to be respected.

2. Moral Objections:

a. While the surrogate may agree to the contract out of financial need, such a cause is not the only possible reason for becoming a surrogate; thus, exploitation cannot be said to necessarily be a moral objection, and to insist that it is reverts to a paternalistic stance.

b. Neither is surrogacy necessarily an affront to human dignity: it is not comparable to slavery, and any compensation could be restricted to medical expenses and the like. Furthermore, should the surrogate decide to keep the child, she would break the contract and no longer be entitled to any fee or compensation. Given such restrictions, there does not appear to be any infringement upon human dignity; neither that of the child nor that of the surrogate mother.

3. The Right to Privacy: The provision of a postnatal waiting period in surrogate agreements would allow the surrogate time to respond to any unexpected feelings of attachment, and, as such, would effectively protect the surrogate's right to privacy.

4. Harm to Others: Presently, there is no evidence to indicate that surrogacy produces children with serious psychological problems; rather, such children may be likened to adopted children. Should evidence emerge that surrogacy is indeed psychologically damaging to the child, then such would be a strong reason to ban the practice.

Cybernetics:

Ben-Aaron M. The function of 'brain waves': a cybernetic model of electroencephalography. Med Hypotheses 2003;61:593-596.

"Pacemakers" set to operate at the fundamental dominant waveform characteristic of the waking state (i.e., the "waking frequency") of narcoleptic patients might render resistance to narcoleptic fits. In a reinterpretation of the brain rhythms recorded by an EEG in earlier pieces of literature, the author formulates six propositions in a new conceptual framework which aim at understating the etiology of narcolepsy from a cybernetic perspective:

* Proposition 1: Each stage (as characterized by its dominant wave form) results from a single, robust, underlying physiological process in the brain.

* Proposition 2: Normally, only one such dominant periodic process is active at any given time.

* Proposition 3: It must be possible to appropriately sequence the sleep-time processes (e.g., by EEG).

* Proposition 4: Each separate sleep stage process is differentiated by a dominant wave form which differs from the dominant waking wave form.

* Proposition 5: Each sleep stage is generated by the dominant periodic wave form respective to that sleep stage.

* Proposition 6 (formed from combining propositions 4 and 5): A sleep stage is active if and only if the characteristic dominant periodic wave form is being generated.

The author theorizes that the rapid-eye movement (REM) state is the most likely state to be entrained because of the close similarity between the dominant wave forms for REM and waking states. Consequently, it follows that there may well be a "continuum" that ranges from narcoleptics, whose waking-state wave form is weak and easily overwhelmed by entrained stimuli, to "normal" people, whose waking-state wave form is not easily overridden. It is important to note that electroencephalograph (EEG) frequencies vary greatly among individuals.

Warwick K, Gasson M, Hutt B, et al. The application of implant technology for cybernetic systems. Arch Neurol 2003;60:1369-1373.

A bidirectional link was established between a human nervous system and a computer. A microelectrode array, surgically implanted in the subject's median nerve, enabled the direct transmission of neural signals from the subject's peripheral nervous system to a computer, permitting radio control of a robotic hand. Feedback from the robotic fingertips was sent back as neural stimulation, thus giving a sense of the degree of force being applied to the object held by the robotic hand. As the amount of force applied to the object by the prosthetic hand increased, so, too, did the neural stimulation.

Initially, the subject, who was blindfolded, achieved a mean correct identification of stimulation of 70%; by the end of the study (96 days later), however, a 95% perception rate was being achieved. Further experimentation showed that the subject was able to control the direction and velocity of a fully autonomous mobile robot platform (i.e., an electric wheelchair), achieving greater than 90% accuracy in desired control of motion in less than one hour of training.

This experiment was conducted using the Internet to relay the processed neural stimuli, thus allowing the subject, who was in New York, USA, to control the prosthetic hand, which was in Reading, UK.

No indication of either infection or rejection was observed. The subject's body did react to the microelectrode array: fibrous scar tissue had grown around the implant site, thus holding the micro-electrode array in place. Signs of neuropathy were assessed regularly; no perceivable loss of hand sensation or motion control was experienced. Gradual degradation of the implant wire bundle was experienced, but this was due to mechanical fatigue of the connection wires at the exit point on the arm; upon extraction, the silicon electrodes of the array were found to be intact.

To offset criticism of investigator bias (the subject was also one of the researchers), each stage was monitored by independent observers as well as being documented with video footage for later independent analysis. That said, many of the results stand independently of subject bias; these include: biocompatibility, reliability, neuropathy, and infection.

Warwick K, Gasson M, Hutt B, et al. Thought communication and control: a first step using radiotelegraphy. IEE Proceedings on Communications 2004;151:185-189.

This article discusses two successful cybernetic experiments; first, the establishment of a link between a human nervous system and a computer and, second, the establishment of a link between the nervous systems of two able-bodied human subjects.

Elaborating upon a previous publication, the author begins by discussing the successful establishment of a direct human-computer neurological link which allowed for a form of teleoperational articulated hand motion of a robotic hand (see previous annotation for further details). The success of this silicon/biological interface permitted the researchers to attempt to directly interface the nervous systems of two human beings.

In the instance of human-to-human communication, a second subject had two active microelectrode arrays inserted into the median nerve of her left arm at approximately the same location as the first recipient's implant; to ensure correct positioning, the procedure was conducted without anesthetic. Neural signals produced as a result of finger movements by both subjects were transmitted by RF link to the other subject. These motor neural signal pulses (generated by the first subject) were subsequently perceived by the second subject, and vice versa. This result was achieved with >98% accuracy. A series of double-blind tests were performed and correctly identified by the two subjects.

As in the previous study, there was no problem with either rejection or infection. It was evident to the researchers "that the nervous system ... adapted in a positive way in response to the bidirectional experimental studies being carried out."

According to the authors, in the next stage, implants would be placed not in the peripheral nervous system, but rather, directly into the brain motor cortex region. If successful, such a signaling system would be a direct neural signal transmission/reception from brain to brain.

Kennedy P, Andreasen D, Ehirim P. et al. Using human extra-cortical local field potentials to control a switch. J Neural Eng 2004;1:72-77.

Success of a direct brain-to-computer interface opens the possibility of providing several communication channels for locked-in patients. In this study, a cognitively intact subject with amyotrophic lateral sclerosis (ALS) was able to activate a light switch using online time-domain detection techniques.

Electroencephalographic (EEG) signals recorded from scalp electrodes were found to be significantly degraded due to skull and scalp attenuation and ambient noise. Conductive skull screws were driven approximately 1 mm below the inner table of the skull,* thus giving access to the subject's cortical local field potentials (LFPs) without entering the brain itself.

Recording was achieved by powering the electronics with an external power induction coil and transmitting the signal via RF to a radio receiver integrated with a computer. The subject was able to turn on and off a light switch by means of electromyographic (EMG) activity, which was recorded by an electrode placed over the hallucis longus muscle in his right foot. This activity was amplified and a voltage level detected threshold crossings that were converted into pulses that activated the switch.

While monitoring EMG activity, the LFPs from the electrode over the foot area were converted into pulses in the computer. In order to prevent learning or adaptation effects, the subject was kept unaware of those instances when the output from the computer processor to the light switch changed from the threshold EMG activity to the thresholded LFP activity. To activate the switch, two repeated crossings of the LFP threshold were required. The data support the conclusion that LFP activity was capable of substituting for EMG activity; they do not address the question of relatedness of LFPs and EMGs.

While presenting the possibility of providing a robust communication system for almost locked-in patients, it does require surgery, albeit short and relatively benign. An alternative system ought to be feasible consisting of skull screws implanted without any electronic hardware.

*See Kennedy PR, Kirby MT, King B, et al. Computer control using human cortical local field potentials. IEEE Trans Neural Syst Rehabil Eng 2004;12:339-344 for details of the surgical procedure.

Conrad C. Daly, MTh