Reflexiones sobre la ingeniería genética: a propósito del nacimiento de gemelas sometidas a edición génica / Considerations on genetic engineering: regarding the birth of twins subjected to gene edition

Resumen En este ensayo se analizan las implicaciones bioéticas de la reciente manipulación genética en embriones humanos con CRISPR-Cas9 para eliminar el gen CCR5 y el nacimiento de dos gemelas discordantes. El experimento se divulgó en medios sociales. Los principales problemas bioéticos identificados son la justificación del modelo, el proceso de consentimiento informado y la falta de declaración de evidentes conflictos de interés. No se evaluaron apropiadamente las consecuencias del experimento sobre la vida de las gemelas nacidas como la afectación a su autonomía, los supuestos beneficios por recibir y los riesgos futuros de daño durante su vida. Habiendo manipulado la línea celular germinal, no se consideraron los efectos sobre su descendencia futura. Este tipo de acciones tiene un impacto negativo en la forma como la sociedad concibe la ciencia. La ingeniería genética debe reservarse al contexto experimental básico o bien como investigación cínica para la corrección de enfermedades conocidas graves de origen genético, bajo estricta supervisión regulatoria y bioética y de manera gradualista de acuerdo con el progreso de las técnicas de edición genética.

Abstract In this essay, the bioethical implications of the recent genetic manipulation in human embryos with CRISPR-Cas9 to eliminate the CCR5 gene and the birth of a pair of discordant twin girls are analyzed. The experiment was disseminated via social media. The main bioethical flaws identified include the justification of the model, the informed consent process and the lack of disclosure of evident conflicts of interest. The consequences of the experiment on the life of the twins that were born were not properly evaluated, such as the impact on their autonomy, the alleged benefits to be received and the future risks of harm during their lifetime. Having manipulated the germ cell line, the effects on their future offspring were not considered. This type of actions negatively affects the way society conceives science. Genetic engineering should be reserved to the basic experimental context or as clinical research for the correction of known serious diseases of genetic origin under strict regulatory and bioethical supervision and using a gradualist approach in accordance with the advances of gene editing techniques.

Ethical issues on the "synthetic" phosphoethanolamine clinical trial.

Notwithstanding its approval by the National Committee for Ethics in Research (Conep) on April 19, 2016, a trial of the so-called "synthetic" phosphoethanolamine (syn-phospho) pill in cancer patients raises ethical concerns. An analysis by a laboratory contracted by the Ministry of Science, Technology and Innovation (MCTI) revealed that syn-phospho contained a great amount of impurities and did not meet standards of pharmaceutical quality required for an investigational drug. Cytotoxicity against human tumor cell lines and in vivo rodent xenograft tumor assays consistently failed to demonstrate a potential anticancer activity of syn-phospho. Preclinical safety studies of syn-phospho were also insufficient to support a trial of this investigational drug in cancer patients. Moreover, the ethical approval decision apparently overlooked two previous findings that suggested a possible enhancement of mammary carcinoma cell proliferation by phosphoethanolamine, and an apparent increase in lung metastases (rat implanted tumor assay) by syn-phospho. The syn-phospho risk-benefit ratio is clearly unfavorable and, thus, this trial in cancer patients does not fulfill a key requirement to make a clinical research ethical. There are also concerns regarding whether the study design is robust enough (scientific validity), and the social value of the trial of syn-phospho in cancer patients is questionable.

Ethical issues on the "synthetic" phosphoethanolamine clinical trial / Questões éticas sobre o ensaio clínico da fosfoetanolamina "sintética"

Summary Notwithstanding its approval by the National Committee for Ethics in Research (Conep) on April 19, 2016, a trial of the so-called "synthetic" phosphoethanolamine (syn-phospho) pill in cancer patients raises ethical concerns. An analysis by a laboratory contracted by the Ministry of Science, Technology and Innovation (MCTI) revealed that syn-phospho contained a great amount of impurities and did not meet standards of pharmaceutical quality required for an investigational drug. Cytotoxicity against human tumor cell lines and in vivo rodent xenograft tumor assays consistently failed to demonstrate a potential anticancer activity of syn-phospho. Preclinical safety studies of syn-phospho were also insufficient to support a trial of this investigational drug in cancer patients. Moreover, the ethical approval decision apparently overlooked two previous findings that suggested a possible enhancement of mammary carcinoma cell proliferation by phosphoethanolamine, and an apparent increase in lung metastases (rat implanted tumor assay) by syn-phospho. The syn-phospho risk-benefit ratio is clearly unfavorable and, thus, this trial in cancer patients does not fulfill a key requirement to make a clinical research ethical. There are also concerns regarding whether the study design is robust enough (scientific validity), and the social value of the trial of syn-phospho in cancer patients is questionable.

Resumo Não obstante a sua aprovação pela Comissão Nacional de Ética em Pesquisa (Conep) em 19 de abril de 2016, um ensaio da pílula de fosfoetanolamina "sintética" (sin-fosfo) em pacientes com câncer levanta preocupações éticas. Uma análise feita por um laboratório contratado pelo Ministério da Ciência, Tecnologia e Inovação (MCTI) revelou que a sin-fosfo continha grande quantidade de impurezas e não satisfazia os padrões de qualidade farmacêutica exigidos para um medicamento experimental. Os ensaios de citotoxicidade com linhagens de células originárias de tumores humanos e testes in vivo em roedores com tumores xeno-enxertados falharam consistentemente em demonstrar uma potencial atividade anticâncer da sin-fosfo. Os estudos pré-clínicos de segurança da sin-fosfo também foram insuficientes para apoiar a realização de um ensaio desse medicamento experimental em pacientes com câncer. Além disso, a aprovação ética aparentemente desconsiderou dois achados anteriores, sugerindo uma possível exacerbação da proliferação de células de carcinoma de mama pela fosfoetanolamina, e um aparente aumento de metástases pulmonares (ensaio de tumores implantados em ratos) pela sin-fosfo. A relação risco-benefício é claramente desfavorável para a sin-fosfo e, portanto, esse ensaio em pacientes com câncer não atende um requisito essencial para que uma pesquisa clínica seja ética. Há também preocupações quanto ao delineamento do estudo ser suficientemente robusto (validade interna), e o valor social do ensaio da sin-fosfo em pacientes com câncer é questionável.

Is a New Protocol for Acute Lymphoblastic Leukemia Research or Standard Therapy?

In the United States, doctors generally develop new cancer chemotherapy for children by testing innovative chemotherapy protocols against existing protocols in prospective randomized trials. In the Netherlands, children with leukemia are treated by protocols that are agreed upon by the Dutch Childhood Oncology Group. Periodically, the Dutch Childhood Oncology Group revises its protocols. Sometimes, these revisions are categorized as research, sometimes as treatment. In this Ethics Rounds, we analyze whether enrollment in a new protocol ought to be considered research and, if so, we discuss the implications of that designation. Our discussion highlights the different ways different countries approach complex issues of research ethics.

Examining the ethics of clinical use of unproven interventions outside of clinical trials during the Ebola epidemic.

The recent Ebola outbreak in West Africa began in the spring of 2014 and has since caused the deaths of over 6,000 people. Since there are no approved treatments or prevention modalities specifically targeted at Ebola Virus Disease (EVD), debate has focused on whether unproven interventions should be offered to Ebola patients outside of clinical trials. Those engaged in the debate have responded rapidly to a complex and evolving crisis, however, and this debate has not provided much opportunity for in-depth analysis. Additionally, the existing literature on access to unproven therapies has focused on contexts like HIV/AIDS and oncology, which are very different than the Ebola epidemic. In this paper, we examine the ethical issues surrounding access to unproven therapies in the context of the recent Ebola outbreak to yield new insights about this controversial and unsettled issue. We argue first that, in this context, the interests of patients in obtaining access to unproven therapies are not fully aligned with the interests of their providers and drug developers. Second, we focus on the resource constraints facing providers, funders, and patients and conclude that they often counsel against the use of unproven interventions against EVD.

Innovation in pediatric surgery: the surgical innovation continuum and the ETHICAL model.

Innovations are indispensable to the practice and advancement of pediatric surgery. Children represent a special type of vulnerable population and must be protected since they do not have legal capacity to consent, and their parent's judgment may be compromised in circumstances when the child is very ill or no adequate therapy exists. In an effort to protect patients, legislators could pass and enforce laws that prohibit or curtail surgical innovations and thus stifle noble advancement of the practice. The goals of this paper are, 1) To clearly define the characteristics of surgical innovation types so interventions may be classified into 1 of 3 distinct categories along a continuum: Practice Variation, Transition Zone, and Experimental Research, and 2) To propose a practical systematic method to guide surgeon decision-making when approaching interventions that fall into the "Transition Zone" category on the Surgical Intervention Continuum. The ETHICAL model allows those that know the intricacies and nuances of pediatric surgery best, the pediatric surgeons and professional pediatric surgical societies, to participate in self-regulation of innovation in a manner that safeguards patients without stifling creativity or unduly hampering surgical progress.

The ethics of surgically invasive neuroscience research.

A clear understanding of distinctions and definitions is necessary before determining which types of surgically invasive neuroscience research should be permitted and how the experimental protocols can properly be undertaken. A failure to clarify the ethical distinctions in invasive neuroscience research hinders attempts at ethical analysis and guidance. At least four main distinctions need to be addressed: "invasiveness" as an important moral characteristic; special brain-mind-related risks; research participant selection; and ideologic interpretation of human function. Harm and not invasiveness is the metric by which to measure the ethical permissibility of research. Because of a class of harms to minds and selves, special attention should be paid to value considerations. These considerations need to be addressed by researchers, funders, and review boards to create proper safeguards from conception of research through final application of results.

Experimentation in organ transplants compared with clinical trials: ethical problems.

The origins of new techniques in transplant surgery vary widely. Frequently, new procedures are the result of small step-by-step departures from protocols already established in clinical practice; or they may be the result of radical innovation. Whatever their origin, experimental techniques in transplant surgery do not follow the route of randomised clinical trials; nor are they subject to the same procedures of review by an ethics committee. The present paper discusses some of the ethical implications of this situation.

Surgical experimentation and clinical trials: differences and related ethical problems.

Surgical techniques are not introduced into clinical practice as the result of randomised clinical trials (RCT), but usually through the gradual evolution of existing techniques or, more rarely, through audacious departures from the norm that are decided by a surgical team on the basis of experience. Sham surgery is held by some to be not only an ethically acceptable procedure but also a perfectly fit and proper one, as it could endow surgical experiments with the strict methodological and statistical precision typically associated with RCTs. This article first briefly examines some of the methodological aspects of both RCTs and surgical experiments and then offers a few considerations regarding the ethical issues raised by sham surgery.

Enthusiasm, evidence and ethics: the triple E of minimally invasive pediatric surgery.

Minimally invasive techniques are applicable in more than 60% of abdominal and thoracic operations in children. Enthusiasts promoted these techniques for many years. However, level 1 evidence on advantages of minimally invasive surgery in children remains limited. Randomized controlled trials have been conducted for some types of procedures such as laparoscopic appendectomy, fundoplication, pyloromyotomy, and inguinal hernia repair. The results of these studies confirm some advantages of minimally invasive surgery, but for most types of laparoscopic and all types of thoracoscopic procedures, such data remain to be established. This article also focuses on reports on complications and disadvantages which are relevant for final conclusions and recommendations. The ethical implications of the application of new techniques in children are also discussed. On the basis of evidence based data and ethical principles, minimally invasive techniques may be appropriately used in the future.

Ethical, anatomical and physiological issues in developing vestibular implants for human use.

Effort towards the development of a vestibular implant for human use are being made. This paper will summarize the first important steps conducted in Geneva towards this ambitious goal. Basically, we have faced three major issues. First, an ethical issue. While it was clear that such development would require the collaboration of human volunteers, it was also clear that stimulation of the vestibular system may produce periods of significant incomfort. We know today how to minimize (and potentially eliminate) this type of incomfort. The second issue was anatomical. The anatomical topology of the vestibular system is complex, and of potentially dangerous access (i.e. facial nerve damage). We choose not to place the electrodes inside the ampullae but close the vestibular nerve branches, to avoid any opening of the inner ear and limit the risk of hearing loss. Work on cadaver heads, confirmed by acute stimulations trials on patients undergoing ear surgery under local anesthesia, demonstrated that it is possible to stimulate selectively both the posterior and lateral ampullary nerves, and elicit the expected vertical and horizontal nystagmic responses. The third issue was physiological. One of the goal of a vestibular implant will be to produce smooth eye movements to stabilize gaze direction when the head is moving. Indeed, after restoring a baseline or "rest" activity in the vestibular pathways with steady-state electrical stimulation, we demonstrated that modulation of this stimulation is producing smooth eye movements. In conclusion, humans can adapt to electrical stimulation of the vestibular system without too much discomfort. Surgical access to the posterior and lateral ampullary nerves have been developed and, electrical stimulation of the vestibular system can be used to artificially elicit smooth eye movements of different speeds and directions, once the system is in adapted state. Therefore, the major prerequisites to develop a prototype vestibular implant for human use are fulfilled.

Impact of in-patient research participation on subsequent heroin use patterns: implications for ethics and public health.

AIMS: Research on drug dependence often involves the administration of drugs of abuse to experienced drug users under controlled laboratory conditions. The primary objective of this study was to assess whether participation in such research alters the frequency of heroin use by non-treatment-seeking opioid-dependent volunteers after study completion. DESIGN: Data were examined from four in-patient studies involving controlled opioid administration. SETTING: Substance Use Research Center at Columbia University, New York State Psychiatric Institute. PARTICIPANTS: Sixty-nine heroin-dependent volunteers. MEASUREMENTS: Participants' self-reported heroin use prior to and 1 month after study participation was compared using a Wilcoxon test. Because a number of participants reported that they had stopped using heroin, a logistic regression was used to identify correlates of heroin cessation 1 month after study completion. FINDINGS: One hundred and one participants entered laboratory studies and 69 completed them. Self-reported heroin use significantly decreased 1 month after study participation [1.7 (±2.0) bags per day] compared to baseline [6.8 (±4.2) bags per day], P < 0.001 among the 69 completers. In addition, 42% of the completers were heroin-abstinent 1 month after study completion. Being African American, having a history of opioid dependence treatment, reporting heavier heroin use at baseline and a longer history of heroin use were correlated with cessation of heroin use. CONCLUSIONS: Participation in opioid administration studies does not increase subsequent heroin use and for some individuals leads to accessing opioid dependence treatment and cessation of heroin use in the short term.

A case study in unethical transgressive bioethics: "Letter of concern from bioethicists" about the prenatal administration of dexamethasone.

On February 3, 2010, a "Letter of Concern from Bioethicists," organized by fetaldex.org, was sent to report suspected violations of the ethics of human subjects research in the off-label use of dexamethasone during pregnancy by Dr. Maria New. Copies of this letter were submitted to the FDA Office of Pediatric Therapeutics, the Department of Health and Human Services (DHHS) Office for Human Research Protections, and three universities where Dr. New has held or holds appointments. We provide a critical appraisal of the Letter of Concern and show that it makes false claims, misrepresents scientific publications and websites, fails to meet standards of evidence-based reasoning, makes undocumented claims, treats as settled matters what are, instead, ongoing controversies, offers "mere opinion" as a substitute for argument, and makes contradictory claims. The Letter of Concern is a case study in unethical transgressive bioethics. We call on fetaldex.org to withdraw the letter and for co-signatories to withdraw their approval of it.