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Knowledge and Quality of Knowledge and Quality of Life with Particular Life with Particular
Reference to the Ageing Reference to the Ageing PopulationPopulation
George K RaddaGeorge K RaddaUniversity Laboratory of University Laboratory of Physiology and Cardiac Physiology and Cardiac
ScienceScienceUniversity of Oxford UKUniversity of Oxford UK
The 20th centuryThe 20th century saw a saw a dramatic increase in life dramatic increase in life expectancy from 47y in 1900 to expectancy from 47y in 1900 to around 80y todayaround 80y today
Most of this gain can be Most of this gain can be attributed to improved social attributed to improved social conditions and success in conditions and success in preventing and treating major preventing and treating major infectious diseases (eg TB)infectious diseases (eg TB)
Further gains will depend on Further gains will depend on delivering new healthcare delivering new healthcare advancesadvances
0
10
20
30
40
50
60
70
80
90
1900 1950 2000
Age
Life ExpectancyLife Expectancy
By 2030 the UK will By 2030 the UK will have 19m people over have 19m people over 60 who will out number 60 who will out number younger adults by one younger adults by one fifthfifth
FORESIGHT REPORT MAY 2000
The Global Age ShiftThe Global Age Shift
10
11
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15
16
17
18
19
20
2000 2020 2030
Po
pu
lati
on
(m
illi
on
s)
20-39
60 andover
Improve Quality of Life in Improve Quality of Life in AgeingAgeing
Challenges
• to promote healthy ageing
• to improve the management of age-related illnesses
• to encourage leading edge, multidisciplinary research that will inform these aims
Babraham Institute - Laboratory of Cognitive & Developmental Neuroscience
Genes, Brain and Ageing - Mouse to Man
• What are the key genes in ageing?
• How do they relate to ageing effects on brain and cognitive function?
• Can we use the information from functional genomics to delay or reverse the effects of ageing?
Major Health Major Health ChallengesChallenges
AgeingAgeing Mental healthMental health Infectious diseasesInfectious diseases Obesity/NutritionObesity/Nutrition Heart diseaseHeart disease CancerCancer
Mental HealthMental Health DementiaDementia
200 new cases/day in UK;200 new cases/day in UK; 1.5 million anticipated by 1.5 million anticipated by
20302030 No drug slows the diseaseNo drug slows the disease Prevention desirablePrevention desirable
Alzheimer’sAlzheimer’s 5% of cases genetically 5% of cases genetically
determineddetermined 95% not truly familial95% not truly familial Many modifiable risk Many modifiable risk
factors are shared with factors are shared with vascular heart disease and vascular heart disease and strokestroke
Annual age and gender specific incidence rates of dementia per 100 person years of risk
0
2
4
6
8
10
12
14
16
18
65-69 70-74 75-79 80-84 85-89 90-94 95+
Age Group
Inci
den
ce r
ate Women
Men
• Mental ill health and neurodegenerative diseases cost the UK economy £6.3bn each year
• Costs will increase still further as the population ages
• Current treatments contain symptoms, but do not effect cure
Multidisciplinary Research and
Neurodegenerative Disease
Understanding and Treating Brain Disease
e.g. bipolar disorder
Individual
Cell
Brain
Genome Environment
Population
Families
cognitive behavioural therapy
couple therapy
e.g. depression
e.g. risk behaviour
e.g. Huntington’s
L-Dopa, stem cells
e.g. Parkinson’s public health
antipsychotics e.g. schizophrenia
gene therapy parenting
e.g. antisocial behaviour
Magnetic Resonance Imaging
Safe and non-invasive
Detects changes in normal, diseased or injured patients
Can identify those at risk of disease before symptoms
develop
Selective degeneration of a subpopulation of dopaminergic (DA) midbrain neurons
200 µm
DA neurons are essential for voluntary movement control.
Dopaminergic midbrain neurons in mouse brain slice (tyrosine hydroxylase immunostain).
Selective survival of a subset of dopaminergic neurons in a mouse model of Parkinson’s disease.
Define molecules governing the activity of living DA neurons (brain-slice patch-clamp techniques).
Birgit Liss & Jochen Roeper, MRC Anatomical Neuropharmacology Unit
cortex
Pathophysiology of Parkinson’s Disease
Functional Genomics with Single-cell Resolution
Genes responsible for selective survival of individual dopaminergic neurons provide novel therapeutic targets for Parkinson‘s disease
B: laser-based microdissection (fixed neurons)
laser PCR-tube
single cell
A: cytoplasm harvesting via patch-pipette (living neurons)
PCR-tube
DA neuron 1 DA neuron 2
1. Isolation of mRNA from individualvulnerable and resistant DA neurons
2. Linear mRNA amplification, synthesis of labelled cDNA
3. DNA-array based comparison of single-cell geneexpression profiles
Birgit Liss & Jochen Roeper, MRC Anatomical Neuropharmacology Unit, Oxford
oror
cDNA Hybridisation with DNA array
• Parkinson’s Disease is controlled by drugs but these become less effective over time and the period of relief they offer also decreases
• Surgery provides longer periods of quality living as opposed to the 1-2h that drugs offer, but the long term effects on quality of life of the patient and carer need to be evaluated
• The trial is being led from the QE hospital in Birmingham
The MRC and Parkinson’s Disease Society have recently funded a £1.25m trial to test the long-term effectiveness of surgery versus drug treatment for Parkinson’s Disease
Treating Parkinson’s Disease
UK NICHEUK NICHE Pioneering UK research by Martin EvansPioneering UK research by Martin Evans
TheThe UK recently became the first country in UK recently became the first country in the world to approve properly conducted the world to approve properly conducted research on the use of embryonic stem cellsresearch on the use of embryonic stem cells
This provides a window of opportunity and This provides a window of opportunity and indeed an obligation to grasp the potential indeed an obligation to grasp the potential
of stem cell based therapiesof stem cell based therapies
Embryonic Stem Cells
Derivation and in vitro differentiation of Embryonic Stem (ES) cells
Blastocyst ES cells
Embryoid bodies ES cell derived neurons
Feeders
+ LIF
Suspension
- LIF
+/-RA, +FGF/ -FGF
+/-G418 selection for Sox2geo
Stem Cells
R Lovell-BadgeNIMR
International
Agencies
ResearchCouncils
MRC BBSRC CCLRCEPSRCESRC
Government
STEM CELLS
DonorsPatientsCliniciansScientists
DRIVERS
• Serious diseases
• UK legislation
• Scientific advances
• Opportunity
Consumersand Focus
Groups
GovernmentDepartment
s& Ministers
Regulatory
AgenciesHFEA MHRA DH
Industry
StakeholderStakeholderss
Charities
AS BHFCRUKDUK JDRFPDSWT
Forum of 13
Large pharma
and SME’s
STEM CELLS: SHAPING THE FUTURESTEM CELLS: SHAPING THE FUTURE
Funders Co-ordinating CommitteeFunders Co-ordinating Committee
STEM CELLS: SHAPING THE FUTURESTEM CELLS: SHAPING THE FUTURE
Res. CouncilsRes. Councils: BBSRC, CCLRC: BBSRC, CCLRC, , EPSRC, ESRC, MRCEPSRC, ESRC, MRC Res. CharitiesRes. Charities: AS, BHF: AS, BHF, , CRUK, DUK, JDRF, PDS,CRUK, DUK, JDRF, PDS, WTWTReg. AgenciesReg. Agencies: DH, HFEA, MHRA: DH, HFEA, MHRA
15 Agencies15 Agencies
Communications CoalitionCommunications Coalition
Annual ConferenceAnnual Conference
Career Development FellowshipsCareer Development Fellowships
Training CourseTraining Course
Research Funding (JDRF/MRC MoU)Research Funding (JDRF/MRC MoU)
National FacilitiesNational Facilities
UK Stem Cell BankUK Stem Cell Bank
-- established at NIBSC with funding from MRC & BBSRC established at NIBSC with funding from MRC & BBSRC
- - local management committee established local management committee established
-- one year devoted to recruitment/refurbishment one year devoted to recruitment/refurbishment
-- clinical grade facilities installed; MHRA accreditation clinical grade facilities installed; MHRA accreditation required -- research grade facilities completed research grade facilities completed
-- ready to accession research grade lines ready to accession research grade lines
-- applications to bank research grade lines currently under applications to bank research grade lines currently under
review by Steering Committeereview by Steering Committee
STEM CELLS: SHAPING THE FUTURESTEM CELLS: SHAPING THE FUTURE
Codes of PracticeCodes of Practice
STEM CELLS: SHAPING THE FUTURESTEM CELLS: SHAPING THE FUTURE
Draft Code of Practice for the UK Stem Cell Bank
Draft Code of Practice for the Use of Human Stem Cell Lines
Currently on the MRC web site for consultation
www.mrc.ac.uk
Shortly to be on the MRC web site for consultation
Communications Communications
UK Funders Communications CoalitionUK Funders Communications Coalition
-- briefing pack on stem cells briefing pack on stem cells
-- MORI poll of public attitudes MORI poll of public attitudes
Corporate Communication ActivitiesCorporate Communication Activities
-- UK and EU parliamentary briefings UK and EU parliamentary briefings
-- MRC attitudinal survey of IVF and other donors MRC attitudinal survey of IVF and other donors
ConsumersConsumers
-- Consumer Liaison Groups review guidance documents Consumer Liaison Groups review guidance documents
-- Steering Committee includes two lay members Steering Committee includes two lay members
STEM CELLS: SHAPING THE FUTURESTEM CELLS: SHAPING THE FUTURE
EuropeEurope European CommissionEuropean Commission
-- FP6: €17.5b total FP6: €17.5b total - - €€ 2.2b for genomics & biotechnology for health2.2b for genomics & biotechnology for health - - stem cell research a priority stem cell research a priority European ParliamentEuropean Parliament
-- EU EU Tissues and Cells Directive (April 2004)Tissues and Cells Directive (April 2004) -- provides a regulatory framework provides a regulatory framework United NationsUnited Nations -- cloning debate cloning debate
STEM CELLS: SHAPING THE FUTURESTEM CELLS: SHAPING THE FUTURE
International Stem Cell ForumInternational Stem Cell Forum
13 agencies from 12 countries13 agencies from 12 countries
-- meets twice per year meets twice per year
-- portfolio sharing portfolio sharing
-- policy discussions policy discussions
-- joint funding initiatives joint funding initiatives
-- collaborative agreement collaborative agreement
STEM CELLS: SHAPING THE FUTURESTEM CELLS: SHAPING THE FUTURE
AUSTRALIA, CANADA, FINLAND, FRANCE, GERMANY, ISRAEL, JDRF, AUSTRALIA, CANADA, FINLAND, FRANCE, GERMANY, ISRAEL, JDRF, JAPAN, SINGAPORE, SWEDEN, THE NETHERLANDS, UK, USAJAPAN, SINGAPORE, SWEDEN, THE NETHERLANDS, UK, USA
International Stem Cell ForumInternational Stem Cell Forum
Joint Initiatives Joint Initiatives
-- characterisation of stem cell lines (UK lead) characterisation of stem cell lines (UK lead)
-- ethics landscape (Canada lead) ethics landscape (Canada lead)
-- IPR Landscape (Australia lead) IPR Landscape (Australia lead)
-- web database of international research and web database of international research and
training opportunities (UK lead)training opportunities (UK lead)
STEM CELLS: SHAPING THE FUTURESTEM CELLS: SHAPING THE FUTURE
How to extend the active participation of older people How to extend the active participation of older people
with dementia in societywith dementia in society
• Investigate cognition of the external Investigate cognition of the external environment by people with dementiaenvironment by people with dementia
Identify design factors which influence the Identify design factors which influence the
ability of older people with dementia to ability of older people with dementia to
negotiate their external environmentnegotiate their external environment
Offer guidance to designers on the criteria Offer guidance to designers on the criteria
to consider in developing urban areas that are to consider in developing urban areas that are
accessible to those with dementia accessible to those with dementia
Find ways to promote communication for Find ways to promote communication for
elderly people with dementia using elderly people with dementia using
multimedia techniquesmultimedia techniques
Dementia & Quality of Dementia & Quality of LifeLife
Locator – A device to help people locate lost items e.g. purse, glasses
Bath monitor – A monitor to help stop people filling the bath to overflowing whilst still allowing full control of the taps
Cooker monitor – A device that monitors the cooker and acts to prevent dangerous situation occurring
Night-time guidance – Guides the resident of a house to the toilet with gentle lighting
Communications – Research into reliable and accurate means of communication with people with dementia
Gloucester Smart House
Major Health Major Health ChallengesChallenges
AgeingAgeing Mental healthMental health Infectious diseasesInfectious diseases Obesity/DiabetesObesity/Diabetes Heart diseaseHeart disease CancerCancer
Obesity Rates: Obesity Rates: Current and ProjectedCurrent and Projected
00
1010
2020
3030
4040
5050
1960196019701970
1980198019901990
2000200020102010
EnglandEngland
Population Population percentage with percentage with BMI BMI >> 30kg/m 30kg/m22
0%
5%
10%
15%
20%
25%
6yrs 8yrs 10yrs 12yrs 14yrs
AdultsAdults
ChildrenChildren
0
5
10
15
20
25
30
Peo
ple
(m
illi
on
s)
1960
1970
1980
1990
2000
2010
2020
2030
2040
2050
Diagnosed cases
Projected diagnosed cases
Prevalence of Diagnosed Diabetes in the United States
Diagnosed (1960-1998) and Projected Diagnosed (2000-2050) Cases
Data for 1960-1998 from the National Health Interview Survey, NCHS, CDC.
Projected data for 2000-2050 from Boyle JP, et al, Diabetes Care 24:1936-40, 2001.
Year
QuickTime™ and aCinepak decompressor
are needed to see this picture.
Heart DiseaseHeart Disease
0
100
200
300
400
500
600
0 7 14 21 28 35
Days
Cum
ulat
ive
num
ber o
f vas
cula
r dea
ths
Placebo and tablets
Aspirin
Streptokinase
Streptokinase plusaspirin
Courtesy of Stefan Neubahrer
After allowance for non-compliance, 40mg daily After allowance for non-compliance, 40mg daily simvastatin safely reduces the risk of heart attack, simvastatin safely reduces the risk of heart attack, of stroke, and of revascularisation by at least one-of stroke, and of revascularisation by at least one-third third
5 years of statin treatment typically prevents these 5 years of statin treatment typically prevents these “major vascular events” in about:“major vascular events” in about:
100 of every 1000 with previous MI100 of every 1000 with previous MI 8080 " " " " other CHD other CHD 70 70 " " " diabetes (age 40+) " diabetes (age 40+) 70 70 " " " previous stroke " previous stroke 70 70 " " " other PVD " other PVD
irrespective of cholesterol level (or age, or sex, or other treatments)
Heart Protection Study
Clinical Trials Service Unit,Oxford (R Collins)Supported by MRC, BHF & Merck & Roche Vitamins
Genetic DiversityGenetic Diversity The current world population of 6 The current world population of 6
billion descends from a few tens of billion descends from a few tens of thousands of progenitors who thousands of progenitors who inhabited Africa some 200,000 years inhabited Africa some 200,000 years agoago
Small, isolated populationsSmall, isolated populations (eg in (eg in remote parts of Sardinia) interbreed remote parts of Sardinia) interbreed and maintain only a limited degree and maintain only a limited degree of genetic variationof genetic variation
In contrast, In contrast, large populationslarge populations (eg in (eg in the UK) show much greater variationthe UK) show much greater variation
This offers 2 routes into studying This offers 2 routes into studying genetic diversitygenetic diversity and mapping and mapping common diseases like heart disease common diseases like heart disease and dementiaand dementia
BioBank UK
Long term prospective research Long term prospective research frameworkframework
Relative contributions of genotype, Relative contributions of genotype, environmental exposure and chance to environmental exposure and chance to risk of common diseasesrisk of common diseases Cohort of 500,000 adults (aged 45 – Cohort of 500,000 adults (aged 45 –
69)69) Nested case control studiesNested case control studies Monitoring for incident diseaseMonitoring for incident disease
Central repository of biological samples Central repository of biological samples and linked database and linked database GenotypeGenotype Other biological assaysOther biological assays Exposure dataExposure data