genetics - 1997 - issues in human genetics european initiative for biotechnology education unit 4

5/28/2018 Genetics - 1997 - Issues in Human Genetics European Initiative for Biotechnology Education Unit 4

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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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3EIBE European Ini tiati ve for Biotechnology Education1 9 9 5 UNIT4: ISSUESINHUMANGENETICS.......

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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

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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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10UNIT4: ISSUESINHUMANGENETICS EIBE European Ini tiati ve for Biotechnology Education1 9 9 5

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


14/41

.......


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.


15/41


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


16/41

.......


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


17/41


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.


18/41

.......


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.


19/41


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


20/41

.......


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.


21/41


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


22/41

.......


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



23/41


GENET

ICSCARDS

P hotocopy thes e ca rds onto coloured ca rd for us e in


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


24/41

.......


U

N

IT

4European I ni ti ati ve for Biotechnology Education

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

BRIE

FINGNOTES


25/41


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


26/41

.......


U

N

IT


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

BRIE

FINGNOTES


27/41


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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.......


U

N

IT


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

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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...

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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

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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

genetics - 1997 - issues in human genetics european initiative for biotechnology education unit 4

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