Legal Impediments to Advances in

Medical ResearchInstitute of Biotechnology Law and Ethics

Sheffield June 17th 2011

Sir John Burn MD FRCP(Lond. & Edin.) FRCPCH FRCOG F MedSci

Honorary Consultant Newcastle Hospitals NHS Foundation Trust

Professor of Clinical Genetics, Newcastle University

NHS North East Lead Clinician

Genetics Chair, National Institute of Health Research

CEO Northgene Ltd, non-exec director Newgene Ltd, Medical Director Quantum Dx

Institute of Genetic Medicine

Newcastle University

Centre for Life, Newcastle UK

Genetics Specialty Group

Barriers to research

Institutional

Attitudinal

Financial

legal

Manhattan plot for flucloxacillin GWAS

HLA B*5701 responsible for liver toxicityDaly A et al Nature Genetics 2009

MHC region

Strongest signal with

HCP5 SNP-marker for

B*5701

In defined populations we can

limit our tests to only those changes

we know the meaning of

Sequenom mass spectrometry

T

G

G

A

C

C

G

T

T

C

A

A

C- ve - ve

- ve

- ve- ve

- ve

- ve

- ve - ve

- ve

- ve- ve

- ve

- ve C

We will soon be able to test DNA very quickly and

cheaply but what will it mean?

Direct to consumer genetic testing

2011

The current crop of tests for sale on the

internet are mostly pointless or

misleading

Only by massive data merger and

analysis will real health gains be

achieved

Functional classification of JDW

SNPs

SNP Type Known SNPs Novel SNPs

Missense 8967 2421

Nonsense 44 5

Synonymous 9121 2261

UTR 18517 7102

Intron 922048 381924

Imagine if there were only 2

genes for height, each with only 2 alleles H

or T of equal frequency

T T T T

T T

T T

H

T

H

H

H

H

HH H

H

H

H

H H

HH

H H H H H H T T T

T

T

TTT T

T T

H

HH H T

T

T

H H H

H HH

HT TT

T T

T T

T T

43210

10

We discover one of the genes and

call it BYH1: somebody would suggest using it

for disease prediction

T T T T

T T

T T

H

T

H

H

H

H

HH H

H

H

H

H H

HH

H H H H H H T T T

T

T

TTT T

T T

H

HH H T

T

T

H H H

H HH

HT TT

T T

T T

T T

43210

averageshortVery

shorttall

Very

tall

Always bump

your head

Often bump

Your head

What causes inflammatory bowel

disease?

2001

NOD2

2007

IL23R

ATG16L1

IRGM

First 2 millennia

IBD is “genetic”:

Twin studies

Ethnicity

Family studies

Linkage analysis

timeline

2009

IL23R

ATG16L1

IRGM

2011- at least 32 genes

Innate immune signalling

Autophagy

ER biology

Pathogenic Th17-Treg balance

2ndary immune response

Henderson P& Satsangi J Clin Med 2011:11;8-10

RISK SCORE METHOD

PROCAM/Framingham

HDL score

LDL score

+Diabetes score

Total for every subject

Assign a value to each level of risk factor

Trait PROCAM F’Ham

Age <55

55-59

>60

SYS <120

120-129

130-139

140-159

>160

Smoke no

yes

+16

+21

+26

0

+2

+3

+5

+8

0

+8

+6

+8

+10

0

0

+1

+1

+2

0

+3

0

0.2

0.4

0.6

6 7 8 9 10 11 12

Risk score

Pro

ba

bil

ity

5%

24%

Risk

Of MI

What % of events does

score predict in NPHSII?

19

RISK SCORE METHOD

PROCAM/FraminghamClassical Risk factors

0

0.25

0.5

0.75

1

10 10.5 11 11.5 12 12.5 13 13.5

Risk Score

Pro

ba

bil

ity

no CHD CHD Set Specificity at

5% False Positive

in no-CAD

11% of men who get

CAD have baseline

score over cut-off

89% of the events that occurred over 10 years

would not be predicted by the score !!.

Can we improve on this with genotypes?

Whıch genes

to study ?

20

Genotype - smoking interactions

in risk score

Better than classical +

genotypes p<0.0001

Adding Environment-Genotype interactions

enhances (DOUBLES) risk prediction score

0

0.2

0.4

0.6

6 7 8 9 10 11 12

Risk score

pro

bab

ilit

y

no CHD CHD

EVEN BETTER!

24% of cases

have score

over cut-off

5% FPR

Classical Risk factors + Genotypes + Smokıng

22

Human Variome Project

Aims to create a network of locus specific databases linked to a shared

repository to enable efficient and effective interpretation of himan genomic

variation

Written and verbal consent given to any ethical use to investigate the gentic factors in childhood disease

(January 1996-January 2002)

0

10

20

30

40

50

60

70

80

90

100

% T

otal

mon

thly

bir

ths

The North Cumbria Community genetics project

Chase et al J Med Genet 1998;35:413-416

6000 cord bloods

3000 mothers

Legal Issues for consideration

Human Tissue Act

Data Protection Act

Section 251 NHS Act 2006

Article 8 Eu Convention on

Human Rights

Can the NHS collect generic consent

to use of genomic information?

Recognise the need for more

knowledge

Standardise hospital consents to

allow generic use of material

Consider security

Consider incidental findings

Engage with ethics committees

A final thought

Should Members of Parliament be

required to speak to each constituent

before being elected to their seat?