Knowledge and Quality of Life with Particular Reference to the Ageing Population George K Radda...

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

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10

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60

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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

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2000 2020 2030

Po

pu

lati

on

(m

illi

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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

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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

M Rossor & N Fox, Institute of Neurology

expandingcontracting

M Rossor & N Fox, Institute of Neurology

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


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


Codes of PracticeCodes of Practice


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


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


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


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)


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

Gloucester Smart House

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

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1010

2020

3030

4040

5050

1960196019701970

1980198019901990

2000200020102010

EnglandEngland

Population Population percentage with percentage with BMI BMI >> 30kg/m 30kg/m22

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10%

15%

20%

25%

6yrs 8yrs 10yrs 12yrs 14yrs

AdultsAdults

ChildrenChildren

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1960

1970

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2000

2010

2020

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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

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200

300

400

500

600

0 7 14 21 28 35

Days

Cum

ulat

ive

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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

The UK Biobank

Medical Research CouncilWellcome TrustDepartment of Health

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

Individual

Families

Environment

GenomeCell

Animal

Populations

Organ

The Continuum of Biological Research

Understanding Health and

Disease

Prevention

TreatmentDiagnosis

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