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4Issues inhum a n g ene ticsEuropean I ni ti ati ve for
Biotechnology Education
Contributors to this UnitWilbert Garvin (Unit
Co-ordinator)Catherine Adley, Bernard Dixon, Jan Frings,Dean
Madden, Lisbet Marcussen, Jill Turner, Paul E.O. Wymer.
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2 UNIT4: ISSUESINHUMANGENETICS EIBE European Ini tiati ve for
Biotechnology Education1 9 9 5
The European Initiative for Biotechnology Education (EIBE)
seeks
to promote skills, enhance understanding and facilitate
informedpublic debate through improved biotechnology education
inschools and colleges throughout the European Union (EU).
EIB E Co -ordina t orHorst Bayrhuber, Institut fr die Pdagogik
der Naturwissenschaften an der Universitt Kiel, Olshausenstrae
62,D-24098 Kiel 1, Germany. Telephone: + 49 (0) 431 880 3137 (EIBE
Secretary: Regina Rojek). Facsimile: + 49 (0) 431 880 3132.
EI B E C o nt a c t s
AUS TRIA
Rainhart Berner, Hhere Bundeslehr- und Versuchsanstalt fr
Chemische Industrie Wein, Abt. fr Biochemie,Biotechnologie und
Gentechnik, Rosensteingasse 79, A-1170 WIEN.
BE LGI U M
Vic Damen / Marleen van Strydonck, R&D Groep VEO, Afdeling
Didaktiek en Kritiek, Universiteit vanAntwerpen, Universiteitsplein
1, B-2610 WILRIJK.
DENMARK
Dorte Hammelev, Biotechnology Education Group, Foreningen af
Danske Biologer, Snderengen 20, DK-2860 SBORG. Lisbet Marcussen,
Biotechnology Education Group, Foreningen af Danske Biologer,
Lindevej 21, DK-5800 NYBORG.
EIRE
Catherine Adley / Cecily Leonard, University of Limerick,
Plassey, LIMERICK.
FRANCE
Grard Coutouly, LEGPT Jean Rostand, 18 Boulevard de la Victorie,
F-67084 STRASBOURG Cedex. Laurence Simonneaux, Ecole Nationale de
Formation Agronomique, Toulouse-Auzeville, Bote Postale 87,F-31326
CASTANET TOLOSAN Cedex.
GERMANY
Horst Bayrhuber / Eckhard R. Lucius / Regina Rojek / Ute Harms /
Angela Kro, Institut fr die Pdagogik derNaturwissenschaften,
Universitt Kiel, Olshausenstrae 62, D-24098 KIEL 1. Ognian
Serafimov, UNESCO-INCS, c/o Jrg-Zrn-Gewerbeschule, Rauensteinstrae
17, D-88662 BERLINGEN. Eberhard Todt, Fachbereich Psychologie,
Universitt Gieen, Otto-Behaghel-Strae 10, D-35394 GIEEN.
ITALY
Antonio Bargellesi-Severi / Stefania Uccelli / Alessandra Corda
Mannino, Centro di Biotechnologie Avanzate,
Largo Rosanna Benzi 10 , I-16132 GENOVA.LU XE MBOU R G
John Watson, Ecole Europenne de Luxembourg, Dpartement de
Biologie, 23 Boulevard Konrad Adenauer,L-1115 LUXEMBOURG.
THE NETHERLANDS
David Bennett, Cambridge Biomedical Consultants, Schuystraat 12,
NL-2517 XE DEN HAAG. Fred Brinkman, Hogeschool Holland, Afd
VP&I, Postbus 261, NL-1110 AG Diemen. Guido Matthe, Hogeschool
van Arnhem en Nijmegen, Technische Faculteit, HLO, Heijendaalseweg
45, NL-6524 SENIJMEGEN. Liesbeth van de Grint / Jan Frings,
Hogeschool van Utrecht, Educatie Centrum voor Biotechnologie, FEO,
Afdeling ExacteVakken, Biologie, Postbus 14007, NL-3508 SB
UTRECHT.
S P A I N Maria Saez Brezmes / Angela Gomez Nio, Facultad de
Educacin, Universidad de Valladolid,Geologo Hernndez Pacheco 1,
ES-47014 VALLADOLID.
S WEDEN
Margareta Johanssen, Freningen Gensyn, PO Box 37, S-26800 SVALV.
Elisabeth Strmberg, strabo Gymnasiet, PO Box 276, Kaempegatan 36,
S-45181 UDDEVALLA.
THE UNITED KINGDOM
Wilbert Garvin, Northern Ireland Centre for School Biosciences,
NIESU, School of Education, The Queens University ofBelfast,
BELFAST, BT7 1NN.John Grainger / John Schollar / Caroline Shearer,
National Centre for Biotechnology Education, The University of
Reading,PO Box 228, Whiteknights, READING, RG6 6AJ.Jill Turner,
Department of Science and Technology Studies, University College
London, Gower Street, LONDON, WC1 6BT.
Paul Wymer, The Wellcome Centre for Medical Science, The
Wellcome Trust, 210 Euston Road, LONDON, NW1 2BE.
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U
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4Is s ue s inhum a n g e ne t ics
World Wide We b
Few areas are developing as rapidly asbiotechnology. So that
they can be revised andkept up-to-date then distributed at minimum
cost,the EIBE Units are published electronically.
These pages (and the other EIBE Units) areavailable throughout
Europe and the rest of
the world on the World Wide Web. They canbe found at:
http:/ / www.reading.ac.uk/NCBE
All of the EIBE Units on the World WideWeb are Portable Document
Format (PDF)files. This means that the high-qualityillustrations,
colour, typefaces and layout ofthese documents will be maintained,
whatevercomputer you have (Macintosh - including
Power PC, Windows, DOS or Unix platforms).PDF files are also
smaller than the files fromwhich they were created, so that it will
take lesstime to download documents. However, to viewthe EIBE Units
you will need a suitable copy oftheAdobe Acrobat Reader
programme.
TheAcrobat Reader 3.0 programme isavailable free-of-charge in
several languages(Dutch, UK English, French, German,
Italian,Spanish and Swedish). It can be downloaded
from the EIBE Web site or:
http:/ / www.adobe.com/
With this software, you can view or print theEIBE Units. In
addition, you will be able tonavigate around and search the
documentswith ease.
PLEASE NOTE:AdobeandAcrobatare trademarks ofAdobe Systems
Incorporated, which may be registeredin certain
jurisdictions.Macintoshis a registered
trademark of Apple Computer Incorporated.
Contents
MATERIALS
European Ini ti ative for Biotechnology Education
Development team, copyright
and acknowledgements 4 About this Unit
Introduction 5 B ackground informat ion 7
Cells, chromosomes, genes and proteins;Different forms of genes;
What is a geneticdisease?; Recessive conditions;
Dominantconditions; Sex-linked conditions;Multifactorial
conditions; Finding disease-causing genes; Screening and
counselling;Screening in early pregnancy; Screening forhaemoglobin
disorders; Pinpointing the cysticfibrosis gene; Preimplantation
diagnosis;Principles of gene therapy; First steps in genetherapy;
Cell therapy.
Using thes e ma terials
Guidelines for teachers 18 P hotocopy mas ters
Genetics cards 21Cystic fibrosisBriefing notes 24
Duchenne muscular dystrophyBriefing notes 26
Huntingtons diseaseBriefing notes 28
Worksheet 1 30
Worksheet 2 3132Genetic disorders diagram 33 Appendix 1
Eugenics 34 Appendix 2
Cultural contexts of genetic screening 36
Appendix 3
Additional resources andsources of information 38
Appendix 4
Human genetics questionnaire 4041
http://www.reading.ac.uk/NCBEhttp://www.adobe.com/http://www.reading.ac.uk/NCBEhttp://www.adobe.com/
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Development team
Catherine AdleyThe University of Limerick, Eire.
Jan FringsHogeschool van Arnhem en Nijmegen, Netherlands.
Wilbert Garvin (Unit Co-ordinator)
The Queens University of Belfast,The United Kingdom.
Lisbet MarcussenNyborg Gymnasium, Nyborg, Denmark.
Jill TurnerUniversity College London,The United Kingdom.
Paul E.O. WymerThe Wellcome Centre for MedicalScience, London,
The United Kingdom.
Design, illustration, typesetting,additional text and
editing:Dean Madden, NCBE, The University ofReading, The United
Kingdom.Illustrations and typographyCopyright Dean Madden, 1996
AcknowledgementsWe are grateful to Dr Bernard Dixon for his
permission to use extracts fromGenetics and the understanding
oflifein the background information in this Unit.The Daily
Telegraphnewspaper, London gave permission forthe use of their
opinion poll on human genetics. Useful comments on the first draft
were made byProfessor Norman Nevin of the Northern Ireland Genetics
Service at Belfast City Hospital.
Dorte Hammelev (Frederiksberg HF Kursus, Kbenhavn, Denmark),
Wilbert Garvin (Northern IrelandCentre for School Biosciences, The
Queens University of Belfast, The United Kingdom) and John
Schollar(National Centre for Biotechnology Education, The
University of Reading, The United Kingdom) arrangedand ran a
multinational workshop in which the materials in this Unit were
tested. EIBE would like to thankthem and the teachers from Denmark,
Eire and Germany who took part and gave many helpful commentson the
draft materials. The workshop participants were:
From Denmark: Lisbet Leonard; Lene Tidemann; Mario Bro
Hassenfeldt; Greta Grnqvist; JytteJrgensen; Tine Bing; Per
Vollmond; Anker Steffensen.From Eire: John Lucey; Michael OLeary;
Bruno Mulcahy; Tim OMeara; Tom Moloney; BrendanWorsefold; Frank
Killelea.
From Germany: Ulrike Schnack; Werner Bhrs; Jrgen Samland;
Cristel Ahlf-Christiani; Erhard Lipkow;Hubert Thoma.From the EIBE
team: Eckhard R. Lucius; Catherine Adley; Jan Frings; Wilbert
Garvin; Jill Turner; DeanMadden; John Schollar; Dorte Hammelev.
Copyrig ht
This EIBE Units is copyright. The contributors to thisUnit have
asserted their moral rights to be identified as
copyright holders under Section 77 of the Designs,Patents and
Copyright Act, UK (1988).
Educational use.Electronic or paper copies of thisEIBE Unit, or
individual pages from it may be madefor classroom use, provided
that the copies aredistributed free-of-charge or at the cost of
reproduction,and the contributors to the unit are credited
andidentified as the copyright holders.
Other uses.The Unit may be distributed by
individuals to individuals fornon-commercialpurposes,but not by
means of electronic distribution lists,mailing (listserv) lists,
newsgroups, bulletin board orunauthorised World Wide Web postings,
or other bulkdistribution, access or reproduction mechanisms
thatsubstitute for a susbscription or authorised individualaccess,
or in any manner that is not an attempt in goodfaith to comply with
these restrictions.
Commercial use.The use of materials from this Unit forcommercial
gain, without the prior consent of thecopyright holders is strictly
prohibited.Should you wish
to use this material in whole or in part for commercialpurposes,
or to republish it in any form, you should
contact:
Regina Rojek, EIBE Secretariatc/o Institut fr die Pdagogikder
NaturwissenschaftenUniversitt KielOlshausenstrae 62D-24098
KielGermany
Telephone:+ 49 (0) 431 880 3137
Facsimile: + 49 (0) 431 880 3132E-Mail:
[email protected]
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About this Unit
INTRO
DUCTIONThis Unit comprises a rle play about
human genetic diseases, with supportingeducational resources.
These materials havebeen devised by practising teachers and
educationalists from several Europeancountries, brought together
with supportand encouragement from DGXII of theEuropean Commission,
under the auspicesof EIBE, theEuropean Initiative forBiotechnology
Education.
The EIBE materials have been extensivelytested in workshops
involving teachersfrom across Europe.
This Unit is designed to stimulate debate inthe classroom. The
implications of medicalgenetics and screening are wide-ranging
andprofound. Some of the more frequently-raised concerns will be
examined. Thequality of the discussion will be enhancedby the
teachers own knowledge andunderstanding of the issues involved.
An introductory section provides somebackground information on
basic humangenetics and recent developments inmolecular genetics
and medicine.
The remainder of this Unit is a rle playcentred around three
serious inheritedconditions: Cystic fibrosis; Duchennemuscular
dystrophy and Huntingtonsdisease.
Many important moral and social questionscan be raised regarding
the application of
scientific and technological knowledge tohuman genetics.
Issues that could be explored using thisUnit include:
individual privacy and theconfidentiality of genetic
information;
how can we draw a distinction be drawnbetween health and illness
?;
what, in the context of human genetics,
isnormal?; the application of prenatal diagnosis; termination of
pregnancy (abortion)
and the alternatives;
reproductive technologies and humanmolecular genetics in
different culturalcontexts;
medical genetics and disability rights.
Among the questions raised by the applicationof human gene
therapy are:
Who should be given the treatment first?(e.g. people on the
verge of death, forwhom there is no other hope; theyoungest and
fittest, who will have timeto recover if things go wrong; those
forwhom existing treatments do little ornothing to alleviate their
symptoms.)
Were it possible to do so, should doctorsbe allowed to alter
characteristics such asintelligence or physique?
Should we ever permit germ-line therapy,
which could affect future generations? Who, or what sort of
organisations,
should regulate and supervise genetherapy?
What disciplinary action should be takenif the rules are
broken?
All of the above (and other) points are ofdirect relevance to
the students as futurecitizens and possibly as future
parents.Teachers have an important duty to address
these issues fairly.
Where appropriate, the materials in thisUnit should be
supplemented by additionalresources, especially from
organizationsthat support people whose lives are directlyaffected
by serious genetic conditions.Several of these are listed
inAppendix 3.
The classroom activities in this Unit were devisedby Wilbert
Garvin, Director of the Northern
Ireland Centre for School Biosciences at theQueens University of
Belfast, with advice from DrLorraine Stefani. Comments on this Unit
are verywelcome and should be sent to:
Wilbert GarvinNorthern Ireland Centre for School
BiosciencesNIESU, The School of EducationThe Queens University of
BelfastBELFASTBT7 1NNThe United Kingdom
Telephone: + 44 (0) 1232 245133 extn. 3919Telefax: + 44 (0) 1232
331845E-Mail: [email protected]
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Different forms of ge nesEach gene can come in alternative
forms,calledalleles. Say, for example, that there was asingle gene
governing eye colour. There mightbe one form (or allele) that leads
to blue eyes,another allele for brown eyes, one allele forgreen
colour and so on. For all genes we
inherit two alleles, one carried on each of thepair of
chromosomes we have received fromeach of our parents. Some alleles
aredominantand their effects are seen regardless of thenature of
the other allele on theaccompanying chromosome. Other alleles
arerecessiveand their effects are only seen whenboth chromosomes
carry an identical form ofthe gene.
Variation in genes arises naturally by random
mutation. Some mutations can be damagingwhile others have no
obvious effect. In somecases they can bestow benefits. For
instance,there are several genes involved in theproduction of
haemoglobin, the oxygen-carrying pigment that is found in red
bloodcells. One Olympic Gold medallist, a Finnishcross-country
skier, has an allele that giveshim a higher level of haemoglobin in
hisblood than most people. This means that he(and others in his
family) find endurance
sports easier than the average person does.
G ene t ic d is e as e
BACKGROUNDIN
FORMATION
Cells, chromosomes,ge nes and proteinsHumans are made from about
100 million,
million cells. Within most of these cells are 23pairs of
chromosomes. One of each pair comesfrom each of our parents. The
chromosomesare made of DNA (deoxyribonucleic acid)andprotein.
Particular sequences ofinformation in the DNA are calledgenes.Genes
provide the information necessary forthe production of proteins.
Recent estimatessuggest that human beings have between 50and 100
thousand genes.
All inherited characteristics are controlled bygenes. Sometimes
a single gene is associatedwith a particular feature, so it is
possible totalk about a gene for that feature. Forexample, there is
a gene for each of thedifferent enzymes that enable you to
digestyour food. More often, however, our visiblecharacteristics
are the result of many genesworking together and interacting with
theirsurroundings. Features such as intelligenceand height for
example, result from such
complex interactions.
Most of the 100 million million cells fromwhich a human is made
contain 23 pairs ofchromosomes. The DNA from which they arecomposed
includes 50 to 100 thousandgenes, which are the instructions
requiredfor assembling proteins from amino acids.
Body
Cells
ChromosomesDNA
AminoacidsProtein
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What is ge netic dis ea s e?About 4 000 diseases in humans are
thoughtto result from changes to single genes. Mostof them are
rare, but many cause severesuffering and often lead to an early
death.Although individual genetic diseases are quiterare, the total
number of people affected is
significant roughly 2% of all live birthsevery year. At present
there is no effectivetreatment or cure for most of them.
Most genetic disorders are maintained in thepopulation by both
the passage of genes fromparents to offspring and by the steady
input ofnew mutations. However, not all geneticdisorders run in
families. Some changes to theDNA or the chromosomes arise during
theformation of the sex cells (eggs and sperm) orin the early
development of the foetus. Oneexample is Downs syndrome, which
causesmental retardation, below-average stature andother changes.
It usually arises from an errorduring cell division (meiosis)
leading to thechild having 47 chromosomes instead of 46,one of them
(chromosome 21) being duplicated.
Because genetic diseases cannot be caughtlike infectious
diseases, some people prefer tomake this distinction clear by
calling suchdiseases syndromes or dysfunctions butthere is no
commonly-accepted term forgenetic changes of this type.
All of the diseases caused by changes to singlegenes have clear
patterns of inheritance, whichmeans that it is often possible to
predict thechances that someone will inherit a particularcondition.
Three main patterns of inheritanceare involved.
1. Recess ive conditionsSome disease-causing alleles are
recessive: tobe affected a person must carry two identicalforms of
the gene. For example, sickle cellanaemia occurs when someone
receivestwocopies of a certain form of one of thehaemoglobin genes.
However, because thealtered form of the gene is recessive,
thosepeople who inherit just one copy of it areunaffected the
mutant allele is dominatedby its partner on the other chromosome.
Insome situations people with one sickle cellallele can even be at
an advantage, becausethey are less susceptible to malaria
thanpeople with two normal alleles.
People with a single copy of a particularrecessive allele are
sometimes called carriers,because although they are
unaffectedpersonally, they can still pass on the allele totheir
children. These children will not sufferthe disease unless they
have also inherited asimilar allele from the other parent.
7 8 9 10 11 124 5 61 2 3
19 20 21 2213 14 15 16 17 18Y
X
Below: Most human genes are packaged into 23 pairsof
chromosomes.
Virtually all cells contain a full set of chromosomes.Two major
exceptions are mature red blood cells (whichhave no chromosomes)
and the sex cells (eggs andsperm) which carry only one set of 23
unpairedchromosomes.
Men have an X and a Y chromosome; women have twoX chromosomes.
After staining with various dyes, eachchromosome reveals a unique
pattern of bands.
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S ickle ce ll anaemiaOne of the commonest genetic diseases
is
sickle cell anaemia. People who are affected
by the disease have red blood cells that alter
their shape when the oxygen concentrationbecomes low. These
sickle-shaped cells often
burst open or clog the small blood capillaries,
starving the tissues of oxygen and causing the
affected person to suffer mild to extreme pain.
Additional complications can arise, especially
during exercise.
In 1949, the U.S. chemist Linus Pauling traced
sickle cell anaemia to a specific change in the
structure of haemoglobin, the red oxygen-
carrying pigment in the blood. When heexamined the molecular
structure of
haemoglobin from sickle cell anaemia patients
Pauling found that it differed from normal
haemoglobin.
Adult haemoglobin is constructed of two-
globin chains, each 140 amino acids long, and
two-globin chains, each with 146 amino
acids.
The sole change in the abnormal haemoglobinwas the replacement
of one amino acid,
glutamic acid (glu) by valine (val) at the sixth
position in the-globin chain.
val his leu thr pro glu glu
Normal ami no acid sequence
val his leu thr pro val glu
Sickle c ell amino acid sequence
Haemoglobin molecule
-globin prot eins
Red blood cel ls
2. Dominant conditions
If a disease is caused by a dominant allele, aperson has only to
inherit one copy to havethe disease. If any of that persons
children
receive the affected allele, they will alsoinherit the disease
and have a 50% chanceof passing it on to their offspring.
A particular problem with diseases causedby dominant alleles is
that if they do notdevelop until later in life, parents
mayunwittingly pass them on to their children.
One such condition isHuntingtons disease,which is characterised
by the progressive
development of involuntary muscularmovements and dementia, from
the mid-thirties onwards. Huntingtons disease isdiscussed in detail
later in this Unit.
3. S ex-linked conditions
Among the 23 pairs of chromosomes that allhumans have, one pair
is connected with thepersons gender or sex. Females have two
similar X chromosomes whereas males haveone X and a smaller Y
chromosome. Recentresearch has shown that a single gene on theY
chromosome determines gender: withoutthis gene, females develop.
Other genes thathave nothing to do with sex are also carriedon the
X and Y chromosomes. Such genes aresometimes described as
sex-linked.
Genetic disorders that are caused by changesto the X chromosome,
although rare, are
more common in males. They are oftendescribed as X-linked. For
example, an allelethat can cause red-green colour blindness
iscarried on the X chromosome. Females are
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very rarely affected by thiscondition, becausethe offending
allele (if present)is usuallymasked by ordinary gene (allele) on
theaccompanying X chromosome. Males,however, have no second X
chromosome, sostand a greater risk of being red-green colour
blind.
4 . Multifactorial conditionsIndividual disorders caused by
changes tosingle genes are comparatively rare. Far morecommon are
those conditions which arisefrom the interaction of many genes.
Predicting the pattern of inheritance for theseconditions and
disentangling the influence ofgenetic and environmental factors
(such assmoking, diet, stress, or exposure to certainchemicals) is
only in its infancy. The hope is
that people who are at risk can be identifiedand advised to
avoid environmental factorsthat might lead to the development of
disease.The worry is that employers, insurancecompanies or others
who do not understandthe relative contribution of the
geneticcomponent may overreact and discriminateagainst affected
individuals.
Finding disea s e-ca using g ene sLinkage analysis, based on the
extent to whichparticular characteristics tend to be
inheritedtogether, allows the positions of mutant
allelesresponsible for certain inherited conditions to belocated on
the human chromosomes. Thetechnique requires several generations
and large
numbers of individuals, and is thus much moredifficult when
applied to humans than, say, to fruitflies or pea plants.
Nevertheless, many genes havebeen located in this way and their DNA
sequencesdetermined. This makes it possible to
producecorrespondinggene probesthatallow conclusiveidentification
of those who carry potentiallyharmful genes.
Many other disorders, whose genes have notyet been isolated,
have been mapped to their
approximate locations in a chromosome.These genes too can be
identified by usinggene probes, although with less certainty.One
recent success involved Huntingtonsdisease, a devastating condition
that usuallyappears between the ages of 30 and 50 andleads to
uncoordinated limb movements, mentaldeterioration and death. In
1983, JimGusella and
Mode of D is e a s e / Main Time of onset
inheritance condition features of sym ptoms
Sporadic Downs syndrome Range of mental retardation, etc.
BirthKlinefelters syndrome Defect in sexual differentiation
Birth
Autosomal recessive Cystic fibrosis Wide range of complications
dueto excessively thick mucus secretion,especially in the
lungs/digestive system 12 years
Phenylketonuria Mental deficiency BirthSickle cell anaemia
Chronic anaemia/ infections/painful
or haemolytic crises 6 months onwardsTay-Sachs disease Deafness/
blindness/ seizures/ spasticity 36 months
Thalassaemias Severe anaemia/ skeletal deformity Six months
onwards
Autosomal dominant Familial hyper- High cholesterol level leads
tocholesterolaemia early coronary heart disease 2030
yearsHuntingtons disease Involuntary movements/ dementia 3545
yearsPolycystic kidney disease Cysts in liver/ pancreas/ spleen/
kidney 4060 years
X-linked Haemophilias Failure of blood to clot. Bruising
andexcessive bleeding after injury 1 year onwards
Duchenne musculardystrophy Muscle wasting 13 yearsLesch-Nyhan
syndrome Mental retardation/ self-mutilation Birth
Multifactorial(often with a high Asthma Difficulty breathing
Birthgenetic contribution) Coronary heart disease Arteries become
narrowed,
can lead to heart failure Middle age
Some of the 4,000 known genetic conditions. Mendelian conditions
(recessive, dominant and X-linked) follow aclear pattern of
inheritance, whereas it is less easy or impossible to predict the
occurrence of sporadic andmultifactorial conditions.
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colleagues at the Massachusetts GeneralHospital, Boston,
reported that they hadpinpointed a marker gene close to
theHuntingtons disease allele on chromosome 4.Then, in 1993,
following a decade ofpainstaking research, they and collaborators
atother U.S. centres and the University of Wales
College of Medicine in the UK announced theprecise position of
the Huntingtons allele.
While these were major advances whichhelped in screening for the
disease, they alsocreated a dilemma. In the past, children of
aperson with the disorder, who have a 50%chance of developing the
condition, simply hadto wait until middle age to see whether they
wereto be afflicted. Now they can choose to betested but may then
have to cope with the newsthat they face this horrendous disease
later in life.
Like Huntingtons disease, many other geneticdisorders are
serious and distressing conditionsthat cannot be cured or even
treated directly.Identification of the genes concerned raises
thepossibility that scientists may be able to find outprecisely
what causes the condition, bydetermining the protein produced by
the gene anddiscovering its effects. It also helps in
thedevelopment of screening tests, whether applied tothe unborn
foetus, to test-tube embryos or adults.
S cree ning a nd couns ellingGenetic screening identifies those
individuals whocarry alleles that may lead to disease.
Geneticcounselling provides individuals and couples withadvice
about the conditions, the risks of havingchildren who will be
affected, the severity of thedisorder and the options available.
This allowspotential parents to make informed choices:whether or
not to have children, or to avoid therisk of having affected
children by choosing the
option of using donated eggs or sperm, or tocontinue normally
but to terminate pregnanciesif prenatal tests show that the foetus
is affected.
Among the issues associated with screening,prenatal testing and
counselling are whoshould be screened, when, and for
whatconditions? What educational backup isnecessary to ensure that
all those who areaffected fully understand the results of testsand
their implications? A further complication
arises because genetic conditions may affectrelatives of the
individual who is directlyaffected, so it may not be easy to apply
normalrules of medical confidentiality.
A genetic map of a human X chromosome,showing the relative
positions of some of the350 or so genes which can lead to
variousdisorders that are located there.
The width of the line alongside the drawingreflects the
precision with which thelocation of the gene is currently
known.
The bands are caused by the differentialuptake of various stains
that are used tomake the chromosome visible.
Steroidsulphatasedef ic iency
Duchennemusculardystrophy
Ornithinetranscarbamoylasedef ic iency
Androgen insensi t iv i ty
Lowe syndrome
Lesch-Nyhan syndrom e
Haemophil ia B
Haemophil ia A
Fragile Xsyndrome
Chronicgranulomatousdisease
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Amniocentesis
Biochemical
studies
DNA
analysis
Chromosomeanalysis
Prenataltes t ing
Chorionic vill ussampling
S cree ning in early pregna ncyThere are currently two
approaches to treatinggenetically-based diseases. The first, which
isalready reducing the burden of sufferingcaused by disorders such
as cystic fibrosis, isto locate the gene responsible for such
acondition, or at least a closely-linked markergene; to screen
foetal cells early in pregnancyfor that marker; and thus to prevent
disease byterminating a pregnancy. The second is toscreen early
embryos produced outside thebody to test for the gene or gene
marker, andto implant one of the embryos that does notcarry a
defective allele.
Prenatal diagnosis is usually offered when afamily has a history
of a disorder caused by asingle gene or inherited
chromosomalabnormality, when a couple already have anaffected
child, or when the parents arecomparatively old (and therefore more
likelyto give birth to a child with Downssyndrome). It can provide
results that eitherreassure the parents or give them evidenceupon
which to make a decision.
Amniocentesisis carried out from 10 weeksgestation. A small
quantity of amniotic fluid istaken through a needle from the
amniotic
cavity and amniotic cells (shed from the skinof the foetus) are
cultured and theirchromosomes examined to confirm orexclude
conditions such as Downs syndrome.
Chorionic vill us sampling, introducedmore recently, has the
same purpose.Chorionic villus comes from the developingplacenta,
and is removed directly through aneedle. Most centres carry out
chorionicvillus sampling after 10 weeks. Because thecells are
derived from the fertilized egg,they nearly always provide a
reliable guideto the genetic constitution of the foetus.But both
techniques have a disadvantage,because they increase the rate
ofmiscarriage slightly.
Coelocentesis, reported in 1993 by a team atKings College School
of Medicine andDentistry, London, promises to facilitatescreening
before 10 weeks. In thisprocedure, cells are taken from thecoelomic
cavity which surrounds theamniotic sac. The new technique,
although
relatively untried as yet, is thought topresent significantly
less risk to the safety ofthe unborn child than either
amniocentesisor chorionic villus sampling.
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The sex of a foetus can be determined bythese methods. Although
parents couldexploit the results to choose the sex of
theiroffspring for non-medical reasons, theprincipal purpose is to
help them decide whatto do if the mother is likely to give birth to
achild affected by a condition determined by
one of the sex chromosomes. In certaindisorders with genes
carried on the Xchromosome, for example, knowledge of thesex of a
foetus is useful when a more specifictest is not available.
S creening for haem oglobin disordersThe World Health
Organisation forecaststhat by the year 2 000 approximately 7% ofthe
worlds population will be carriers of themost important
haemoglobinopathies.
These are serious conditions, caused by afailure of the
haemoglobin in red bloodcells to carry oxygen to the tissues in
thenormal way. They are the commonest of allhuman genetic diseases.
As there is nosatisfactory treatment, prenatal diagnosisand the
detection of carriers will remain theprinciple means of combating
thesedisorders in the foreseeable future. In somecases, such as
sickle cell anaemia, anabnormality in the structure of the
haemoglobin molecule is to blame.Thalassaemias, in contrast,
occur when oneor more of the four globin chainscomprising the
molecule are produced at adiminished rate, leading to an imbalance
intheir proportions. Over 90 differentmutations have been found to
cause onesuch condition,-thalassaemia.
Southern blotting (named after its inventor EdSouthern) is one
simple test which illustrates thediagnosis of a condition such as
sickle cell
anaemia. First, DNA is extracted from the patientswhite blood
cells. This is then exposed to anenzyme that recognises the site
coding for theglutamic acid (glu) that is present in
normalhaemoglobin but replaced by valine (val) in sicklecell
haemoglobin. The resulting mixture of DNAfragments are separated by
size, and treated with aprobe for the normal gene.
If the patients haemoglobin is normal, the enzymesplits it into
two fragments, each containing part ofthe gene. The probe DNA binds
to each of these,
and because the probe has been made slightlyradioactive the two
fragments can be detected astwo black bands on a photographic film.
If thehaemoglobin is the sickle cell variety, it is not cutby the
enzyme, and only one black band appears.
Normal globin allele
Sickle cell globin
alleleGTG(Val)
1 300 base pairs
1 100 base pairsGAG(Glu)
NormalCarrier
200bp
11 00bp
13 00bp
Movement o fDNAfragments
Sickle
Human blood
sample
DNA is extracted from
t he white blood cells
The DNA is cut into fragment s...
...which are separatedby size...
...and transferredto a nylon membrane
A radioact iveprobe binds tothe DNA...
...revealing apattern ofbands on X-rayfilm
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P reimplantat ion diag nos isRecently, genetic screening was
extended toembryos produced byin vitrofertilization by adding
spermatozoa to egg cells growing inlaboratory glassware. This
method ofproducing embryos was originally developedto allow certain
infertile couples to have test
tube babies. Now, however, a healthy embryocan be identified and
reimplanted in thewoman, who is then assured that herpregnancy is
free of any risk from thatparticular inherited disorder and
indeedseveral different conditions.
First, Robert Winston and colleagues inLondon reported that they
had been able totake single cells from very early (610 cell)embryos
and then to sex them by examining
specific DNA markers on the Ychromosome. Their aim was to help
coupleswith a history of an X-linked condition.Removal of the
individual cell did not damagethe rest of the embryo. Although
thistechnique could not guarantee the birth of ahealthy boy, it
could ensure that the motherreceived a female embryo. It could
alsoprevent unnecessary abortion: for certain X-linked conditions,
all male pregnancies wouldbe terminated following sex determination
by
amniocentesis or chorionic villus sampling,although half of
these would be unaffected.
Winston, together with Bob Williamson andother collaborators,
has also used thisapproach to screen for CF and Duchennemuscular
dystrophy. Initially, their targets weregene markers close to the
mutationresponsible for cystic fibrosis, and part of thesequence
coding for dystrophin, which whenmutated causes Duchenne
muscular
dystrophy. Such tests should facilitatescreening for other than
X-linked conditions(for example, CF) and also permit the
implantationof male embryos unaffected by X-linked traitssuch as
Duchenne muscular dystrophy.
Considerable progress has been made recentlyin the diagnosis of
haemoglobinopathies,much of the work being pioneered by SirDavid
Weatherall and colleagues at the JohnRadcliffe Hospital, Oxford.
These advances ingenetic diagnosis have followed earliertechniques
that identified abnormal forms of
haemoglobin in red blood cells, obtained bypassing a needle into
the placenta or umbilicalcord. Although these methods were
effective(resulting in, for example, a marked fall in thebirthrate
of people with-thalassaemia inGreece), they could not be used until
late inthe second trimester of pregnancy.
Focusing on genes, rather than on thehaemoglobins they produce,
the newerapproaches can be adopted before blood cellsare available
for sampling. The first such
advances, in the late 1970s, were made usingamniocentesis early
in the second trimester. Indue course, the first successful
diagnoses ofDNA in chorion villus, sampled late in thefirst
trimester, occurred during the early1980s. In some cases, when a
specific geneprobe is available, prenatal diagnosis isrelatively
simple. In other cases, morecomplex methods have to be used.
P inpointing the c ys tic fibros is ge ne
In 1989, researchers at the Hospital for SickChildren, Toronto,
and the universities ofToronto and Michigan announced that theyhad
located the mutant gene responsible forcystic fibrosis (CF). This
was a triumph forLap-Chee Tsui and his co-workers in their useof
elegant but nevertheless laborious techniques.Beginning by studying
members of familieswith the disease, they used linkage analysis
tolocate the gene on chromosome 7 (in 1985),and then painstakingly
homed in on the gene itself.
The Toronto discovery led quickly to thedevelopment of a gene
probe specific for theCF mutation. As well as being used in
affectedfamilies, this seemed likely to be taken upquickly as the
basis for major screeningprogrammes in whole populations.
Thesehopes were dimmed, however, when thenewly-identified mutant
gene was found inonly about three quarters of CF
patients.Subsequent identification of further mutations(over 450
are now known) has made it
possible to identify 8595% of carriers,depending on racial and
ethnic background.This begins to make population screeningseem more
feasible.
Right: Preimplantation diagnosis. A sample(biopsy) is taken from
the early embryo atthe 8 cell stage. While the sample cells
aretested, the remainder of the embryo isstored to be implanted
should the tests
show that it is free of serious geneticdisease. Since the cells
of such earlyembryos are undifferentiated, the removal ofone cell
does no harm, and subsequentdevelopment proceeds as normal.
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P rinciples of ge ne thera pyUntil recently, it was only
possible to suppressthe symptoms of inherited disease. Only asmall
proportion of those affected were thusable to lead fully active
lives.
Gene therapy is the repair or replacement of
disease-causing genes or the introduction offunctional alleles
alongside dysfunctional onesin living cells. In this way doctors
hope to treatinherited diseases effectively for the first time.Gene
therapy has been given the go-ahead bygovernments in several
countries andalthough this work is still in its infancy, theresults
of some early trials are encouraging.
In all of the tests to date, functional geneshave been
introduced alongside the
dysfunctional genes in affected individuals(hence this work is
currently limited totreating conditions caused by recessive
alleles).An alternative would be to alter amalfunctioning gene to
correct its erroneousmessage. Although this appears at least
asdifficult as the replacing of a faulty gene,genetic sequences
have been modified inseveral different types of mammalian
cellculturedin vitro.
Whatever the technique adopted, thefunctional alleles have to be
inserted into (ormodified within) cells in the affected tissue.This
is clearly a much simpler prospect for atissue such as blood or
bone marrow, whichcan be removed, treated in the laboratory
andre-injected, than for tissues such as liver, lungsor brain. In
the treatments so far, geneticmaterial has been ferried into the
body cells byspecially-tailored viruses or encased in fattydroplets
called liposomes.
All of this treatment has involved only thebody cells of the
affected person (somatic genetherapy). No attempt has been made,
nor hasapproval been given for genetic modificationof the sex cells
eggs and sperm or theembryo (germ-line therapy). Modification of
thistype could affect future generations. Atpresent, germ-line
therapy is consideredunacceptable, since so little is known about
itspossible consequences and hazards. For
example, it may not be desirable to removecarrier potential from
the population, since insome circumstances apparently
deleteriousalleles may be beneficial.
Samplecell
tested
Select ed embryoimplanted in
womb, where itdevelops normally
Fertilized cell
divides to form anembryo of 610
cells
Remainder ofembryo f rozenunti l tests are
complete
Egg fer t ilizedin vit ro
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First s teps in ge ne therapyThe first tangible moves towards
gene therapycentred on four very different conditions. In1993,
researchers at Oxford and Cambridge inthe United Kingdom announced
that they hadrestored normal function to cells in the lungsof mice
with artificially-induced CF. They did
so by squirting into the lungs copies of a genecalled CFTR
encased in liposomes (tinyglobules of fat). The liposomes fused
with theanimals cell membranes, allowing the DNAto pass through
into the cells and thus correctthe defect. Trials with humans began
shortlyafter, and some success in dealing with thesymptoms of CF
has been reported, althoughthis therapy is not a cure.
In the second advance, researchers inserted anormal gene into
certain white blood cellsfrom a patient with leucocyte
adhesiondeficiency, a rare genetic disorder that leavesvictims
exposed to recurrent, life-threateninginfections. Using a virus as
the vector, they
introduced a normal allele to compensate forthe abnormal one
responsiblefor the condition.The allele was expressed, causing the
cells tobehave normally. There are now hopes oftransferring the
gene into stem cells (where thewhite cells are formed), leading to
the formation ofa new population of normal white cells.
The third approach has been pioneered byFrench Anderson and
colleagues at theNational Cancer Institute and National Heart,Lung
and Blood Institute in Bethesda, USA.The long-term aim is to
optimize thetreatment of cancer by using certain of thepatients own
white blood cells, together withinterleukin-2. This is a natural
substancewhich stimulates growth of the white cells thatattack what
they recognise as foreign tissue.
The researchers took white cells from patientssuffering from
advanced melanoma and thenused a virus to introduce into the nuclei
of thecells a gene conferring resistance to aparticular antibiotic.
This enabled them to
Below: Gene therapy to combat Severe Combined Immunodeficiency
(SCID) was carried out in Italy in 1991 andin the following year,
at Londons Great Ormond Street Hospital, with the help of
colleagues from the TNOResearch Institute in Delft. The treatment
involved the replacement of a missing gene for an enzyme (ADA).
Thegene was placed in the stem cells of the bone marrow, so that
blood cells derived from them would produce ADA.
Bone marrow stem cells were taken fromthe affected baby by Dr
Gareth Morgan at
Londons Great Ormond Street Hospital.
The babys stem cells wereinfected by t he modified virus
The cells were cultured for several days,then ret urned to
London
The modified virusinserted the ADA
gene into t he stem
cells
The virus was renderedharmless by removing thegenes which
allowed it to
reproduce
At the TNO Research Institute inDelft, Professor Tinco Valerio
isolatedthe missing ADA gene from the
bone marrow of a healt hy donor
The modified stem cellswere injected into the
babys bone marrow,where they produced
healthy blood cells
complete with t he ADAgene
The cells
were flownto theNetherlands
The ADA gene
was insertedinto a virus
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monitor the survival and behaviour of thecells when reinjected
back into patients. Thispreliminary experiment is now being
followedby efforts to enhance the tumour-destroyingcapacity of
white cells, by giving them genesto overproduce a potent protein
calledtumour necrosis factor.
A fourth target is severe combinedimmunodeficiency disease
(SCID), a raredisorder affecting about 40 childrenworldwide each
year. In nearly half thepatients, the gene for the enzyme
adenosinedeaminase (ADA) is defective, preventing theimmune system
from defending the bodyagainst invading microbes. Efforts to
combatthe condition by taking a patients white bloodcells,
introducing a normal gene coding forthe enzyme, and then
retransfusing the cells,began in the USA in 1990. More
advancedtreatment, using modified stem cells andthus removing the
need for repeatedtransplants began in Italy in 1992 and withhelp
from doctors in the Netherlands, in theUnited Kingdom a year
later.
Potential targets for therapy where diseasesarise from single
genes include: otherimmunodeficiency diseases;
hypercholesterolaemia(replacing a receptor protein);
haemophilia(Factors IX and VIII); phenylketonuria(where the enzyme
phenylalanine hydroxylaseis missing); Hurlers syndrome (involving
anenzyme called-iduronisase); thalassaemiasand sickle cell anaemia
(where the-globingene is faulty).
Cell therapyCell therapy involves injecting cells from adonor
who is unaffected by a particulardisease at an appropriate site in
a personwho has the disease. Cells can also be takenfrom someone
who is affected by thedisease, genetically modified in culture,
thenreturned to the patient.
A trial of cell therapy to combat Hurlerssyndrome was announced
in France inApril 1995. Doctors at the Institut Pasteurin Paris
plan to transplant a copy of amissing gene for an enzyme into skin
cellstaken from six babies who are affected by
the disease. The modified cells will bebound together with
collagen, thenreimplanted into the peritoneum (the bodycavity that
contains the gut and other
Normalmusclefrom ahealthydonor
Early stagemuscle cells(myoblasts)carrying
normaldystrophingene
Cellstransferredto dystrophic
muscle
Rescuedmuscle, nowmakingdystrophin
Above: How cell therapy might be used to alleviatethe symptoms
of Duchenne muscular dystrophy.
organs). It is hoped that the implanted cellswill
secrete-iduronisase, an enzymewithout which the babies would suffer
fromsevere damage to organs, bones, nerves andbrain and eventually
die in early childhood.
In Duchenne muscular dystrophy (DMD),where the cells do not
produce the proteindystrophin, healthy muscle cells might
becultured and then injected into the patientsmuscles. Since the
injected cells wouldcontain normal copies of the dystrophingene
they would produce enoughdystrophin to prevent further
degenerationof muscle fibres. This sort of treatment mayprove to be
the only route in theforeseeable future for treating DMD, as
thedystrophin gene is too large to transplant
by current genetic techniques. Cell therapycould also provide a
means of treatingdiseases such as cancer and AIDS, andmanaging
chronic conditions like diabetes.
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Us ing thes emater ia ls
INSTR
UCTIONS
This activity involves rle-play and aims toinform students about
three serious genetic
diseases (Cystic fibrosis, Duchenne musculardystrophy and
Huntingtons disease).
Students adopt the rle of potential parentswho are carriers of
inherited diseases. Asparents they have to make importantdecisions,
which are agreed between thepartners. This introduces the task of
makinginformed decisions about several issues,including: having
children, prenataldiagnosis, termination of pregnancy and
other choices that are now becomingavailable.
The exercise can foster an awareness thatscientific developments
must be viewedwithin wider social, ethical and politicalcontexts. I
t should also help students tolearn more about their own and
othersvalues and attitudes, and help them todevelop communication
skills andconfidence.
This activity is not meant to be definitive. Itlends itself to
modification according to thedepth of information that it is
necessary toconvey to the students. Teachers may wishto add to or
replace the genetic diseasesmentioned in this Unit with others
theyconsider to be more appropriate for theirown students e.g.
sickle cell anaemia.
Dea ling w ith s ens itive issues
It would be prudent for teachers to find outwhether any members
of a class or their closefriends or relatives are affected by
seriousgenetic conditions before starting the work inthis Unit.
This must be done with sensitivity.
One approach would be to ask the classwhether anyone is familiar
with the inheritedconditions mentioned in the Unit and
toinvestigate further if necessary. Alternatively,use the
questionnaire in the Unit, the answers
to which may indicate if anyone is affectedpersonally. Consider
whether to discuss someconditions at all and if so, be prepared
toproceed with caution and sensitivity.
Some students may wish to talk in confidenceabout inherited
conditions in people theyknow. Groups may need to be managed
todevelop an atmosphere of non-judgementalacceptance and trust.
Aims
To increase awareness amongst teachersand their students: about
the nature of and the effects of
some inherited conditions; of the new technologies involved
in
locating the genes involved, prenataland carrier testing;
about some of the issues that arise fromdevelopments in human
genetics.
Advance prepara tion
Studentsshould read and understand theBriefing notesabout the
three genetic diseasesdescribed in this Unit.Teachersshould prepare
to act as a sourceof information and to deal with the issuesthat
may arise during this activity. Teachersshould be aware that people
in their classesor their relatives may be directly affected bythe
conditions described (seeDealing withsensitive issues).
Organisation
A minimum of 60 minutes should beallowed for this activity, in
addition to thepreparatory work.
MaterialsRequired by each class of students
SufficientGenetics cards(in male and
female pairs) for all the studentsinvolved (from the photocopy
master inthis Unit)
Sufficient copies of theWorksheetsandBriefing notesfor each
student (from thephotocopy masters in this Unit)
Optional
Background informationfrom this Unit Resource materials from
various
associations and groups (seeAppendix 3) If they are available,
video recordings
explaining Cystic fibrosis, Duchennemuscular dystrophy and
Huntingtonsdisease might prove useful.
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of issues associated with genetic disease.
Participants should be told thatBriefing noteson the diseases
are available forconsultation so that they can answer thequestions
on the worksheets.
The c ardsThere are male cards and female cards ofeach
colour:No. 1 Blue cards CF = Cystic fibrosis;No. 2 Pink cards DMD =
Duchennemuscular dystrophy;No. 3 Green cards HD =
Huntingtonsdisease.
Workshee t 1The couple has to decide which genetic
disease their children might suffer fromand the probability of
this occurring.Cystic fibrosisOnly if both parents are carriers are
theoffspring likely to be affected .Duchenne muscular dystrophyIf
the mother is a carrier then there is alikelihood of the sons being
affected.Huntingtons diseaseIf one of the parents is affected then
theoffspring are at risk of developing the
disease.
Workshee t 2Once the parents have identified that theyare at
risk of having children who mightsuffer from one of the genetic
diseases andhave found out that these diseases can bepassed on to
future generations, they areasked to make a number of decisions.
Theteacher should try to avoid making any
decisions for the parents. Instead, theteacher should adopt the
rle of afacilitator, providing information when it isasked for.
Students should be encoraged to thinkthrough the problems and to
write downtheir reasons for making particulardecisions, using the
information that isavailable to them.
Decision 1
Even if a couple chooses not to havechildren at this stage, they
should continueto Question 2. TheBriefing notesshould helphere.
P rocedure in brief
1. Do whateverAdvance preparationisnecessary.
2. Give out theGenetics cardsto individuals.Allow the students
to organisethemselves to work in pairs.
3. Give outWorksheet 1.4. Give out theBriefing notesand use
the
other resource materials as appropriate.5. Give outWorksheet
2.6. Show video recordings if they are
available and appropriate.
Extension
For biology students in particular thegenetics and the DNA
technology involvedmay be extended to relate to other parts of
the curriculum. (TheBackground informationin this Unit may be
useful here.)
P rocedure in deta ilThe accompanyingGenetics cardsshould
bephotocopied onto coloured card so thatthey are colour-coded e.g.
Card 1 on blue,Card 2 on pink, Card 3 on green. Eachcard states
whether it refers to a male orfemale, and has details of
predisposition tothree serious genetic diseases.
Each participant selects a card at randomfrom a shuffled deck
(ensure that thecorrect number of cards is in the deck insuitable
pairs). You can arrange things sothat females are given female
cards andmales male cards but this is not alwaysfeasible or
necessary.
Participants are then invited to find aspouse (husband or wife)
someone with
the same colour (and number) of card asthemselves, but of the
opposite sex (asspecified on the card).
Once the parents are settled they are givenWorksheet 1. This
instructs the parents toexamine and compare their cards to findout
if they are at risk. Note: The cardshave been designed so
thateverycouple willbe at risk of having children who areaffected.
Card 1 for Cystic fibrosis, Card 2
for Duchenne muscular dystrophy and Card3 for Huntingtons
disease. These diseaseshave been chosen to represent a range
ofmodes of inheritance and to raise a variety
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Decision 2The parents then have to discuss all thepossibilities
and to place these in rank order- this encourages them to seek
informationand to think carefully about possiblecourses of
action.
Again the teacher should resist thetemptation to make any value
judgements.The parents should be encouraged tomake decisions by
themselves.
Decision 3The third decision the parents have tomake is whether
or not they are going tohave a prenatal diagnosis. Even if
theydecide not to take this test they shouldcontinue the exercise,
imagining that theydid agree to a test and that it was
positive.
They then have to decide what to do next,considering all the
options with care. Evenif they agree to an abortion they
shouldcontinue to consider all other possibilitiesand place these
in rank order of preference.
Finally the parents should consider otherdiseases with a genetic
component, or verymild conditions, to try to find out if their
decisions differ from those of the seriousconditions considered
previously.At all times the parents should beencouraged to write
down the reasons fortheir decisions.
Confidentiality between the parents shouldbe respected at all
times.
If more time is available, or particularparents complete the
exercise morequickly than others, give them theopportunity to
consider one or both of theother disorders by giving them another
setof cards and worksheets.
Try to provide sufficient time for discussionwith each group of
parents. When runsuccessfully, this Unit stimulates discussion
around related topics such as embryoresearch, surrogate
motherhood, theproblems associated with applying a widerrange of
diagnostic tests, and what shouldbe considered as abnormal as more
andmore probes become available.
It is advisable to have a debriefing session,however short, to
round things off andreturn to normality.
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GENET
ICSCARDS
P hotocopy thes e ca rds onto coloured card for us e in
the rle play. Ea ch pa rticipant w ill nee d a ca rd.
CARD 1 : M ALE
CF CARRIER
DM D NORM AL
HD NORM AL
CARD 1: FEMALE
CF CARRIER
DM D NORM AL
HD NORM AL
CARD 1 : M ALE
CF CARRIER
DM D NORM AL
HD NORM AL
CARD 1: FEMALE
CF CARRIER
DM D NORM AL
HD NORM AL
CARD 1 : M ALE
CF CARRIER
DM D NORM AL
HD NORM AL
CARD 1: FEMALE
CF CARRIER
DM D NORM AL
HD NORM AL
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CARD 2 : MALE
CF NORM AL
DM D NORM AL
HD NORM AL
CARD 2 : FEM ALE
CF NORM AL
DM D CARRIER
HD NORM AL
CARD 2 : MALE
CF NORM AL
DM D NORM AL
HD NORM AL
CARD 2 : FEM ALE
CF NORM AL
DM D CARRIER
HD NORM AL
CARD 2 : MALE
CF NORM AL
DM D NORM AL
HD NORM AL
CARD 2 : FEM ALE
CF NORM AL
DM D CARRIER
HD NORM AL
GENET
ICSCARDS
P hotocopy thes e ca rds onto coloured card for us e in
the rle play. Ea ch pa rticipant w ill nee d a ca rd.
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GENET
ICSCARDS
P hotocopy thes e ca rds onto coloured ca rd for us e in
the rle play. Ea ch pa rticipant w ill nee d a ca rd.
CARD 3 : M ALE
CF NORM AL
DM D NORM AL
HD AFFECTED
CARD 3 : FEMALE
CF NORM AL
DM D NORM AL
HD NORM AL
CARD 3 : M ALE
CF NORM AL
DM D NORM AL
HD AFFECTED
CARD 3 : FEMALE
CF NORM AL
DM D NORM AL
HD NORM AL
CARD 3 : M ALE
CF NORM AL
DM D NORM AL
HD AFFECTED
CARD 3 : FEMALE
CF NORM AL
DM D NORM AL
HD NORM AL
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Cystic fibrosis (CF) is a serious inheritedcondition which
affects mainly the lungs anddigestive system, leading to recurrent
chestinfections and poor absorption of food. It isone of the
commonest genetic diseasesamong people of European origin.
Frequency
In the United Kingdom about 1 in 2 000births are affected by CF,
which means thatabout five babies are born every week withthis
condition. At any one time about 6 000people in the United Kingdom
have CF. Onaverage, three people die every week in theUnited
Kingdom because of CF.
SymptomsNot every person is affected to the samedegree; for some
the symptoms are less severe
than others. CF causes thick, sticky mucus tobe produced in the
bronchi. This becomesdifficult to cough up so that recurrent
lunginfections like pneumonia occur. Each bout ofinfection leaves
the lungs slightly moredamaged than before and the persons
healthdeteriorates. Vigorous chest physiotherapy (toremove the
mucus) and treatment withantibiotics helps to control the
infections.
The pancreas becomes blocked by the sticky
secretions and fails to produce digestive juicesin adequate
amounts, leading to chronicdiarrhoea, poor weight gain and ill
health.Males are infertile because of abnormalmucous secretions in
the vas deferens. Theloss of chloride ions in the sweat can be
severeenough to cause heat stroke in warm weather.
Hereditary bas isThis condition is caused by a single gene,which
was localised to chromosome 7 in
1985. A protein encoded by the gene regulatesthe movement of
chloride ions in and out ofcells. One form of this protein does not
workproperly so that the secretions that are
produced are thicker and stickier than normal.If you have one
copy of a faulty allele and onecopy of the normal allele you remain
healthybut you are a carrier. Roughly 1 in 25 peopleof European
origin carry one copy of a CF allele.
If both parents are carriers and contribute acopy of a CF allele
then their child will haveCF. If one parent contributes a copy of
thenormal allele and the other parent contributesa copy of a CF
allele then the child, like theparents, will be a carrier of CF but
will notshow any signs of the condition.
Every time two carriers of CF have a baby thechance on average
that he or she will have CFis 1 in 4; the chance of being a carrier
is 2 in 4;and the chance of having no CF genes is 1 in4. These
risks apply at each pregnancy theydo not change the more
pregnancies you have.CF affects girls and boys in equal
numbers.
Early s ymptomsAll babies in the United Kingdom have asample of
blood taken when they less than aweek old. The sample is tested for
signs ofseveral diseases which in some healthauthorities will
include CF. About 1 in 10babies born with CF are very ill in the
firstfew days of life with an obstruction of thebowel. If the test
suggests that the baby might
have CF then a sweat test is given. In the1950s it was
recognised that children with CFhave more salt in their sweat than
normal sothe sweat test measures the amount of salt inthe sweat. If
the salt level is very high then thechild has CF. Other early
symptoms are atroublesome cough, repeated chest
infections,prolonged diarrhoea or poor weight gain.
The caus eIn 1989 the CF gene was identified. A large
number of mutations (about 450 are known)can occur which alter
the structure of a largeprotein called theCystic Fibrosis
TransmembraneConductance Regulator (CFTR) which carries
Cyst ic
fibrosis
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chloride ions across the membrane of cellslining the lungs and
digestive tract. The alteredprotein doesnt do its job properly, so
that toomuch chloride ion is secreted.
P redictive tes tsFor most carriers of CF (about 75% of
those
affected in Britain) the cause is the same amutation calledF508.
It is now possible tofollow the CF mutation in families. A test
hasbeen developed which identifies who is acarrier, or for prenatal
diagnosis. This isusually carried out during the first third
ofpregnancy (the first trimester) at between tenand twelve weeks
using chorionic villussampling (CVS). A small sample of
thedeveloping placenta is removed and sent tothe DNA laboratory for
analysis. The results
are then compared with those of the parents.If the tissue from
the foetus has only CFalleles, then the child will have CF at
birth.Most prenatal diagnoses have been carried outfor couples who
already have one child with CF.
P rimary ca reThis is designed to keep the lungs as healthyas
possible. Physiotherapy helps to clear thesticky mucus from the
lungs; breathing exercisesand regular physical exercise also
help.
Physiotherapy is normally done twice a day.Chest infections are
prevented and treated withantibiotics. As children get older the
problemsincrease. To date there have been severalsuccessful
heart-lung transplants in CF sufferers.
The future85% of CF carriers can easily be identified. Insome
places all pregnant women are beingoffered a CF carrier test as
part of a pilotscheme. If the mother is a carrier, the husbandwill
also be offered a carrier test. Such aprogramme has the potential
of reducing the
incidence of CF in the population.A recent development is the
genetic screeningof very early stage embryos resulting
frominvitrofertilization. Those embryos which willnot develop into
CF children are selected forimplantation into the mother who
thenundergoes a normal pregnancy. Furtherexperimental work is at
present being directedtowards detecting CF genes in the eggs
beforefertilization.
Is research leading to a cure for CF? Now thatthe gene has been
located and the function ofthe protein that is affected is
beginning to beunderstood, scientists are trying several
newapproaches. New genetic techniques arebeing used to make better
drugs there willsoon be new pancreatic supplements availablemade
using human genes, and also humanDNase which loosens the mucus in
the lungs.Other scientists are using the human CFTR
gene to make protein which will beintroduced directly into lungs
of patients.Gene therapy is another technique where anormal copy of
the CFTR gene is put into thecells lining the lungs to restore
normal function.
cf N N cf
Carrierfather
Carriermother
N= dominant normal allele
cf= recessive CF allele
Inheritance ofCystic fibrosis
(Autosomal recessive)
N N N cf c f c fc fUnaffected
childCarrierchild
Carrierchild
Affectedchild
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Duchenne
m us cula r dys trophy
More than 20 conditions can be calledmuscular dystrophies since
they affectmuscle cells, causing them to breakdown. In the United
Kingdom severalthousand children have some type of MDand about half
of these are boys withDuchenne Muscular Dystrophy (DMD).It is so
called because it was firstdescribed by the French
neurologistG.A.B. Duchenne in 1858.
FrequencyDMD is one of the most common andsevere disorders
caused by a single gene. Itaffects about 1 in every 3 000 males
born.Girls are affected only extremely rarely.
Symptoms
During their first few years of life infantsappear normal but
then a gradual, relentlessweakening of the muscles begins in
earlychildhood. Infants may be late in starting towalk and they
have problems connectedwith walking. Between the ages of 3 and 7,as
the disease progresses, they becomemore and more clumsy and have
difficultywalking, running, climbing stairs andgetting up after a
fall. At this stage doctorscan usually diagnose the disease by
means
of chemical tests (creatine kinase, anenzyme, is usually present
in large amountsin the blood of those affected) or by amuscle
biopsy. Muscle weakness getsprogressively worse and in most
casescontractures develop in the ankles, kneesand hips. This means
that the muscles getshorter because they are not used, causingthe
joints to become stiff and tight. By theage of 10 or 12 most boys
with DMD areunable to walk. They have to use a
wheelchair, and after this their arms growslowly weaker. Pushing
their ownwheelchair becomes impossible, so theybecome dependent on
others (or an electric
wheelchair) for mobility. Sitting and lyingdown become difficult
and uncomfortablebecause of the stiffening in the lower body.As the
muscles get weaker and weaker, thebreathing muscles eventually
becomeaffected. Boys with DMD therefore have ashortened life
expectancy because they findit difficult to recover from chest
infections.All attempts to find out why the childrensmuscles
suffered breakdown wereunsuccessful. There are about 10 000proteins
involved in the development andfunction of muscles and the vast
majority ofthese remain unstudied. Biochemists couldnot find any
difference between normalmuscle and that from DMD sufferers.
Hereditary bas isThis disease is caused by a recessive allele
on
the X chromosome. With extremely rareexceptions, only boys are
affected.
Daughters receive one X chromosomefrom their mother and one X
chromosomefrom their father while sons receive the Xchromosome from
their mother and the Ychromosome from their father. In femalesthe
normal allele on one of the Xchromosomes masks the DMD allele onthe
other X chromosome, so that the
individual is not affected but is a carrier ofthe condition. In
males there is noequivalent allele on the Y chromosome tomask a DMD
allele on the X chromosome.
Daughters have a 50% chance of beingunaffected or being
carriers; sons have a50% chance of being unaffected oraffected.
With each pregnancy therefore, acouple in which the female is a
carrier has a25% chance of having an unaffected
daughter, a 25% chance of having a carrierdaughter, a 25% chance
of having anaffected son, and a 25% chance of havingan unaffected
son. The 50% risk does not
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mean thatexactlyhalf of the sons will getthe disease if the
mother is a carrier of theDMD allele.
If there were four sons, then none, one, two,three or even all
four could be affected. It isalso possible for DMD to appear for
the first
time in a family in which there is no history ofthe disease this
is due to a genetic mutationand occurs in about a third of
cases.
The caus eIn 1987 the gene responsible for DMD wasisolated. It
is located on the short arm of theX chromosome and is the largest
gene yetdiscovered. Some 60% of boys with DMDshow a piece of the
gene deleted. The proteinthat it encodes is named dystrophin,
and
forms part of the structure of the tissue thatsurrounds muscle
fibres.
P redictive tes tsAt present it is possible to identify from
thefamily tree which women are at risk of beingcarriers. A
combination of creatine kinase andDNA tests allow the great
majority of suchwomen to be either identified as carriers orgiven a
strong reassurance that the risk is very low.
The condition can be diagnosed at about the10th week of
pregnancy using DNA studiesperformed beforehand on all the
necessarymembers of the family. These can give preciseinformation
which allows the status of theunborn baby to be identified when its
DNA is
studied e.g. by a chorion villus biopsy (CVS).If this is not
possible, the sex of the foetus canbe determined by amniocentesis
at about 16weeks but this will not show whether themale is affected
or not.
P rimary ca re
Primary care can be provided by: Family members
good general health, regular active exerciseand not being
overweight to maintainmuscle strength;
Physiotherapistsearly identification of contractures andspinal
curvature to allow effective andpreventative treatment using
specialexercises;
Occupational therapists
special equipment to maintain independence; Surgeons
surgical treatment for contractures andspinal deformity may be
considered.
The futureIn 1990 the first stages in the development ofcell
therapy took place and small-scale humanexperiments began in boys
affected by DMD.In 1991 the first stages in the development of
gene therapy took place. A copy of the genecoding for dystrophin
was inserted intocultured cells, and these were shown to becapable
of manufacturing dystrophin. Thesearch for a treatment and an
eventual curecontinues.
Unaffected
father
Carrier
mother
n= normal al lele on Xchromosome
Inherit ance ofDuchenne musculardystrophy
(X-linked)
n Carrier
daughterAffected
sonUnaffecteddaughter
Unaffectedson
D= DMD allele on Xchromosome
= no allele on Ychromosome
D
D D
n n
nnn
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Huntingtons
d i s e a s e
In 1872 George Huntington, a 22 year-oldAmerican doctor from
Long Island, New
York, presented his scientific paper onChorea to the medical
academy inMiddleport, Ohio. The paper, the onlyone Huntington ever
had published,appeared later in theMedical and SurgicalReporter of
Philadelphia. He accuratelydescribed the inherited nature of a
diseaseas it passed through the generations ofseveral Long Island
families. The diseasewas later named after him asHuntingtons chorea
(a term meaningpurposeless movements) today it ismore commonly
called Huntingtonsdisease (HD).
An important feature of HD is that thesymptoms do not appear
until the personapproaches or reaches middle age;usually years
after he or she has bornechildren. In the past people with HD
didnot live long enough for the disease tohave much effect on them.
Nowadays thesingle allele responsible for the diseasehas more time
to express itself.
FrequencyAbout one in every 2 700 people are borncarrying the
allele that causes Huntingtons
disease. However, as the onset of the diseaseis late, only about
one in 10 000 has thedisease at a given time. Both males andfemales
are affected equally.
SymptomsHuntingtons disease is caused by the gradualdestruction
of brain cells, particularly in thoseparts of the brain known as
the basal gangliaand the cerebral cortex. By some mechanismas yet
unknown, the gene, which for years
remains inactive, begins to take its toll. Oncebrain cells die
they can never be replaced. Thegradual destruction of brain cells
causessymptoms which are similar to, but more
BRIE
FINGNOTES
pronounced than, the normal process ofageing. Early signs of the
illness, which startaround 3545 years of age, are mild andincrease
very slowly and gradually with achange in the persons usual
behaviour; theybecome depressed and moody, haveunreasonable
outbursts of anger, or haveunusual jerky, fidgety movements and
atendency to be clumsy or to fall down.
Over the years the symptoms become moresevere. Walking is
increasingly difficult, theperson suffers from dementia, loss of
physicalcontrol and wasting of the body. The diseaseusually lasts
for about 1020 years after whichtime death occurs, often from
secondaryinfections, heart failure, pneumonia orchoking. HD has
been called the mostdemonic of diseases and in the past,
manystories of demonic possession and witchcraftmay have stemmed
from the behaviour ofHuntingtons sufferers.
Hereditary bas is
In 1968 it was discovered that Huntingtonsdisease followed the
pattern of a dominantallele if either parent has this allele
theneach son and daughter has a 50% chance ofinheriting HD and they
are said to be at risk.
The 50% risk factor does not mean thatexactly half of the
children will inherit thedisease in a family where HD is known tobe
present. Each individual child stands a50% chance at the moment of
conceptionof inheriting HD. This could mean, forexample, that one
child in a family of fourchildren will develop HD, or two
mayinherit it, or three, or perhaps all four ornone. Huntingtons
never skips ageneration. If a parent with HD has a child
who escapes the disease, then that childcannot pass on the risk
to any of his or herchildren: all people who are unaffected arefree
of the disease-causing allele.
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P redictive te stsIn the past a person known to be at risk
fromHD had to live until middle age withoutshowing any sign of the
disease before his orher children could be sure that they (and
theirchildren) were free from risk. In 1983,markers close to the HD
allele were located
on chromosome 4 people who inheritthese markers are likely to
inherit the HDallele as well. In different people, even fromthe
same family, different forms of themarkers can be identified.
Predictive testsbased on these markers can be used, althoughthe
test will not work for every individual whois at risk. In the near
future tests based on thedetection of the HD allele itself will
becomeavailable.
Difficulties w ith HD
The hereditary nature of HD makes theprospect of starting a
family particularlydifficult. Many individuals who are at risk
havealready established families before they learnabout HD or fully
understand the nature of it.Some who fully understand HD and
itshereditary implications may choose to havechildren; others may
decide not to havechildren of their own in order to avoid
passingthe disease on to another generation. Throughcounselling the
full implications of the genetic
characteristics of HD should be discussed andall the
alternatives available should beconsidered. For those affected by
HD, overtime the marriage relationship will alter andthe partner
with HD will be less of a friend,companion and lover this adds
personal
grief to a complex situation for all concerned.Other important
worries about HD are inrelation to insurance, employment,
mortgagesand so on.
P rimary carePrimary care can be provided by:
Occupational therapistsassess what help and/or home
extensionsare needed to help the patient;
Physiotherapistscan help patients to reduce difficultieswith
balance and physical co-ordination;
Speech therapistsgive advice on methods of
maintainingcommunication skills;
Public health nurseshelp with bathing, dressing, skin and
basic
care; Community psychiatric nurses
advise the family on patients behaviouralor psychological
problems.
The futureIn 1993, the exact location of the HD allelewas
pinpointed. It will only be a matter oftime before the structure of
the HD gene isworked out. Then it will be possible todetermine
which protein is affected.
Treatment of this disorder might then beachieved by
administering this protein toalleviate the condition this may be
possibleusing cell therapy techniques. Eventually genetherapy might
alleviate the symptoms of orprevent Huntingtons disease.
Affected
father
Unaffected
mother
H= dominant HD allele
n= recessive normal
Inheritance ofHuntingt ons disease
(Autosomal dominant )
Affectedchild
Affectedchild
Unaffectedchild
Unaffectedchild
nnn
nnnnnn
H
HH
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1 You have selected a male or a female card of a particular
colour and number.Do not be concerned if it is not the correct
sex!
2 Look for a partner, that is, someone who has a card of the
same colour as yours
but the opposite sex (on the card). For the duration of this
simulation you are nowhusband and wife!
3 Turn your cards over and set them side by side. Each card
contains informationfrom genetic screening tests regarding your
inheritance for one of three severegenetic diseases CF = Cystic
fibrosis, DMD = Duchenne muscular dystrophy
and HD = Huntingtons disease.
From this information do you, as parents, think that you are you
at risk ofhaving children who will suffer from CF, DMD or
HD?Explain your reasoning.
4 Now read about the relevant disease from the briefing
notes.
Work out the reasons why your children might suffer from this
geneticdisease and what the chances of them being affected are.Find
out as much information as possible about the disease, what
treatmentsare available etc. Ask for help if you need it.
Works he e t 1
ISSUESINHUMA
NGENETICS
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Works he e t 2
1 Having identified the genetic disease in your at-risk family
and found out as much asyou can about it, try to make the following
decisions, which must be agreed upon byboth partners. Ask for
further information if you need it.
DECISION 1 Will we have any children?
Give reasons for your decision.
2 Whether or not you have decided to have any children, assume
that you have decidedthat you do want children. Examine the sheet
GENETIC DISORDERS: preventionand cure, and ask for any help if you
need it.
Consider the various options that are open to you e.g. to have
children in the normal
way, to adopt children (rare nowadays), embryo selection, in
vitro fertilization bydonor, surrogate motherhood, abortion
etc.
DECISION 2 Discuss all the possibilities and place them in rank
order ofpreference (most preferred first).
3 No matter what your decision in 2 was, imagine that the female
partner has just foundout that she is pregnant.
DECISION 3 Will we have a prenatal diagnostic test?Give reasons
for your decision.
CONTINUED OVERLEAF...
ISSUESINHUMA
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Works hee t 2 (continued)
4 Imagine that you have decided to have a prenatal diagnosis
test and that theresult is positive your child will definitely
suffer from CF, DMD or HD.
DECISION 4 Decide what options are now available and what you
woulddo. Once again, give reasons for your decision.
5 No matter what decision you made in 4, imagine that you
decided to continue the
pregnancy.
DECISION 5 Look again at all the information, but this time
consider
carefully the treatments that are available at present, ormight
be in the future e.g. primary care, therapeutic drugs,organ
transplants, cell therapy or gene therapy etc. Try torank them in
order of preference.
6 The situation above considered a very serious genetic disease.
As we learnmore about the genetic predisposition to more and more
diseases e.g. cancer,
heart disease etc. decisions such as those above might become
more common-place (and in some cases, more difficult).
DECISION 6 Would the decisions that you made above be different
if thedisease under consideration was: heart disease;
diabetes;schizophrenia; cancer; or flat feet?
ISSUESINHUMA
NGENETICS
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PROSPECTIVE PARENTS
somatic (body) cellseg white blood cells
KARYOTYPEchromosomeirregularities
To have children
or not; or choose
to adopt childrengeneirregularities
(carriers)
sperm
productionof sex cells
fertilisation (normal orin vitro)prevention bycontraception
ovum (egg)
fertilised egg(zygote)
divides divides
divides
PCR DNA analysis
DNAregular
DNAirregular
implant
discard
divides
8 -12 weekembryo
one cell
removed
DNA
isolated
chorionic villus samplingkaryotyping
16 we