1. Human tissue use December 2008

2. Evolving attitudes towards medical uses of the body, organs and tissue D Sean O’Briain December 2008

3. Lecture outline Development of medicine Incentive to use human tissue for research and diagnosis Dissection; anatomy; the autopsy Use of tissue for therapy Transplantation Use of tissue in diagnosis or research Implication of using tissue Property/ownership Law and guidelines

4. Development of Medicine: diagnosis I Early theories: myths, magic, pragmatism and religion Galen: The 4 temperaments –Eucrasia (balance) and dyscrasia –Influenced by seasons, food –Balance restored by purges, bleeding, emetics Claudius Galenus of Pergamum (129-200 AD), better known in English as Galen, was an ancient Greek physician. Galen's views dominated European medicine for over a thousand years. BloodBlack bileYellow bilePhlegm Sanguine (hopeful) Melancholic (sad) Choleric (angry) Phlegmatic (calm, dull)

5. Development of Medicine: diagnosis II From Middle ages: Observation-based –dissection and autopsies –Clinical signs 19th century: Test-based, –chemistry, galvanism, microscopy, bacterial culture, X-ray 20th century –Diagnostic imaging –Pathology: microbiology, clinical chemistry, haematology, immunology, cytopathology, histopathology, molecular biology

6. The research imperative Inquiry a human characteristic Experience has show that inquiry/research has developed better therapy/better prevention Is it unethical not to advance research? Research must be ethical; respect for persons (Declaration of Helsinki)

7. Hippocratic Oath I swear by Apollo… Duty to teacher (and sons) Therapy and consultations –For the benefit of patients –No hurt, wrong, deadly drug, abortion, wrongdoing, corruption, seduction Confidentiality Pure and holy will I keep my life and art –If I fulfill this oath…be it mine to enjoy Life and Art alike, with good repute among men –If I transgress…may the reverse be my lot

8. Evolution of research ethics Hippocratic oath: the patient is silent and dutifully obedient to the beneficient—and trusted—physician Nuremberg (1947): The doctors’ trial: 16/23 of Nazi doctors guilty; 7 executed The Nuremberg code focuses on the human rights of the research subjects Declaration of Helsinki focuses on the obligation of physician- investigators to research subjects

9. The Nuremberg Code (1947) (medical research) 10 points 1 consent 2, 3 research must pose a significant question, scientifically valid 4, 5, 6, 7 minimise risk, avoid suffering, injury, death to the research subject 8 high scientific standards 9.10 allow withdrawal by subject/termination of study

10. Declaration of Helsinki 1964 (last revised Edinburgh 2000) Introduction (9 points) –Statement of ethical principals, safeguarding patient and peoples health –Progress is based on research but this involves risk –Purpose of research –Patient’s wellbeing takes precedence Basic principles (17 paragraphs) Research combined with care (5 paragraphs)

11. Human dissection and the autopsy - 1 Cultural and religious attitudes to the dead –Respect –After-life, resurrection –burial, cremation, embalming, mummification –Development of custom, ritual, taboos, regulations, laws Quest for knowledge/understanding vs custom: –human dissection forbidden –Human dissections allowed in middle ages Anatomy becomes requirement for surgery –Military surgeons required for Napoleonic wars Supply of cadavers –adequate in European law, scarce in British law –Grave-robbing (sack’em ups), Burke and Hare –Anatomy acts 1830s-60s

12. Human dissection and the autopsy - 2 Development of the autopsy, 1800s Germanic pathology; Berlin and Vienna Development of specialty of pathology (morbid anatomy, anatomical pathology) Hospital autopsy Forensic autopsy

13. Authorisation Informed consent (developed in clinical medicine) implies telling the patient all the risks and benefits before allowing the patient to consent or refuse the procedure For autopsy, information on autopsy is distressing at the time of bereavement Authorisation: release of information to the degree required by relatives who can authorise the procedure when satisfied they have enough information (Madden 2006)

14. Human dissection and the autopsy - regulations Common Law: No property in a corpse Regulations –Anatomy Acts (1800s), Coroner’s Acts, Human Tissue Acts, Coroner’s Rules (where applicable) –Focus on concept of invasion and possession of body –No or indirect consideration of the details of examination (retention of tissues and organs, use of retained material for diagnosis, teaching or research and ultimate archiving or disposal) Coroner (forensic, medicolegal) autopsy –Direction from coroner –Examination to establish cause of death Hospital autopsy –Consent (absence of objection); informed consent, valid consent, authorisation

15. The autopsy - procedure Confirm permission – (authorisation/consent from next-of-kin, direction from coroner) Review history External examination Internal examination –Incisions body and scalp –Remove all organs –Dissect/slice – Sample for histology, toxicology, microbiology, molecular biology (neonate), other –Retain organs appropriately Reconstruct body, release to relatives Review test results, issue report Archive, store or dispose of specimens as appropriate

16. Autopsy controversy Parents of dead children learned that organs had been retained following autopsy, late 1990s Public controversy leading to –New guidelines (Faculty of Pathology, RCPI, 2000) –inquiries (Dunne inquiry, 2000-2005, completed by Madden 2006) Coroner autopsy: –no consent required for determining cause of death. Inform relatives if organs retained –Consent/authorisation is required for research or teaching use of tissues or organs. –Options for disposal of tissue provided to relatives Hospital (authorised/consented) autopsy –Authorisation/informed consent; provide details of what autopsy involves –Separate authorisation/consent for retention of tissues and organs and for their use for teaching and research –Options for disposal of tissue provided to relatives

17. Uses of tissue Therapy –Blood donation: whole blood, components, factors –Pharmaceutical products: Pituitary extract HGH Transplantation –from living –From dead: cornea, skin, bone chips Diagnosis –Clinical pathology, cytopathology, histopathology, molecular biology Research Teaching Placenta (cosmetics?) Hair, teeth Display, entertainment

18. Use of tissue for therapy Blood transfusion –Blood products; immunoglobulin, clotting factors, white cells, platelets Transplantation Pituitary glands –harvested at autopsy –only source of HGH (short stature children) –later problems: CJD, absence of consent? Payments made by pharmaceutical companies (for work done or for organs?)

19. Sayegh M and Carpenter C. N Engl J Med 2004;351:2761-2766 Mean Rates of Graft and Patient Survival for Transplantations in the United States from 1993 through 2002

20. How many people need organs? Weekly updates of this information are available at www.unos.org, under "Data/Critical Data.” (united network for organ sharing) All organs kidneyliverpancreasKidney/ pancreas heartlungHeart/ lung intestine 10093073019175261785246628552881143255 USA figures 2005; organ procurement and transplantation network

21. A potential organ donor is defined by the presence of either brain death or a catastrophic injury to the brain with the physician's and the family's intent to withdraw life support. The diagnosis of brain death requires the absence of brain-stem reflexes, motor responses, and respiratory drive in a normothermic, non-drugged, comatose patient with a known irreversible brain lesion and no contributing metabolic derangements.

22. Morris P. N Engl J Med 2004;351:2678-2680 The First Successful Kidney Transplantation, by Joel Babb, 1996 The first successful kidney transplantation, (painting by Joel Babb, 1996) Morris P. NEJM 2004;351:2678-2680 History of Transplantation 1902: animal experiments 1954: Identical twin kidneys (Joseph Murray, Nobel prize) 1950s Total body irradiation 1960s: 6MP, azothiaprine, (Nobel Prize) steroids: high mortality (40% 1 year) 1980: cyclosporine, low dose steroids 1990s other immunosuppressive agents; 90% 1-year survival Current problems  Chronic graft loss (acute and chronic rejection)  Immunosuppressive complications (nephrotoxicity, hypertension, diabetes)  Infections and cancer (cardiovascular disease)  Supply and demand ethical problems (5-15% annual mortality on waiting list): equity versus utility in the allocation of this increasingly valuable resource; only 50% consent for cadaveric donors; increasing use of living donors

23. Ethics of organ donation by living donors Half kidney donors are living (also can donate lobe of liver or lung) Directed donation to relative or friend: –risk: coercion; dangerous sacrifice (potential death or injury) Non-directed: altuism, requires scrutiny (Zell Kravinsky) Directed donation to stranger; –response to advert, to best story or publicity rather than most need; –unfair and threat to gift of live vs commodity to race –religion ethnic group; white or Jewish recipient –Potential for buying and selling (prohibited by law) –Matchingdonors.com (increased visibility)

24. Transplantation Solid organs: kidney, heart, liver, etc –No Irish legislation, guidelines from Medical Council Donor –Supply: scarcity –Choice of donors, consent –Living, question of payment –Dead, question of definition of death Safeguard: specific tests ereformed by independent doctors Choice of recipients Bone marrow: autograft, allograft –Live donor, Match required, related or unrelated, umbilical cord, stem cells

25. Do you own your body and tissues?

26. Clinical Pathology clinical chemistry, microbiology, haematology Samples (blood, urine, fluids) taken and analysed for diagnosis –(eg chemistry, endocrinology, serology, haematology, immunology, flow cytometry) Diagnosis –narrow definition or does it include use for quality assurance, audit, training of diagnosticians? Report issued Surplus stored in freezer for days/weeks/months according to guidelines, practice or protocols Disposal –Dignified, human biological waste protocol –stored in separate containers/bags, incinerated or deep burial –DOHC contract to export all Irish hospital biological waste to Belgium

27. Cytopathology Scrapings, smears, fluids, fine needle aspirates Received –A) fixed to slide; stained (papanicolau (pap) or other stains) and examined –B) as liquid: centrifuged or smeared on slide, stained, examined Slides stored for years according to protocols, may be reexamined years later Surplus liquid disposed as biological waste

28. Histopathology Tissue (biopsy, excision, resection) Sent fresh (must be processed rapidly) Sent in a preservative (also called fixative, usually formalin) –Accessioned, identified, described –Processed to replace tissue water by wax (paraffin wax block produced) –Sections one cell thick cut and stained (glass slides) –Slides examined, report issued –Slides and blocks stored for years, according to protocols, as part to medical record. –Can be retested with dyes, antibodies, molecular techniques at any time in the future

29. Molecular biology Blood, tissue, cells: any biological specimen containing DNA or RNA May be fresh, frozen, on slides, in paraffin Extract DNA, analyse by amplification techniques (such as polymerase chain reaction, PCR) Human genome sequenced: potential to analyse any part of the sequence. Material, or DNA may be stored for years, and then analysed with current for newly developed techniques

30. Diagnosis and research Diagnosis: clinical material, taken for diagnosis, consent usually implied in consent to be treated in hospital and for specific operations Specific consent sometimes advised; eg HIV, genes (BRACA) Research –Requires specific informed consent including purpose, type of research, any risks or advantages to the subject Approval by research ethics committee (institutional review board) Difficulties: –biobanks: provision of lasting consent –archives: access to huge resource, contact of subject difficult »anonymisation, waiver of consent requirement

31. Implications of laboratory biological information Appropriate implication: –Diagnosis; diagnosis, choice of therapy, prognosis –Research; new information from consented approved research projects Hazard: –failure of confidentiality –testing for unrelated substances Infections (eg HIV, Hepatitis) Germ line gene abnormalities (eg BRACA, Cystic fibrosis) Paternity –The results may be unwelcome to the subject –Is there a requirement to inform the subject? –Who informs the subject? Outcome: –Financial: difficulty with life assurance, mortgages, loans –Personal: distress, implications for partner, family –Distress for researcher: what information should or must be given to subject

32. Moore v Regents of the University of California John Moore had a splenectomy for hairy cell leukaemia (variant) His physician, Dr David Golde used Moore’s tumour cells to develop a cell line which became commercially lucrative. Moore sued. The court ruled on two issues: Informed consent: Moore won. His physician should have given him the information a ‘reasonable patient’ would expect to know: ‘the extent of his research and his economic interest in Moore’s cells’ Property and ownership: Moore failed to prove an ownership interest in the cells and thus failed to get a share of the profits from the ‘Mo’ cell line.

33. No property in a corpse I Slavery recognised property rights in a human body Slavery was abolished ‘No property’ rule long accepted in common law (although of dubious origin) Basis for Moore v Regents Many exceptions

34. No property in a corpse II Exceptions Doodeward v Spence (1908) –2-headed fetus preserved, sold, later seized by police. Held that work and skill gave it property rights. R v Kelly. –Body parts taken from Royal College of Surgeons to make bronze sculptures. Conviction for stealing. Museum exhibits; medical use of cadavers Quasi property rights in corneas, sperm, fetus, hair, urine, bone marrow Grave-robbing misdemeanor, wrongful autopsy tort

35. Property rights Bundle of rights –exclusive use, donation, sale, alteration, destruction Imply right to sell and inherit tissue but governments can limit property rights

36. Trusteeship of the body Extensive and exclusive rights to body while alive Body is part of common heritage of humanity Use for common good (unless interferes with one liberties, privacy, social interests) Public right to excised tissue (but can’t remove it; battery, injury, deprivation of liberty) Presumed consent for tissue and organ transplantation

37. Current laws and guidelines No Irish Human Tissue Act European blood directive and European tissue directive Guildelines, Medical Council, Faculty of Pathology Coroners Act and coroners rules Anatomy Act Common law