Science & Research Ethics PDF

SCIENCE & RESEARCH ETHICS - ETHICS IN GENETICS GEMD-101 2024-2025 Dr Eirini Kampriani Assistant Professor of Medical Anthropology & Medical Ethics...

SCIENCE & RESEARCH ETHICS - ETHICS IN GENETICS GEMD-101 2024-2025 Dr Eirini Kampriani Assistant Professor of Medical Anthropology & Medical Ethics [email protected] LOBs Outline key issues with reference to ethical-social aspects of scientific and genetic research Briefly explain an example of bioethics in social context Medical research; uses and abuses Dark history of scientific medical research/experimentation In the 19th and mid 20th century; Eugenics movement had profound effect in the US and Europe Public eugenic programmes that included sterilization, miscegenation & immigration restriction laws experiments on patients without their consent research that clearly violated fundamental human rights Medical experimentation; Europe WWII Background; Nazi medicine Mengele’s genetic experimentation & eugenics VIDEO https://www.youtube.com/watch?v=kFpcFScVKog Public outrage with social harm from eugenic practices, misuse of science and human rights violation led to the definition of ethical guidelines for medical research Science, society & Responsibility “Science must respond to societal needs and global challenges. Public understanding and engagement with science, and citizen participation including through the popularization of science are essential to equip citizens to make informed personal and professional choices.” https://en.unesco.org/themes/science-society If society is to remain in step with new technology, the scientific community needs to be better educated about the social and ethical implications of its research. [Beckwith & Huang 2005]  Ethics in Genetics & Genomic medicine Geneticists criticised eugenics as poor science Sense of social responsibility of science emerged When initiating the Human Genome Project In the late 1980s, James Watson, announced that several percent of the funds for the project would go to addressing the ethical, legal, and social implications of the research (J Beckwith (1993) https://www.genome.gov/human-genome-project Genetics Research frameworks ELSI/ELSA frameworks Ethical, Legal & Social Issues/Aspects of genomic medicine & genetic technologies ELSI Research Program was born in the genome analysis project that started in the US in 1990. ELSA framework in Europe; mid-2010s shifted to Responsible Research & Innovation (RRI) framework Image source: https://www.technologynetworks.com/diagnostics/articles/exploring-the-ethics- of-genetic-testing-what-does-consent-mean-334320 Genetics and Genomic research Advances in genetics and genomics have been associated from early on with an interest in Ethical, legal and social implications Understanding the consequences of genetic advances for individuals and societies Defining the ethical boundaries or genetic research and associated technologies of screening/testing in the clinic and beyond Addressing concerns of privacy, consent, access to genetic information Preparing the public and healthcare professionals Source: Collins et al (2003) Nature vol 422  Genetic testing; types & purpose Single gene sequencing – Diagnostic testing – to confirm or rule out a genetic disease. investigating a Predictive and pre-symptomatic testing – to determine if condition which is known to be someone possesses any DNA variations that increase the risk associated with of developing a particular disease. mutations in a particular gene. Carrier testing – to identify mutations that may only be present in one copy in the person being tested, but if present Whole genome in two copies, can cause a genetic disease. sequencing – investigating risk for Prenatal testing – to identify disease in a fetus multiple diseases or conditions that have Newborn screening – to determine if a newborn has a health been associated or developmental condition with mutations in Image source: https://www.ucsf.edu/news/2023/08/426071/how- more than one cutting-edge-genetic-test-helps-ill-newborns-pregnant-moms region of the (Large 2020, Soulier et al 2019) genome.  Individual & Relational autonomy (respect of choice and rights) Ownership of genetic data (personal vs familial information, data as public good) Appropriate use of genetic data (guidelines and standards of practice) Focus of Redefining the concept of disease (focusing not just on presenting symptoms but on estimations of risk and genetic profile) bioethical debate Resituating the patient (high-risk and pre-symptomatic patient) Reconfiguring responsibility (information vs action; family interdependencies; health professionals duty) Clinical & Research practices (genetic databases and genetic libraries for multiple uses) Case to consider; ethics of genetic testing Consider cancer genetics, for example genetic testing for breast/ovarian cancer or genetic testing for inherited syndromes that predispose to colon cancer; Should genetic testing for cancer be offered to healthy people of all ages? Right to know Should doctors recommend genetic testing Right not to know for cancer to healthy people of all ages? Proactive patients What are potential harms/benefits? Information-seeking What are possible implications? Care-seeking What are the expectations for information/action? Clinicians as gatekeepers of information Case to consider Imagine, for example, getting genomics test results on a 5-year-old girl with epilepsy and seeing a risk of breast and ovarian cancer. When is it appropriate to order genomic testing? Right to know Are physicians compelled to share all the Right not to know results with patients? Proactive patients What are potential harms/benefits? Information-seeking Care-seeking What are possible implications? Clinicians as gatekeepers of information Co-evolution of science and society genomic medicine and genetic technologies can be conceptualized under a framework of ‘co-production’ of science and society the simultaneous processes through which modern societies form their epistemic and normative understandings of the world scientific knowledge and associated technologies evolve together with the social representations, identities, discourses that give practical meaning to ideas and objects (Jasanoff, S. (2004, 2006). States of Knowledge: The Co-Production of Science and the Social Order) and associated morality changes Scientific Research in/for Society CONSIDER THE ETHICAL-SOCIAL IMPLICATIONS OF GENETICS & GENOMICS Gartner’s hype cycle’ model; innovative research/technology trigger-pick of expectations-public controversy Geneticisation of society Henk A. & M. J. ten Have (2001) Genetics and culture: The geneticization thesis. Biosociality thesis Rabinow. P. 2001; Artificiality and Enlightenment: From Sociobiology to Biosociality Uncertain futures; threats of biotechnology to the notion of human nature F. Fukuyama (2002) Our Posthuman Future. Scientific knowledge/biotechnologies & Bioethics in social contexts Localisation of scientific knowledge & biotechnologies; how they are embedded in people's lives and social worlds Time economies in Breast Cancer Gene Research and Medical Practices (S. Gibbon et al (2014) Moral Horizons of genetic knowledge and technologies (M. Lock 2011; Lock and Nguyen 2010) Situate bioethics in social worlds; (Hoffmaster (2009) Devries et al (1998) Move away from theoretical justification of ethical problems, towards a view of the social shaping of bioethics concerns, claims, practices individual biographies and social relationships the ethos and institutions of health care, economic and political pressures, Belief- and values of communities in specific times and places. Big ethical issues in clinical genetics & genomics Focus on individuals Questions of autonomy Consent & Confidentiality Individual rights and concerns Questions of professional duties When should clinicians order genomic tests? Focus on How much should clinicians share with their patients community Questions of social contribution and benefit for the community Genetic information as public good Questions of equity, representation & intellectual property The reference human genome -mapped by the Human Genome Project-is white Existing cohorts are largely white Historically marginalized racial/ethnic groups have less access to inclusion in studies or limited sharing of benefits Case to Consider; personal reflection You find out that you and your partner are both carriers of a gene that could cause your children to be severely disabled. Your future child will have 25% chance of developing the condition. In the absence of pre-implantation intervention to secure healthy offspring, what would you do? A. Choose not to have children B. Take the chance Why??? Case study; thalassemia screening in Cyprus Preventive programme for the control of beta thalasemia in Cyprus based on mandatory screening of the couples pre-marriage Example of how biomedical technologies and practices and the relevant ethical debates/practices are co-produced (Beck & Niewhomer 2009) influence of specific local historical and social forces on the material and discursive practices within which genetic technologies are enacted what screening or testing is and what ‘effects’ it might have is contingent on its socio-cultural commissioning in specific contexts Image source: https://www.osmosis.org/learn/Beta- thalassemia In the Cyprus case, importance of collective means of coping with genetic diseases over individual choice Case study; group discussion The preventive programme for β-thalassemia in Cyprus was implemented on the basis of mandatory screening for carrier status of couples prior to religious marriage. Even though the programme successfully controlled the incidence of the disease in the population, the approach used has been subject to criticism for violating ethical norms. ▪ What are the ethical issues you can identify in this case? ▪ Consider the ethical principles ▪ Do you think the approach could be justified? UNESCO Universal Declaration of Bioethics & Human Rights (2005) Article 15 - Sharing of benefits 1. Benefits resulting from any scientific research and its applications should be shared with society as a whole and within the international community, in particular with developing countries. In giving effect to this principle, benefits may take any of the following forms: (a) special and sustainable assistance to, and acknowledgement of, the persons and groups that have taken part in the research; (b) access to quality health care; (c) provision of new diagnostic and therapeutic modalities or products stemming from research; (d) support for health services; (e) access to scientific and technological knowledge; (f) capacity-building facilities for research purposes; (g) other forms of benefit consistent with the principles set out in this Declaration. 2. Benefits should not constitute improper inducements to participate in research.  CASE STUDY; Genetic testing in Tonga In 2000, an Australian biotech company, now known as The agreement was strongly criticized from Tongan Autogen, made an agreement with the government of community groups. Objections included: lack of public Tonga an archipelago nation in the South Pacific, to discussion of the project, lack of transparency, lack of collect blood samples for genetic analysis. The Tongan consideration of privacy concerns, opposition to the population seemed well suited to genetics studies of patenting of DNA, no guarantees of any benefit for the factors relating to diabetes and obesity, since the island Tongan people, colonial appropriation of resources of community had had relatively little immigration, was the Tongan people. genetically isolated, and in recent years has had a high At the time Tonga or other Pacific Forum countries had incidence of the diseases in question. The agreement no intellectual property law or regulation of biological was announced in the Australian press and in stock research. market reports, but encountered vigorous opposition from Tongan community groups. Ultimately the plans The Tonga National Council of Churches published a were shelved. Autogen did not collect or analyze statement of opposition to the Autogen project based samples and instead formed new agreements with on religious beliefs and that patenting of ‘life forms’ was other Polynesian groups to gather genetic information. a violation of respect for the sanctity of life and fundamental religious principles. The statement also affirmed the Tongans desire to control research conducted in their country. Adjusted from Case study in Global Forum on Bioethics in Research https://www.gfbr.global/wp-content/uploads/2015/09/Fifth_Casestudy3.pdf Also in UNESCO Bioethics Core Curriculum, Ethics Education Programme 2011 Case to consider; ethics of genetic testing In 2000, an Australian biotech company, now known as Autogen, made an agreement with the government of Tonga an archipelago nation in the South Pacific, to collect blood samples for genetic analysis. The Tongan population seemed well suited to genetics studies of factors relating to diabetes and obesity, since the island community had had relatively little immigration, What ethical concerns arise concerning was genetically isolated, and in recent years has the ability of national governments to decide had a high incidence of the diseases in question. agreements for genetic research concerning The agreement was announced in the Australian their populations? press and in stock market reports, but the case of genetic research projects carried encountered vigorous opposition from Tongan out by commercial companies versus non- community groups. Ultimately the plans were profit entities? shelved. Autogen did not collect or analyze samples and instead formed new agreements the rights of individuals/families participating with other Polynesian groups to gather genetic in research when it concerns isolated information. populations?  UNESCO Universal Declaration on Bioethics and Human Rights: Background, principles and application, UNESCO, Paris 2005; https://www.unesco.org/en/legal-affairs/universal-declaration-bioethics-and-human- rights?hub=387 Beck, Stefan; Niewöhner, Jörg (2009) Localising genetic testing and screening in Cyprus and Germany. Chapter in Atkinson, Paul; Glasner, Peter; Lock, Margaret (eds) Handbook of Genetics and Society: Mapping the New Genomic Era, pp 76–93. Routledge Ioannou, P. (1999). Thalassemia prevention in Cyprus. In: Chadwick, R., Shickle, D., Ten Have, H., Wiesing, U. (eds) The Ethics of Genetic Screening. Springer, Dordrecht. https://doi.org/10.1007/978-94-015-9323-6_4 Ruth Schwartz Cowan (2009) Moving Up the Slippery Slope: Mandated Genetic Screening on Cyprus. American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 151C:95–103 Michael Angastiniotis , et al (2021) The Prevention of Thalassemia Revisited: A Historical and Ethical Perspective by the Thalassemia International Federation, Hemoglobin, DOI: 10.1080/03630269.2021.1872612 Sahra Gibbon, et al (2014) Breast Cancer Gene Research and Medical Practices: Transnational Perspectives in the Time of BRCA. Routledge  Hoffmaster, B. (ed) (2009). Bioethics In Social Context. Philadelphia: Temple University Press Devries, Raymond, and Janardan Subedi. (1998). Bioethics and society. New Jersey: Prentice Hall. Wilkinson, D. et al (2020) Medical Ethics and Law: a curriculum for the 21st century. Chapter 18: Genethics, pp 291-311. Elsevier (3rd edition) Beckwith & Huang (2005) Should we make a fuss? A case for social responsibility in science, in Nature biotechnology 23 (12) Sahan K, Lyle K, Carley H, et al (2024) Ethical preparedness in genomic medicine: how NHS clinical scientists navigate ethical issues. Journal of Medical Ethics 50:517-522. Chadwick R, Levitt M, Shickle D (1997) The right to know and the right not to know, Aldershot: Avebury J Beckwith (1993) A historical view of social responsibility in genetics BioScience Vol. 43 (5) National Human Genome Research Institute. The Ethical, Legal and Social Implications Research Program https://www.genome.gov/Funded-Programs-Projects/ELSI-Research-Program-ethical-legal-social-implications UK Genethics forum. Available: http://genethicsforum.ning.com Introduction to Ethics in Medical Practice MD6 Y1 2024-2025 Dr Eirini Kampriani Assistant Professor of Medical Anthropology & Medical Ethics [email protected] LOBs Define ethics, bioethics and medical ethics Briefly outline of ethical principles and theories relevant to ethical reasoning Discuss the relation between ethics, health law and professional code Evaluate the role of bioethics in the clinic and beyond Outline What is ethics Bioethics & Medical ethics Developments in Bioethics Ethical reasoning in clinical medicine Health Law Professional codes Why ethics matters in medicine Activity Come to pairs and discuss the following question for 2 minutes Should human cloning be allowed? Then shift pairs Repeat the process Any scientific issues? Any ethical issues? Any legal issues? Any medical professionalism issues? Any social issues? Any religious issues? BRIEF INTRODUCTION Local Admissions (EU) What is ethics Ethics in medicine CONSIDER: CASE You are a medical student on your very first placement. An elderly patient asks you a simple question. The patient asks when is her husband coming to visit her. ❑ Will you be honest? ❑ If yes, why? If not, why? Ethics Ethics seeks to determine what a person should do, or the best course of action, and provides reasons why. It also helps people decide how to behave and treat one another, and what kinds of communities would be good to live in. [National Institutes of Health Dept of Bioethics (2009) Exploring Bioethics. Education Development Center] Etymology of ethics Ethics is about human conduct A code or science of what is right and what is wrong Good vs bad, Rights vs Responsibilities Doing what is good or right The word ‘ethics’ is derived from the Greek word yourselves Defending what is good or right Recommending what is good or right means manner/custom/way/practice a way of acting, a religious ethos ‘ETHICS’ English / ‘ETHICUS’ Latin See: Ethics: a general introduction https://www.bbc.co.uk/ethics/introduction/intro_1.shtml Ethics & Morality Ethics Morality concerned with how a person should behave in the value dimension of a way that is morally human behavior; good- correct or good bad duality based on values and adhering to a specific reasoning belief system or code of conduct refers to the rules that form moral codes about what is right/wrong etc ethics is primarily a matter of knowing whereas morality is a matter of doing (WMA Ethics Manual, 2015) Ethics in medicine; one or many? Ethics in medicine refers to how doctors must conduct themselves and how they can address the ethical dilemmas that arise in clinical practice Bioethics and Medical Ethics Applied ethics Specific topics  Bioethics is concerned with ethical issues arising from developments in medical knowledge and biotechnology, societal needs and the future of human life Emerged as a distinct area in the 1960s, influenced by scientific advancements, growing public awareness of ethical issues and social movements like the civil rights and gender equity Established as academic field in 1980s Source: https://hpluspedia.org/wiki/File:Bioethics.jpg#file  Developments in bioethics December 3, 1967: The April 11, 1983: Newsweek first heart transplant published a story that a was done by Dr. mysterious disease called AIDS Christiaan Barnard. July 25, 1978: Baby Louise was at epidemic levels. April 25, 1953: Watson & Crick Brown was born. She was published a one-page paper the first test-tube baby. about DNA. Source: Jonsen, A. R. (2000). A short history of medical ethics. pp. 99–114. Changing bioethical concerns in IVF Ethical acceptability of assisted Funding of IVF reproduction (the nature/ Eligibility for treatment; Upper culture divide in reproduction) age limit for IVF Moral status of embryos Ownership of embryos (esp (personhood and rights) surplus/unused embryos) Social status of the future child Forms of embryo selection (fear of discrimination) (designer babies?) Clinical provision Future child’s welfare Institutionalization Reproductive tourism (monitoring/control of the field) Book Cover: Louise Brown: 40 Years of IVF Paperback (2018) by Martin Powell, Louise Brown Medical ethics (healthcare ethics) an area of ethics concerned with the practice of clinical medicine & doctor-patient interactions Long-standing interest in ethical medical practice has a flexible set of solutions (facts, logic, syllogism) often seen as a prescriptive activity telling you what you cannot do in many cases it can be very freeing; affirming that you are doing the right thing Source: https://pubrica.com/academy/research-services/how-to- overcome-regulatory-and-ethical-challenges-regarding-medical-device/  Any ethical issues? Doctors fit to practice should have sound knowledge and technical competence Obligation to be informed & do what’s good to the patient Source: cartoonstock.com  Any ethical issues? Doctors should do no harm to the patient Have obligation to be transparent in case of medical error Source: bizzaro.com  Any ethical issues? Doctor’s duty to Respect patient autonomy and seek voluntary informed consent Source https://jp.pinterest.com/pin/851110029606028152/  Any ethical issues? Doctors should show respect for and be sensitive to patient vulnerability, have cultural competence, & express empathy Source: bizzaro.com An interdisciplinary field Medicine Distinction between Scientific and Ethical questions Public Philosophy Health Facts and values Ethics in medicine Personal and Professional ethical code Diverse perspectives and challenges Religion Law Sociology & Anthropology ETHICAL CODES Local Admissions (EU) Core values in medicine & Medical ethical code Compassion Concern for patient’s condition and distress Competence Scientific, technical, cultural, ethical Autonomy or self-determination Individual and collective decision-making procedures WMA Medical Ethics Manual 2015 Hippocratic Oath The history and the Content of the Hippocratic Oath Hippocrates 460 BC - 370 BC Translation of the Hippocratic Oath by Ludwig Edelstein (1967) https://www.youtube.com/watch?v=AreFKsYw96Y  HIPPOCRATIC OATH 1. I swear by Apollo Physician and Asclepius and Hygieia and Panaceia and all the gods and goddesses, making them my witnesses, that I will fulfil according to my ability and judgement this oath and this covenant 2. To hold the one who has taught me this art as equal to my parents and to live my life in partnership with him 3. I will apply dietetic measures for the benefit of the sick according to my ability and judgement; I will keep them from harm and injustice 4. I will neither give a deadly drug to anyone if asked for it nor will I make a suggestion to this effect. Similarly I will not give to a woman an abortive remedy. In purity and wholeness I will guard my life and my art. 5. I will not use the knife, not even on sufferers from stone, but will withdraw in favour of such men as are engaged in this work. 6. Into whatever houses I may enter, I will come for the benefit of the sick, remaining clear of all voluntary injustice and of other mischief 7. Things I may see or hear in the course of the treatment or even outside of treatment I will keep to myself holding such things unutterable [‘‘shameful to be spoken’’] 8. If I fulfil this oath and do not violate it, may it be granted to me to enjoy life and art if I transgress it and swear falsely, may the opposite of all this be my lot Contemporary challenges Hippocratic Oath was written specifically to prevent self interested doctors from harming individual patients in ancient times What is its relevance today? Physician-assisted suicide abortion An ethicist’s view of Hippocratic medicine today “The legalisation of abortion, permissive laws in relation to euthanasia (also paediatrics), the production of embryos which are abandoned or used for experimentation, the selection and destruction of embryos through pre implantation diagnosis during assisted fertilization, and prenatal diagnosis during pregnancy, and sterilization, are all examples of a profound threat to Hippocratic medicine, and unfortunately we find many medical doctors aligned on the side opposed to that of the total defense of life.” Angelo Fiori ‘The Figure of the Medical Doctor and the Expectations of Citizens: Continuity and Forms of Conditioning’, p. 144.  DECLARATION OF GENEVA AS A MEMBER OF THE MEDICAL PROFESSION: I SOLEMNLY PLEDGE to dedicate my life to the service of humanity; THE HEALTH AND WELL BEING OF MY PATIENT will be my first consideration; I WILL RESPECT the autonomy and dignity of my patient; I WILL MAINTAIN the utmost respect for human life; I WILL NOT PERMIT considerations of age, disease or disability, creed, ethnic origin, gender, nationality, political affiliation, race, sexual orientation, social standing or any other factor to intervene between my duty and my patient; I WILL RESPECT the secrets that are confided in me, even after the patient has died; I WILL PRACTISE my profession with conscience and dignity and in accordance with good medical practice; I WILL FOSTER the honour and noble traditions of the medical profession; I WILL GIVE to my teachers, colleagues, and students the respect and gratitude that is their due; I WILL SHARE my medical knowledge for the benefit of the patient and the advancement of healthcare; I WILL ATTEND TO my own health, well being, and abilities in order to provide care of the highest standard; I WILL NOT USE my medical knowledge to violate human rights and civil liberties, even under threat; I MAKE THESE PROMISES solemnly, freely, and upon my honour ©2017 World Medical Association Inc. Hippocratic oath today In developing a universal code there is the problem of: “How to develop an all embracing ethical code of practice if one makes the code relative to local circumstances?” (on the resurgence of interest in medical oaths; Millard 1998, BMJ 316; Hurwitz & Richardson, 1997, BMJ 315) Ethical framework (principles of universal acceptance & community values) Country-specific Legal framework Local Admissions (EU) The Law What is the law? “the principles and regulations established in a community by some authority and applicable to its people, whether in the form of legislation or customs or policies which is recognized and enforced by judicial decision” Dictionary.com Medical Law Sets the standards and guidelines that govern the conduct of medical research and medical practice, to ensure order and safety, protection of human subjects and promotion of fairness. Basic distinctions in law Criminal v Civil Law Statute v Common Law Civil law concerns dealings between Statute refers to written law decided by private individuals or groups. the legislature or other government agency (e.g. Acts of Parliament); it is Criminal law concerns matters serious relatively difficult to change enough to be considered offences Common law is based on precedent or against the whole community case; it concerns decisions made by judges and it’s relatively more malleable While the majority of cases that concern healthcare take place in the civil system, occasionally medical cases become criminal (i.e. patient death due to potentially preventable adverse events, claims of negligence) Law & Ethics Medical law & ethics consider the rights/ responsibilities of patients and duties/responsibilities of doctors with reference to complex moral debate The law often reflects our ethical standards, social ideologies/cultural beliefs in certain context and time BUT being legal does not necessarily make an action ethical Ethics Health Law Standards of Rules of conduct behaviour or action  Reading about Ethics & Law Reading academic papers i.e. Journal of Medical Ethics o Impressions o Key points o Assumptions o Alternative D K Sokol (2003) How to be a “good” medical student perspectives http://dx.doi.org/10.1136/jme.2003.003848 o Comparison o Open questions PROFESSIONALISM Local Admissions (EU) Image source https://www.thebalancecareers.com/doctor-career-information-526008 CONSIDER; PERSONAL vs PROFESSIONAL ETHICS Personal & professional ethics Personal ethics refers to the ethical values and standards that a person identifies with in respect to people and situations that they deal with in everyday life. Professional ethics refers to the ethical guidelines and rules that a person must adhere to in respect of their interactions and dealings in their professional life. Professional behaviour & ethical practice With patients; With peers Profession Fitness to practice Code of conduct Medical school Professionalism & Code of conduct In 2009 a group of doctors and nurses were suspended for taking part in “The Lying Down Game”, where participants took pictures of themselves lying face down in unusual places and uploaded them onto Facebook. The group were reported to hospital management after pictures of them lying on resuscitation trolleys, ward floors and the ambulance helipad were spotted on the site. The pictures broke hospital regulations and breached NHS and Trust codes of conduct. The medical director stated that the group faced disciplinary action. American Medical Association General Medical Council (AMA) (GMC) AMA Code of Ethics Adopted June 1957; revised June 1980; revised June 2001. Under the Medical Act 1983 the GMC has 4 main functions: keeping up-to-date registers of qualified doctors fostering good medical practice promoting high standards of medical education & training dealing firmly and fairly with doctors whose fitness to practise is in doubt. Ethical Reasoning Local Admissions (EU) Ethical reasoning Ethical reasoning is an integral part of modern medicine in the same way that clinical reasoning is the ability to identify and assess ethical controversy, and develop ethical arguments from a variety of ethical positions, based on ethical concepts, theories and principles  Identify the ethical problem/dilemma ‘Doing Ethics’; the process What is at stake? Relevant issues, facts, perspectives Who/what is involved? the process of doing ethics is as important as the ethical conclusions drawn Ethical Considerations & Implications What needs to taken into account? What about the “process”? Relevant guidelines, medical law, Involves: listening, asking questions, making assumptions, using regulations critical reflection, deliberately thinking the opposite, using emotion, What applies? being alert to logic etc. Identifying viewpoints, Developing Arguments to justify an ethical position How ethical are possible actions? Which action is preferred & Why??? Normative vs Descriptive Claims descriptive or empirical claims about the world How do people behave? What do people think is right? e.g. Patients often lie to their doctor about sexual health matters Lying to your doctor compromises sexual health care outcomes normative or prescriptive or evaluative claims about how the world should be How should people act? e.g. Patients should not lie to their doctor about their sexual health When making an ethical argument, we use both descriptive and normative claims CONSIDER: EXTENDED CASE You are a medical student on your very first placement. An elderly patient asks you a simple question. The patient asks when is her husband coming to visit her. You know the answer from previous conversation with family members. Patient’s husband died 5 years ago. The patient is suffering dementia and does not remember this fact. ❑ Will you be honest? ❑ If yes, why? If not, why? Developing an ethical argument; ethical theories Basis of ethical reasoning; targeting the question what should a doctor do in the situation? Ethical theories provide Orientation for justified options Ethical theories ❑Consequentialism (outcome-focused) “An action is right if it promotes the best consequences” Utilitarianism “the greatest good to the greatest number of people” Jeremy Bentham (1748-1832), British lawyer “actions are right in proportion as they tend to promote happiness, wrong as they tend to produce the reverse of happiness” - JOHN STUART MILL, English philosopher 19th century Ethical theories ❑Deontology (includes rights/justice) “An action is right if it is accordance with a correct moral rule or principle” Categorical imperative (Immanuel Kant, German philosopher) ❑Virtue Ethics (agent-based) “An action is right if it is what a virtuous agent would characteristically do in the circumstances” (Aristotle, ancient Greek philosopher; Pelegrino 1993, 2006) CONSIDER: EXTENDED CASE You are a medical student on your very Virtues: Honesty; first placement. An elderly patient asks prudence, trustworthiness you a simple question. The patient asks Consequentialism: when is her husband coming to visit her. Benefits/risk of harm of the outcome of You know the answer from previous telling vs non-telling conversation with family members. Deontology: Professional guidelines Patient’s husband died 5 years ago. The on how to handle patient is suffering dementia and does being open and honest with patients if things not remember this fact. go wrong ❑ Will you be honest? ❑ If yes, why? If not, why? Ethical Tools We can analyse ethical scenarios using primary principles or theories (e.g. consequentialism) but we also have a number of practical tools to assist in the analysis of concrete scenarios from an ethical perspective. There are various methods, including: The “Four Principles” approach The Paradigm Case Process Structured Case Analysis Model Ethical Grid etc Four Principles/Pillars The four principles of health care ethics Autonomy developed by Tom Beauchamp and James Beneficence self-rule; respect for the Childress in the 1979 book Principles of actions intended to Biomedical Ethics (8th edition (2019) individual and their benefit the patient ability to make decisions. Non-maleficence Justice actions intended not to being fair/just to the harm or bring harm to patient and wider the patient community Applying the 4 principles The four principles are non-hierarchical. For ethical clinical reasoning, one may be required to take all principles into account when they are applicable to the clinical case under consideration. Yet, when two or more principles apply, we may find that they are in conflict.  Case study; application of the 4 principles the patient dislikes needles forcing the patient to accept and doesn’t want the the needle might be harmful operation (autonomy) (non-maleficence) A patient has an ovarian cyst that, if left untreated, will result in kidney failure. An operation to remove the cyst is the best treatment, but the patient is frightened of needles and is against the surgery that would require a needle to give her anesthesia. if she goes into preventable need to find a solution kidney failure, she’ll need that would prevent dialysis; impact on resources kidney failure available to patients in need of (beneficence) the same treatment (justice) the doctor’s decision making should be guided by achieving the best possible benefits for the patient & society.  Case 1 On a ward at night … A junior doctor gave an elderly patient 5 mgs of morphine to ease his pain after fracturing his ankle while walking his dog. The doctor was busy and neglected to read his medical notes before administering the drug. What should the doctor do? The patient had a history of asthma and became very breathless, had an asthma attack A. Record and report the incident and was treated immediately with a nebulizer B. Say or do nothing since there The patient made full recovery were no consequences for the patient WHY?? Consider possible justification Case 2 A young doctor in a remote rural setting meets with a patient who has been diagnosed with terminal illness but they refuse treatment. The doctor is puzzled by the patient’s attitude; he feels that since he provides care to this patient, he is morally obliged to insist on the patient getting What should the doctor do? treatment, even though evidence shows it A. Accept patient’s request to stop does not significantly alter prognosis. treating them B. Continue prescribing medication knowing that its futile WHY?? Consider possible justification  ‘Doing Ethics’; the challenges Limited resources e.g. time, expertise, staff, accountable sources of advice and ethical support Integrating ethics into clinical practice so it becomes automatic in decision-making Constructing ethics as ‘common sense’, not ‘yet more rules’ CONCLUDING; DOES ETHICS MATTER? Local Admissions (EU) Why Ethics Matters It is morally important to behave morally Professional Regulatory Bodies require their members to behave professionally and ethically The law reflects ethical values and requires doctors to know about professional and ethical guidance It is useful/important in resolving ethical challenges… Ethics & Clinical Practice Consensus statement from 32 medical schools: ‘Knowledge of the ethical and legal basis of medicine is as essential to clinical practice as an understanding of the basic clinical sciences’. Stirrat, 2010. Medical ethics and law for doctors of tomorrow: the 1998 Consensus Statement updated. J Med Ethics, 35: 55 60.  Ethical problems in medical practice Common problems identified in a 2016 Medscape survey: Withholding treatment to meet an organization's budget, or because of insurance policies; Upcoding to get treatment covered; Getting romantically involved with a patient or family member; Covering up a mistake; Reporting an impaired colleague; Prescribing a placebo; Practicing defensive medicine to avoid malpractice lawsuits; Breaching patient confidentiality owing to a health risk. Why Ethical Analysis Matters Patient care is enhanced (Jha 2003, Stein 2006) Staff avoid moral distress and potential ‘burnout’ (when physicians' personal values contradict those of their organisation) (Bischoff et al 1999, Asch et al 2004) Teams function more effectively & inclusively (Stein 2006; Blakely & Biehle 2021) Enhances productivity, efficiency & morale (Longman 2005) Maintains reputation & accountability (Schneiderman 2003) Helps resolve disputes between patients, families and clinicians Ethics quality is integral to the wider quality debate in healthcare (Berwick 2005) FURTHER READING Jonsen , Albert. (2008) A Short History of Medical Ethics. Oxford University Press (in the library) WMA (2015) Medical Ethics Manual, 3rd Ed. (Introduction) https://www.wma.net/what-we- do/education/medical-ethics-manual/ Hippocratic Oath ethical code; In Encyclopedia Britannica https://www.britannica.com/topic/Hippocratic oath WMA Declaration of Geneva. https://www.wma.net/policies post/wma declaration of geneva/ Oxtoby, Kathy (2016) Is the Hippocratic oath still relevant to practising doctors today? British Medical Journal 355 doi : https://doi.org/10.1136/bmj.i6629 AMA Code of Medical Ethics & AMA Principles of Medical Ethics https://code-medical-ethics.ama-assn.org/ GMC (2016) Professional behaviour and fitness to practice. https://www.gmc-uk.org/education/standards- guidance-and-curricula/guidance/student-professionalism-and-ftp/professional-behaviour-and-fitness-to- practise Beauchamp T, Childress J. (2019) Principles of Biomedical Ethics. 8th Edition. New York: Oxford University Press Reese S. Medscape Ethics Report 2016: money, romance, and patients. Medscape News & Perspective. December 1. FURTHER READING Bowman (2011) The Worried Student's Guide to Medical Ethics and Law. (chapters 1 & 2) (in the library) Dominic Wilkinson, Jonathan Herring, Julian Savulescu. 2019 Medical Ethics and Law: A curriculum for the 21st Century. 3rd Ed. Elsevier (Chapter 1) (in the library) Tom Beauchamp (2007) The ‘Four Principles’ Approach to Health Care Ethics. Chapter 1 in the book: Principles of Health Care Ethics (2nd Edition) Edited by R.E. Ashcroft, A. Dawson, H. Draper and J.R. McMillan. John Wiley & Sons (in the library) JUSTIN OAKLEY (2007) Virtue Theory. Chapter 12 in the book Richard E. Ashcroft, et al., Principles of health care ethics MATTI HÄYRY (2007) Utilitarianism and Bioethics. Chapter 8 in the book Richard E. Ashcroft, et al., Principles of health care ethics DAVID A. McNAUGHTON & J. PIERS RAWLING (2007) Deontology. Chapter 9 in the book Richard E. Ashcroft, et al., Principles of health care ethics Chan S. (2014) A bioethics for all seasons. Journal of Medical Ethics 41:17–21. Rodger D. & B. Blackshaw (2017) An introduction to ethical theory for healthcare assistants. British Journal of Healthcare Assistants, Vol 11 No 11  APPENDIX METHODS AND TOOLS FOR ETHICAL ANALYSIS Jonsen, Siegler, and Winslade (2006) have described the “four-topics” or “four-quadrant” approach  APPENDIX METHODS AND TOOLS FOR ETHICAL ANALYSIS “Ethical Grid” The Ethical Grid by David Seedhouse; attempts to bring into perspective several layers/considerations: Core rationale – individuals Deontological layer; duties and motives Consequential layer; External considerations  APPENDIX METHODS AND TOOLS FOR ETHICAL ANALYSIS Summarise the case State the moral dilemma(s) Structured Case State the assumptions being made or to be made Analysis Model Analyse the case with reference to ethical principles consequences Professional codes / virtuous healthcare practitioner the law Acknowledge justifiable ethical solutions and those that are not justifiable State preferred approach with explanation SOURCE: The Ethox Centre APPENDIX METHODS AND TOOLS FOR ETHICAL ANALYSIS Ethical reasoning; a combination of approaches? World Medical Association Medical Ethics Manual (2015) Ethical analysis may comprise the following steps: 1. Determine whether the issue at hand is an ethical one. 2. Consult authoritative sources (medical association codes of ethics and policies, respected colleagues etc). 3. Consider alternative solutions in light of the principles/duties/values/likely consequences 4. Discuss your proposed solution with those whom it will affect. 5. Make your decision and act on it, with sensitivity to others affected. 6. Evaluate your decision. Source: https://www.wma.net/wp-content/uploads/2016/11/Ethics_manual_3rd_Nov2015_en_1x1.pdf SCIENCE & RESEARCH ETHICS - ETHICS IN GENETICS GEMD-101 2024-2025 Dr Eirini Kampriani Assistant Professor of Medical Anthropology & Medical Ethics [email protected] LOBs Outline key issues with reference to ethical-social aspects of scientific and genetic research Briefly explain an example of bioethics in social context Medical research; uses and abuses Dark history of scientific medical research/experimentation In the 19th and mid 20th century; Eugenics movement had profound effect in the US and Europe Public eugenic programmes that included sterilization, miscegenation & immigration restriction laws experiments on patients without their consent research that clearly violated fundamental human rights Medical experimentation; Europe WWII Background; Nazi medicine Mengele’s genetic experimentation & eugenics VIDEO https://www.youtube.com/watch?v=kFpcFScVKog Public outrage with social harm from eugenic practices, misuse of science and human rights violation led to the definition of ethical guidelines for medical research Science, society & Responsibility “Science must respond to societal needs and global challenges. Public understanding and engagement with science, and citizen participation including through the popularization of science are essential to equip citizens to make informed personal and professional choices.” https://en.unesco.org/themes/science-society If society is to remain in step with new technology, the scientific community needs to be better educated about the social and ethical implications of its research. [Beckwith & Huang 2005]  Ethics in Genetics & Genomic medicine Geneticists criticised eugenics as poor science Sense of social responsibility of science emerged When initiating the Human Genome Project In the late 1980s, James Watson, announced that several percent of the funds for the project would go to addressing the ethical, legal, and social implications of the research (J Beckwith (1993) https://www.genome.gov/human-genome-project Genetics Research frameworks ELSI/ELSA frameworks Ethical, Legal & Social Issues/Aspects of genomic medicine & genetic technologies ELSI Research Program was born in the genome analysis project that started in the US in 1990. ELSA framework in Europe; mid-2010s shifted to Responsible Research & Innovation (RRI) framework Image source: https://www.technologynetworks.com/diagnostics/articles/exploring-the-ethics- of-genetic-testing-what-does-consent-mean-334320 Genetics and Genomic research Advances in genetics and genomics have been associated from early on with an interest in Ethical, legal and social implications Understanding the consequences of genetic advances for individuals and societies Defining the ethical boundaries or genetic research and associated technologies of screening/testing in the clinic and beyond Addressing concerns of privacy, consent, access to genetic information Preparing the public and healthcare professionals Source: Collins et al (2003) Nature vol 422  Genetic testing; types & purpose Single gene sequencing – Diagnostic testing – to confirm or rule out a genetic disease. investigating a Predictive and pre-symptomatic testing – to determine if condition which is known to be someone possesses any DNA variations that increase the risk associated with of developing a particular disease. mutations in a particular gene. Carrier testing – to identify mutations that may only be present in one copy in the person being tested, but if present Whole genome in two copies, can cause a genetic disease. sequencing – investigating risk for Prenatal testing – to identify disease in a fetus multiple diseases or conditions that have Newborn screening – to determine if a newborn has a health been associated or developmental condition with mutations in Image source: https://www.ucsf.edu/news/2023/08/426071/how- more than one cutting-edge-genetic-test-helps-ill-newborns-pregnant-moms region of the (Large 2020, Soulier et al 2019) genome.  Individual & Relational autonomy (respect of choice and rights) Ownership of genetic data (personal vs familial information, data as public good) Appropriate use of genetic data (guidelines and standards of practice) Focus of Redefining the concept of disease (focusing not just on presenting symptoms but on estimations of risk and genetic profile) bioethical debate Resituating the patient (high-risk and pre-symptomatic patient) Reconfiguring responsibility (information vs action; family interdependencies; health professionals duty) Clinical & Research practices (genetic databases and genetic libraries for multiple uses) Case to consider; ethics of genetic testing Consider cancer genetics, for example genetic testing for breast/ovarian cancer or genetic testing for inherited syndromes that predispose to colon cancer; Should genetic testing for cancer be offered to healthy people of all ages? Right to know Should doctors recommend genetic testing Right not to know for cancer to healthy people of all ages? Proactive patients What are potential harms/benefits? Information-seeking What are possible implications? Care-seeking What are the expectations for information/action? Clinicians as gatekeepers of information Case to consider Imagine, for example, getting genomics test results on a 5-year-old girl with epilepsy and seeing a risk of breast and ovarian cancer. When is it appropriate to order genomic testing? Right to know Are physicians compelled to share all the Right not to know results with patients? Proactive patients What are potential harms/benefits? Information-seeking Care-seeking What are possible implications? Clinicians as gatekeepers of information Co-evolution of science and society genomic medicine and genetic technologies can be conceptualized under a framework of ‘co-production’ of science and society the simultaneous processes through which modern societies form their epistemic and normative understandings of the world scientific knowledge and associated technologies evolve together with the social representations, identities, discourses that give practical meaning to ideas and objects (Jasanoff, S. (2004, 2006). States of Knowledge: The Co-Production of Science and the Social Order) and associated morality changes Scientific Research in/for Society CONSIDER THE ETHICAL-SOCIAL IMPLICATIONS OF GENETICS & GENOMICS Gartner’s hype cycle’ model; innovative research/technology trigger-pick of expectations-public controversy Geneticisation of society Henk A. & M. J. ten Have (2001) Genetics and culture: The geneticization thesis. Biosociality thesis Rabinow. P. 2001; Artificiality and Enlightenment: From Sociobiology to Biosociality Uncertain futures; threats of biotechnology to the notion of human nature F. Fukuyama (2002) Our Posthuman Future. Scientific knowledge/biotechnologies & Bioethics in social contexts Localisation of scientific knowledge & biotechnologies; how they are embedded in people's lives and social worlds Time economies in Breast Cancer Gene Research and Medical Practices (S. Gibbon et al (2014) Moral Horizons of genetic knowledge and technologies (M. Lock 2011; Lock and Nguyen 2010) Situate bioethics in social worlds; (Hoffmaster (2009) Devries et al (1998) Move away from theoretical justification of ethical problems, towards a view of the social shaping of bioethics concerns, claims, practices individual biographies and social relationships the ethos and institutions of health care, economic and political pressures, Belief- and values of communities in specific times and places. Big ethical issues in clinical genetics & genomics Focus on individuals Questions of autonomy Consent & Confidentiality Individual rights and concerns Questions of professional duties When should clinicians order genomic tests? Focus on How much should clinicians share with their patients community Questions of social contribution and benefit for the community Genetic information as public good Questions of equity, representation & intellectual property The reference human genome -mapped by the Human Genome Project-is white Existing cohorts are largely white Historically marginalized racial/ethnic groups have less access to inclusion in studies or limited sharing of benefits Case to Consider; personal reflection You find out that you and your partner are both carriers of a gene that could cause your children to be severely disabled. Your future child will have 25% chance of developing the condition. In the absence of pre-implantation intervention to secure healthy offspring, what would you do? A. Choose not to have children B. Take the chance Why??? Case study; thalassemia screening in Cyprus Preventive programme for the control of beta thalasemia in Cyprus based on mandatory screening of the couples pre-marriage Example of how biomedical technologies and practices and the relevant ethical debates/practices are co-produced (Beck & Niewhomer 2009) influence of specific local historical and social forces on the material and discursive practices within which genetic technologies are enacted what screening or testing is and what ‘effects’ it might have is contingent on its socio-cultural commissioning in specific contexts Image source: https://www.osmosis.org/learn/Beta- thalassemia In the Cyprus case, importance of collective means of coping with genetic diseases over individual choice Case study; group discussion The preventive programme for β-thalassemia in Cyprus was implemented on the basis of mandatory screening for carrier status of couples prior to religious marriage. Even though the programme successfully controlled the incidence of the disease in the population, the approach used has been subject to criticism for violating ethical norms. ▪ What are the ethical issues you can identify in this case? ▪ Consider the ethical principles ▪ Do you think the approach could be justified? UNESCO Universal Declaration of Bioethics & Human Rights (2005) Article 15 - Sharing of benefits 1. Benefits resulting from any scientific research and its applications should be shared with society as a whole and within the international community, in particular with developing countries. In giving effect to this principle, benefits may take any of the following forms: (a) special and sustainable assistance to, and acknowledgement of, the persons and groups that have taken part in the research; (b) access to quality health care; (c) provision of new diagnostic and therapeutic modalities or products stemming from research; (d) support for health services; (e) access to scientific and technological knowledge; (f) capacity-building facilities for research purposes; (g) other forms of benefit consistent with the principles set out in this Declaration. 2. Benefits should not constitute improper inducements to participate in research.  CASE STUDY; Genetic testing in Tonga In 2000, an Australian biotech company, now known as The agreement was strongly criticized from Tongan Autogen, made an agreement with the government of community groups. Objections included: lack of public Tonga an archipelago nation in the South Pacific, to discussion of the project, lack of transparency, lack of collect blood samples for genetic analysis. The Tongan consideration of privacy concerns, opposition to the population seemed well suited to genetics studies of patenting of DNA, no guarantees of any benefit for the factors relating to diabetes and obesity, since the island Tongan people, colonial appropriation of resources of community had had relatively little immigration, was the Tongan people. genetically isolated, and in recent years has had a high At the time Tonga or other Pacific Forum countries had incidence of the diseases in question. The agreement no intellectual property law or regulation of biological was announced in the Australian press and in stock research. market reports, but encountered vigorous opposition from Tongan community groups. Ultimately the plans The Tonga National Council of Churches published a were shelved. Autogen did not collect or analyze statement of opposition to the Autogen project based samples and instead formed new agreements with on religious beliefs and that patenting of ‘life forms’ was other Polynesian groups to gather genetic information. a violation of respect for the sanctity of life and fundamental religious principles. The statement also affirmed the Tongans desire to control research conducted in their country. Adjusted from Case study in Global Forum on Bioethics in Research https://www.gfbr.global/wp-content/uploads/2015/09/Fifth_Casestudy3.pdf Also in UNESCO Bioethics Core Curriculum, Ethics Education Programme 2011 Case to consider; ethics of genetic testing In 2000, an Australian biotech company, now known as Autogen, made an agreement with the government of Tonga an archipelago nation in the South Pacific, to collect blood samples for genetic analysis. The Tongan population seemed well suited to genetics studies of factors relating to diabetes and obesity, since the island community had had relatively little immigration, What ethical concerns arise concerning was genetically isolated, and in recent years has the ability of national governments to decide had a high incidence of the diseases in question. agreements for genetic research concerning The agreement was announced in the Australian their populations? press and in stock market reports, but the case of genetic research projects carried encountered vigorous opposition from Tongan out by commercial companies versus non- community groups. Ultimately the plans were profit entities? shelved. Autogen did not collect or analyze samples and instead formed new agreements the rights of individuals/families participating with other Polynesian groups to gather genetic in research when it concerns isolated information. populations?  UNESCO Universal Declaration on Bioethics and Human Rights: Background, principles and application, UNESCO, Paris 2005; https://www.unesco.org/en/legal-affairs/universal-declaration-bioethics-and-human- rights?hub=387 Beck, Stefan; Niewöhner, Jörg (2009) Localising genetic testing and screening in Cyprus and Germany. Chapter in Atkinson, Paul; Glasner, Peter; Lock, Margaret (eds) Handbook of Genetics and Society: Mapping the New Genomic Era, pp 76–93. Routledge Ioannou, P. (1999). Thalassemia prevention in Cyprus. In: Chadwick, R., Shickle, D., Ten Have, H., Wiesing, U. (eds) The Ethics of Genetic Screening. Springer, Dordrecht. https://doi.org/10.1007/978-94-015-9323-6_4 Ruth Schwartz Cowan (2009) Moving Up the Slippery Slope: Mandated Genetic Screening on Cyprus. American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 151C:95–103 Michael Angastiniotis , et al (2021) The Prevention of Thalassemia Revisited: A Historical and Ethical Perspective by the Thalassemia International Federation, Hemoglobin, DOI: 10.1080/03630269.2021.1872612 Sahra Gibbon, et al (2014) Breast Cancer Gene Research and Medical Practices: Transnational Perspectives in the Time of BRCA. Routledge  Hoffmaster, B. (ed) (2009). Bioethics In Social Context. Philadelphia: Temple University Press Devries, Raymond, and Janardan Subedi. (1998). Bioethics and society. New Jersey: Prentice Hall. Wilkinson, D. et al (2020) Medical Ethics and Law: a curriculum for the 21st century. Chapter 18: Genethics, pp 291-311. Elsevier (3rd edition) Beckwith & Huang (2005) Should we make a fuss? A case for social responsibility in science, in Nature biotechnology 23 (12) Sahan K, Lyle K, Carley H, et al (2024) Ethical preparedness in genomic medicine: how NHS clinical scientists navigate ethical issues. Journal of Medical Ethics 50:517-522. Chadwick R, Levitt M, Shickle D (1997) The right to know and the right not to know, Aldershot: Avebury J Beckwith (1993) A historical view of social responsibility in genetics BioScience Vol. 43 (5) National Human Genome Research Institute. The Ethical, Legal and Social Implications Research Program https://www.genome.gov/Funded-Programs-Projects/ELSI-Research-Program-ethical-legal-social-implications UK Genethics forum. Available: http://genethicsforum.ning.com Stem cells in genetic diseases Prof Christodoulos Xinaris Nicosia, 2024 Peter Paul Rubens, 1612-8. 2 Simple animals were capable of regeneration 1744 Capacity to renew whole animals from small numbers of dissociated and reaggregated cells Abraham Trembley 3  Limb regeneration in adult salamanders 1768 Abate Lazzaro Spallanzani After amputation, he observed a lot of blood flow and retraction of the skin at the edges of the stump. He observed that along the longer axis of elliptic surface appears a thin crest of flesh, which is the beginning of the “reproduction”. 4 Stem Cells: a key cellular source for regeneration 5 What is a stem cell? stem cell SELF- DIFFERENTIATION RENEWAL (specializing) (the capacity to generate identical copies of themselves,) stem cell specialized cell e.g. nerve cell, muscle cell 6 Where are stem cells found? only some specialized differentiation embryonic stem cells tissue stem cells blastocyst - a very early fetus, baby and throughout life embryo differentiation all possible types of specialized cells 7 8  Sickle Cell Disease Sickle cell disease (SCD) results from a homozygous missense mutation in the β-globin gene that causes polymerization of hemoglobin S. ≈ 90,000 people in the United States have sickle cell disease, and worldwide more than 275,000 infants are born with the disease annually. Inherited abnormality of the oxygen-carrying hemoglobin protein in red blood cells (RBC). Allogeneic hematopoietic stem-cell transplantation currently offers the only curative option for patients with severe SCD. 9 10 Blood. 2015 Apr 23;125(17):2597-604. 11 Case report of a patient with sickle cell disease who received gene therapy with the use of lentiviral gene addition of an antisickling β- globin variant. The patient had complete clinical remission with correction of hemolysis and biologic hallmarks of the disease. 13 The patient In June 2015, a seven-year-old child was admitted to the Burn Unit of the Children’s Hospital, in Germany. He carried a homozygous acceptor splice site mutation (C1977-1G>A, IVS 14-1G>A) within intron 14 of LAMB3. Since birth, the patient had developed blisters all over his body, particularly on his limbs, back and flanks. His condition deteriorated severely six weeks before admission, owing to infection with Staphylococcus aureus and Pseudomonas aeruginosa. Shortly after admission, he suffered complete epidermal loss on about 60% of his total body surface area (TBSA). During the following weeks, all therapeutic approaches failed and the patient’s short-term prognosis was unfavourable. Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Nature volume 551, pages327–332(2017) Gene therapy to treat a skin disease. The authors isolated epidermal cells from a non-blistering skin region and corrected the cells by infecting them with a retrovirus that carried unmutated LAMB3. In vitro growth of epidermal cells produces three types of colony: holoclones, which are proliferative and contain stem cells; differentiated paraclone colonies; and meroclones, which are in an intermediate state of differentiation. Further growth produces sheets of transgenic epidermis derived from these colonies that were transplanted back to the patient. The skin completely regenerates about once a month, with differentiated cells being replaced — after four months, the authors found that many paraclone and meroclone colonies from the initial transplant had been lost, and by eight months, almost the entire skin was derived from the initial holoclones. Thus, skin is maintained by a few stem cells. Nature volume 551, pages306–307(2017) TISSUE AND ORGAN ENGINEERING Human organoids/tissues Studying human disease Development of personalized treatments Studying human development Regenerative medicine applications Modified from Xinaris et al. 2015 3D bio-printing of human organs Wake Forest Institute for Regenerative Medicine The Integrated Tissue and Organ Printing System (ITOP) can fabricate stable, human-scale tissue constructs of any shape v v The system deposits both bio-degradable, plastic-like materials to form the tissue "shape" and water-based gels that contain the cells. Nature Biotechnology 34, 312–319 (2016) 3DBio Therapeutics had for the first time used 3-D printing to make a body part with a patient’s own cells Alexa, the patient, before the surgery, left, and 30 days after the surgery. Microtia-Congenital Ear Institute The kidney is too complex for direct construction 21 Self-organization in biological systems 22  Experimental design mouse E11.5 Dissociation In vitro culture Aggregation Simple suspension of cells Xinaris et al., J Am Soc Nephrol, 2012 23 NCAM 15 days 24  Experimental design mouse E11.5 Dissociation In vitro culture Euthanasia Aggregation 3 weeks Implantation Athymic rat kidney Simple suspension of cells In vitro In vivo 25 + VEGF graft host 26 Xinaris et al., J Am Soc Nephrol, 2015 27 Shinya Yamanaka 28 GENERATION OF ISOGENIC PLURIPOTENT STEM CELLS Pluripotent cell types (can give rise to cells Fibroblasts of the body) Blastocyst Reprogramming* stage embryo using 4 factors: iPS cells ES cells - Oct4 - Sox2 - Klf4 - cMyc 29  Design and Fabrication of 3D-printed scaffolds Step 1 Step 2 Benedetti V et al., EBioMedicine, 2018 30 Engineering human renal tubules from induced Pluripotent Stem Cells Ureteric Bud tubule Benedetti V et al., EBioMedicine, 2018 Engineered tubules can be used to study human UB developmental processes and defects 3D culture assay for studying branching morphogenesis iPSCs hiPSC-derived tubule Patient with Pax2 mutation and focal glomerulosclerosis E-cadherin DAPI Correction of the mutation Branching Tubule Engineering tubules from PKD patient for drug testing and discovery Engineering polycystic tubules Cyst-derived cells E-cadherin DAPI Benedetti V et al., EBioMedicine, 2018 The same treatments on different patients can lead to different results DON 10 DON 7 DON 6 PKD1 PKD1 PKD1/PKHD1 stop gain mutation splice site mutation missense mutation 34 Validation of therapeutic efficacy in vivo PCK rat Treatment 1 Image by Matteo Tironi 36 Modeling diabetic cardiomyopathy in iPSC-derived cardiac spheroids hiPSCs 2D Differentiation Spheroid formation 3D cultures injury Harvesting and seeding on microplates d0 d10 d14 DAPI Troponin F-actin DAPI Myosin-β F-actin 63x 63x zoom 63x Under submission 63x zoom Testing antifibrotic drugs in cardiac spheroids CTR GLUCOSE GLUCOSE+Treatment DAPI DAPI Fibronectin DAPI Fibronectin Fibronectin F- actin Under submission 38  Differentiation into various cell lineages and tissues iPSCs Nephrin+podocytes Collecting ducts Cardiomyocytes  Limitations: - anatomic malformations and insufficiencies - lack of certain organ-specific cell types (e.g. mesenchymal cells and neurons), immune cells and vasculature; - Immaturity (especially in iPSC-derived tissues) and high phenotypical variability - Off-target cell types Xinaris C, Curr Opin Organ Transplant, 2019 file:///Users/BG000045/Desktop/logo.svg Pagina 1 di 1 41  Sall1+/- X Sall1+/- corrected iPS Sall1-/- blastocyst 42 42 Testing contribution of human extended pluripotent stem cells to monkey embryos ex vivo Cell. 2021 Jun 24;184(13):3589. First human-monkey hybrid embryo (19 days after fertilisation) Tan, T. et al. Cell 184, 2020–2032 (2021) Peter Paul Rubens, 1636 46  Additional References Thorat, C. et al. What the Orphan Drug Act has done lately for children with rare diseases: a 10-year analysis. Pediatrics 129, 516–521 (2012). | Article | PubMed | Grieger, J.C. & Samulski, R.J. Adeno-associated virus vectorology, manufacturing, and clinical applications. Meth. Enzymol. 507, 229–254 (2012). | PubMed | http://stemcells.nih.gov/info/scireport/pages/chapter11.aspx http://www.explorestemcells.co.uk/StemCellsAndGeneTherap y.html  These slides belong to Christodoulos Xinaris and can be reproduced or used only with the author's permission. 48 Principles of Gene Therapy Prof Christodoulos Xinaris Nicosia, 2024 Spinal muscular atrophy (SMA) Spinal muscular atrophy is a rare genetic disease that causes motor neurons loss, and as a result muscle weakness and paralysis. The disease is caused by a genetic defect in the survival motor neuron (SMN) gene, which encodes the SMN protein essential for the survival of motor neurons. SMA is categorised into SMA type 1 and SMA type 2. The first form is a more severe variant, causing rapid motor neuron loss and resulting in death or permanent ventilation support requirement in more than 90% of patients if left untreated. SMA type 2 leads to death in more than 30% of patients by 25 years of age. Some common symptoms of SMA are muscle loss and weakening in infants after birth and difficulty in feeding and breathing.  Gene Therapy for Spinal Muscular Atrophy An adeno-associated virus (AAV) 9 was designed to deliver a copy of the SMN1 gene to encode for human SMN protein. It is a recombinant form of self-complementary AAV9, which contains human SMN protein-encoding transgene. The drug is available in single-use vials, each containing a nominal concentration of 2.0 × 1013 vector genomes (vg) per millilitre for intravenous infusion.  What is gene therapy? Gene therapy is the therapeutic delivery of nucleic acid polymers into a patient's cells as a “drug” to treat or stop a disease. 6 The most common approaches involve: Replacing a mutated gene that causes the disease with a healthy copy of the gene Inactivating a mutated gene Introducing a new gene into the cells 7  Gene therapy can be classified into two types Somatic cell gene therapy Germ line gene therapy – Therapeutic genes transferred – Therapeutic genes transferred into the somatic cells; e.g. into the germ cells. E.g. introduction of genes into Genes introduced into eggs bone marrow cells, blood and sperms. cells, skin cells etc. – It is inherited to later – It is not inherited to later generations. generations. – For safety, ethical and technical reasons, it is not being used at present (in humans). 8  Types of somatic gene therapy In vivo gene therapy Ex vivo gene therapy direct delivery of genes transfer of genes to into the cells of a particular cultured cells and tissue in the body. transplantation. 9 10  VECTORS IN GENE THERAPY To transfer the desired gene into a target cell, a carrier is required. Such vehicles of gene delivery are known as vectors. 2 main classes – Viral vectors – Non viral vectors 11  VIRAL VECTORS 1) RETROVIRUS VECTOR SYSTEM The recombinant retroviruses have the ability to integrate into the host genome in a stable fashion. Can carry a single stranded RNA of 3 – 9 kb (1 kilo base pairs = 1,000 bp) Long-lasting transgene expression Target: dividing cells 2) LENTIVIRUS Retrovirus family high-efficiency infection of dividing and non-dividing cells long-term stable expression of a transgene low immunogenicity 12  VIRAL VECTORS 2) ADENO VIRUS VECTOR SYSTEM Adeno virus with a ds DNA of 38-39 kb. Target- dividing and non dividing human cell. Transient transgene expression Highly immunogenic 13  VIRAL VECTORS 3) ADENO ASSOCIATED VIRUS VECTOR It is a single stranded, non pathogenic small DNA virus (8–10 kb). AAV enters host cell, becomes double stranded and gets integrated into chromosome. 4) HERPEX SIMPLEX VIRUS VECTOR Large ds DNA of 120-200 kb Viruses which have natural tendency to infect a particular type of cell: Neural cells. 14  NON VIRAL VECTOR SYSTEM 1. PURE DNA CONSTRUCT Direct introduction of pure DNA construct into target tissue. Low transfection efficiency (endocytosis). Consequently, large quantities of DNA have to be injected periodically. 2. HUMAN ARTIFICIAL CHROMOSOME It can carry a large quantity of DNA, with one or more therapeutic genes with regulatory elements. 15  NON VIRAL VECTOR SYSTEMS Chemical carriers 1. LIPOPLEXES Cationic lipid DNA complexes; DNA construct surrounded by artificial lipid layer. Most of it gets degraded by lysosomes. Immunogenicity. 2. DNA MOLECULAR CONJUGATES Commonly used synthetic conjugate is poly- L- lysine bound to specific target cell receptor. Therapeutic DNA is then made to combine with the conjugate to form a complex. It avoids lysosomal breakdown of DNA. 16  PHYSICAL METHODS OF GENE DELIVERY Needle Genetic material is administered through a needle into tissue or systemic injection. Low efficiency due to rapid degradation. Gene Gun – Ballistic DNA Employs a high-pressure delivery system to shoot tissue with gold or tungsten particles that are coated with DNA. Electroporation The application of an electric field greater than the membrane capacitance which results in a membrane breakdown. 17  EX VIVO GENE THERAPY Isolate cells with genetic defect from a patient Grow the cells in culture Introduce the therapeutic genes/Modify genome Select and expand genetically corrected/modified cells. Transplant the corrected/modified cells to the patient. 18  EXAMPLE OF EX VIVO GENE THERAPY 1st gene therapy – to correct deficiency of enzyme, Adenosine deaminase (ADA)*, Blaese et al., RM et al. (1995). Performed on a 4yr old girl Ashanthi DeSilva. She was suffering from ADA-SCID (Severe Combined Immunodeficiency). ADA-SCID results from an adenosine deaminase (ADA) deficiency, which leads to abnormal T, B, and natural killer cell development; the result is immune deficiency. The condition is fatal within the first year of life due to infection. *, ADA catalyzes deanimation of adenosine to inosine and deoxyadenosine to deoxyinosine 19 Hematopoietic stem cells Retrovirus infects HSCs and transfers the ADA gene 20  Ex Vivo Delivery of Gene Therapy for beta Thalassemia Ex Vivo Delivery of Gene Therapy. KA High, MG Roncarolo. N Engl J Med 2019;381:455-464. Chimeric antigen receptors (CARs) T-Cell Therapy: Engineering Patients’ Immune Cells to Treat Their Cancer http://bloodjournal.hematologylibrary.org/content/118/18/4761.full Gene therapy to fight a blood cancer succeeds in a study perfomed by Kite Pharma An experimental gene therapy that turns a patient's own blood cells into cancer killers worked in a major study, with more than one-third of very sick lymphoma patients showing no sign of disease six months after a single treatment. The therapy is not without risk. Three of the 101 patients in the study died of These scans show a 62-year-old man with non-Hodgkin causes unrelated to worsening lymphoma, at left in Dec. 2015, and three months after of their cancer, and two of treatment with Kite Pharma's CAR-T cell gene therapy those deaths were deemed due to the treatment. (February 28, 2017)  IN VIVO GENE THERAPY Direct delivery of therapeutic gene into target cell in patient’s body. Carried out by viral or non viral vector systems. It can be the only possible option in patients where individual cells cannot be cultured in vitro in sufficient numbers and/or re-implanted in patients effectively. (e.g. brain cells). 24  EXAMPLE OF IN VIVO GENE THERAPY – In patients with cystic fibrosis, a protein called cystic fibrosis transmembrane regulator (CFTR) is absent due to a gene defect. – In the absence of CFTR chloride ions concentrate within the cells and it draws water from the environment. – This leads to the accumulation of sticky mucous in respiratory tract and lungs. – Treated in vivo by liposome-based CFTR gene transfer therapy 25 Patient 26 Normal CFTR gene can be delivered via inhalation of nebulised liposomes mixed with plasmid DNA encoding the protein. The liposomes enhance transport of the CFTR gene into host airway cells via endocytosis or direct fusion with the cell membrane. The plasmid then passes into the cell nucleus where the normal CFTR is transcribed, enabling the cell to make CFTR proteins.  * “Patients who received the gene therapy showed a significant, if modest, benefit in tests of lung function compared with the placebo group and there were no safety concerns. Reference Alton et al. Lancet Respiratory Medi