Human tissue use
December 2007
Evolving attitudes towards
medical uses of the body,
organs and tissue
D Sean O’Briain
December 2007
Lecture outline
•
•
•
•
•
•
•
•
Development of medicine
Incentive to use human tissue for research and diagnosis
Dissection; anatomy; the autopsy
Transplantation
Use of tissue in diagnosis or research
Implication of using tissue
Property/ownership
Law and guidelines
Lecture outline
• Incentive to use human tissue for research
and diagnosis
• Dissection; anatomy; the autopsy
• Use of tissue in diagnosis
• Transplantation
• Use of tissue removed surgically or by
biopsy
• Use of tissue: ownership, permissions
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Development of Medicine:
diagnosis I
• Early theories: myths, magic, pragmatism
and religion
• Galen: The 4 temperaments
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.
– Eucrasia (balance) and dyscrasia
– Influenced by seasons, food
– Balance restored by purges, bleeding, emetics
Blood
Black bile
Yellow bile
Phlegm
Sanguine
(hopeful)
Melancholic
(sad)
Choleric
(angry)
Phlegmatic
(calm, dull)
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
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)
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
The Nuremberg Code (1947)
10 points
• 1 consent
• 2, 3 significant question, scientifically valid
• 4, 5, 6, 7 minimise risk, avoid suffering,
injury, death
• 8 high scientific standards
• 9.10 allow withdrawal/termination of study
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 guilty; 7
executed
• The Nuremberg code focuses on the human rights of the
research subjects
• Helsinki focuses on the obligation of physicianinvestigators to research subjects
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)
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
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
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
Human dissection and the
autopsy - regulations
• 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
The autopsy - procedure
•
Confirm permission
–
•
•
•
Review history
External examination
Internal examination
–
–
–
–
–
•
•
•
(consent from next-of-kin, direction from coroner)
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
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 cause of death. Inform relatives if organs retained
– consent required for research or teaching use of tissues or organs.
– Options for disposal of tissue provided to relatives
•
Hospital (consented) autopsy
– Informed consent; provide details of what autopsy involves
– Separate consent for retention of tissues and organs and for their use for teaching
and research
– Options for disposal of tissue provided to relatives
Mean Rates of Graft and Patient Survival for Transplantations in the United States from 1993
through 2002
Sayegh M and Carpenter C. N Engl J Med 2004;351:2761-2766
How many people need organs?
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
Weekly updates of this information are available at www.unos.org,
under "Data/Critical Data.” (united network for organ sharing)
All
organs
kidney
liver
pancreas
Kidney/
pancreas
heart
lung
Heart/
lung
intestine
100930
73019
17526
1785
2466
2855
2881
143
255
USA figures 2005; organ procurement and transplantation network
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.
Thesuccessful
First Successful
The first
kidney Kidney Transplantation, by Joel Babb, 1996
transplantation, (painting by Joel Babb, 1996)
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
Morris
N Engl
J Med 2004;351:2678-2680
versus utility
in P.the
allocation
of this increasingly valuable resource; only 50% consent for
cadaveric donors; increasing use of living donors
Morris P. NEJM 2004;351:2678-2680
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)
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
Do you own your body and tissues?
Uses of tissue
• Diagnosis
– Clinical pathology, cytopathology, histopathology, molecular biology
• Research
• Teaching
• Transplantation
– from living
– From dead: cornea, skin, bone chips
•
•
•
•
•
Blood donation: whole blood, components, factors
Pharmaceutical products: Pituitary extract HGH
Placenta (cosmetics?)
Hair, teeth
Display, entertainment
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
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
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
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
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
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
• Outcome:
– Financial: difficulty with life assurance, mortgages, loans
– Personal: distress, implications for partner, family
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.
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
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
Property rights
• Bundle of rights
– exclusive use, donation, sale, alteration,
destruction
• Imply right to sell and inherit tissue
• but governments can limit property rights
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
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