Issues in human genetics

UN

IT4Issues inhuman genetics

European Initiative 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.

EIBE

This teaching package (EIBE Unit 4) was produced by the European Initiative for Biotechnology Education. The Unit is available on the World Wide Web, at: http://www.reading.ac.uk/NCBE For more information about this Unit , please contact: Wilbert Garvin, The Queen's University of Belfast, BELFAST, The United Kingdom. Tel: + 44 (0) 1323 245133 Extension 3919. Fax: + 44 (0) 1323 331845. E-Mail: [email protected] Copyright (c) 1995, 1996

....

...

2 UNIT 4: ISSUES IN HUMAN GENETICS EIBE European Initiative for Biotechnology Education 1995

The European Initiative for Biotechnology Education (EIBE) seeksto promote skills, enhance understanding and facilitate informedpublic debate through improved biotechnology education inschools and colleges throughout the European Union (EU).

EIBE Co-ordinatorHorst Bayrhuber, Institut für die Pädagogik der Naturwissenschaften an der Universität Kiel, Olshausenstraße 62,D-24098 Kiel 1, Germany. Telephone: + 49 (0) 431 880 3137 (EIBE Secretary: Regina Rojek). Facsimile: + 49 (0) 431 880 3132.

EIBE ContactsAUSTRIA❙ Rainhart Berner, Höhere Bundeslehr- und Versuchsanstalt für Chemische Industrie Wein, Abt. für Biochemie,Biotechnologie und Gentechnik, Rosensteingasse 79, A-1170 WIEN.

BELGIUM❙ 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, Sønderengen 20, DK-2860 SØBORG.❙ 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❙ Gérard Coutouly, LEGPT Jean Rostand, 18 Boulevard de la Victorie, F-67084 STRASBOURG Cedex.❙ Laurence Simonneaux, Ecole Nationale de Formation Agronomique, Toulouse-Auzeville, Boîte Postale 87,F-31326 CASTANET TOLOSAN Cedex.

GERMANY❙ Horst Bayrhuber / Eckhard R. Lucius / Regina Rojek / Ute Harms / Angela Kroß, Institut für die Pädagogik derNaturwissenschaften, Universität Kiel, Olshausenstraße 62, D-24098 KIEL 1.❙ Ognian Serafimov, UNESCO-INCS, c/o Jörg-Zürn-Gewerbeschule, Rauensteinstraße 17, D-88662 ÜBERLINGEN.❙ Eberhard Todt, Fachbereich Psychologie, Universität Gießen, Otto-Behaghel-Straße 10, D-35394 GIEßEN.

ITALY❙ Antonio Bargellesi-Severi / Stefania Uccelli / Alessandra Corda Mannino, Centro di Biotechnologie Avanzate,Largo Rosanna Benzi 10 , I-16132 GENOVA.

LUXEMBOURG❙ John Watson, Ecole Européenne de Luxembourg, Département 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 Matthée, 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.

SPAIN❙ Maria Saez Brezmes / Angela Gomez Niño, Facultad de Educación, Universidad de Valladolid,Geologo Hernández Pacheco 1, ES-47014 VALLADOLID.

SWEDEN❙ Margareta Johanssen, Föreningen Gensyn, PO Box 37, S-26800 SVALÖV.❙ Elisabeth Strömberg, Östrabo 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 Queen’s 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.

3EIBE European Initiative for Biotechnology Education 1995 UNIT 4: ISSUES IN HUMAN GENETICS

......

.

UN

IT4Issues inhuman genetics

World Wide WebFew 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 ofthe 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 - includingPower 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 ofthe Adobe Acrobat ® Reader programme.

The Acrobat ® Reader 3.0 programme isavailable free-of-charge in several languages(Dutch, UK English, French, German, Italian,Spanish and Swedish). It can be downloadedfrom 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 to‘navigate’ around and search the documentswith ease.

PLEASE NOTE: Adobe and Acrobat are trademarks ofAdobe Systems Incorporated, which may be registeredin certain jurisdictions. Macintosh is a registeredtrademark of Apple Computer Incorporated.

★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★

Contents★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★

MA

TE

RIA

LS


❙ Development team, copyrightand acknowledgements 4

❙ About this UnitIntroduction 5

❙ Background information 7Cells, chromosomes, genes and proteins;Different forms of genes; What is a genetic‘disease’?; 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 these materials Guidelines for teachers 18❙ Photocopy masters

Genetics cards 21Cystic fibrosis

Briefing notes 24Duchenne muscular dystrophy

Briefing notes 26Huntington’s disease

Briefing notes 28Worksheet 1 30Worksheet 2 31–32Genetic disorders diagram 33

❙ Appendix 1Eugenics 34

❙ Appendix 2Cultural contexts of genetic screening 36

❙ Appendix 3Additional resources andsources of information 38

❙ Appendix 4Human genetics questionnaire 40–41

http://www.adobe.com/

http://www.reading.ac.uk/NCBE

....

...


Development team● Catherine Adley

The University of Limerick, Eire.● Jan Frings

Hogeschool van Arnhem en Nijmegen, Netherlands.● Wilbert Garvin (Unit Co-ordinator)

The Queen’s 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 from ‘Genetics and the understanding oflife’ in the background information in this Unit. The Daily Telegraph newspaper, 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, København, Denmark), Wilbert Garvin (Northern IrelandCentre for School Biosciences, The Queen’s 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 Grønqvist; JytteJørgensen; Tine Bing; Per Vollmond; Anker Steffensen.From Eire: John Lucey; Michael O’Leary; Bruno Mulcahy; Tim O’Meara; Tom Moloney; BrendanWorsefold; Frank Killelea.From Germany: Ulrike Schnack; Werner Bährs; Jürgen 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.

© CopyrightThis EIBE Units is copyright. The contributors to thisUnit have asserted their moral rights to be identified ascopyright 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 and identified as the copyright holders.

Other uses. The Unit may be distributed byindividuals to individuals for non-commercial purposes,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 wishto 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 für die Pädagogikder NaturwissenschaftenUniversität KielOlshausenstraße 62D-24098 KielGermany

Telephone:+ 49 (0) 431 880 3137Facsimile: + 49 (0) 431 880 3132E-Mail: [email protected]

EIBE E

INT

RO

DU

CT

ION

About this Unit★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★

This Unit comprises a rôle play abouthuman genetic diseases, with supportingeducational resources. These materials havebeen devised by practising teachers andeducationalists from several Europeancountries, brought together with supportand encouragement from DGXII of theEuropean Commission, under the auspicesof EIBE, the European 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 teacher’s 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 rôle playcentred around three serious inheritedconditions: Cystic fibrosis; Duchennemuscular dystrophy and Huntington’sdisease.

Many important moral and social questionscan be raised regarding the application ofscientific 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,is normal ?;

● the application of prenatal diagnosis;● termination of pregnancy (abortion)

and the alternatives;

uropean Initiative for Biotechnology Education 1995

● 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 addressthese 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 in Appendix 3.

The classroom activities in this Unit were devisedby Wilbert Garvin, Director of the NorthernIreland Centre for School Biosciences at theQueen’s 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 Queen’s University of BelfastBELFASTBT7 1NNThe United Kingdom

Telephone: + 44 (0) 1232 245133 extn. 3919Telefax: + 44 (0) 1232 331845E-Mail: [email protected]

5UNIT 4: ISSUES IN HUMAN GENETICS

......

.

....

...


EIBE

BAC

KGR

OU

ND

INF

OR

MA

TIO

N
Genetic disease★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★
Cells, chromosomes,genes 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)and protein. Particular sequences ofinformation in the DNA are called genes.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 suchcomplex interactions.

European Initiative for Biotechnology Education 1995

Body

Cells

Chromoso

AaProtein

Different forms of genesEach gene can come in alternative forms,called alleles. 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 weinherit two alleles, one carried on each of thepair of chromosomes we have received fromeach of our parents. Some alleles are dominantand their effects are seen regardless of thenature of the other allele on theaccompanying chromosome. Other alleles arerecessive and their effects are only seen whenboth chromosomes carry an identical form ofthe gene.

Variation in genes arises naturally by randommutation. 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 endurancesports easier than the average person does.


......

.

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.

mesDNA

minocids

....

...

8 UNIT 4:

1

1

Belowof chro

VirtuaTwo mhave nspermchromo

Men hX chrochrom

What is genetic ‘disease’?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 issignificant — 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 Down’s 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.

ISSUES IN HUMAN GENETICS

4 5 62 3

3 14 15 16 17 18

: Most human genes are packaged into 23 pairsmosomes.

lly all cells contain a full set of chromosomes.ajor exceptions are mature red blood cells (whicho chromosomes) and the sex cells (eggs and) which carry only one set of 23 unpairedsomes.

ave an X and a Y chromosome; women have twomosomes. After staining with various dyes, eachosome reveals a unique pattern of bands.

Because genetic ‘diseases’ cannot be ‘caught’like 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. Recessive conditionsSome disease-causing alleles are recessive: tobe affected a person must carry two identicalforms of the gene. For example, sickle cellanaemia occurs when someone receives twocopies 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.

EIBE European Initiative for Biotechnology Education 1995

7 8 9 10 11 12

19 20 21 22Y

X

EIBE

Sickle cell anaemiaOne of the commonest genetic diseases issickle cell anaemia. People who are affectedby the disease have red blood cells that altertheir shape when the oxygen concentrationbecomes low. These sickle-shaped cells oftenburst open or clog the small blood capillaries,starving the tissues of oxygen and causing theaffected person to suffer mild to extreme pain.Additional complications can arise, especiallyduring exercise.

In 1949, the U.S. chemist Linus Pauling tracedsickle cell anaemia to a specific change in thestructure of haemoglobin, the red oxygen-carrying pigment in the blood. When heexamined the molecular structure ofhaemoglobin from sickle cell anaemia patientsPauling found that it differed from ‘normal’haemoglobin.

Adult haemoglobin is constructed of two α-globin chains, each 140 amino acids long, andtwo β-globin chains, each with 146 aminoacids.

The sole change in the abnormal haemoglobinwas the replacement of one amino acid,glutamic acid (glu) by valine (val) at the sixthposition in the β-globin chain.

val — his — leu — thr — pro — glu — glu —‘Normal’ amino acid sequence

val — his — leu — thr — pro — val — glu —Sickle cell amino acid sequence

Haemoglobin molecule

β-globin proteins

Red blood cells

2. Dominant conditionsIf a disease is caused by a dominant allele, aperson has only to inherit one copy to havethe disease. If any of that person’s childrenreceive 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 is Huntington’s disease,which is characterised by the progressivedevelopment of involuntary muscularmovements and dementia, from the mid-thirties onwards. Huntington’s disease isdiscussed in detail later in this Unit.


3. Sex-linked conditionsAmong the 23 pairs of chromosomes that allhumans have, one pair is connected with theperson’s gender or sex. Females have twosimilar 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, aremore 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


......

.

....

...

10 UNIT 4

Somclearmulti

very rarely affected by this condition, 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 isthat 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.

: ISSUES IN HUMAN GENETICS

Mode of Disease/ Main inheritance condition featur

Sporadic Down’s syndrome RangeKlinefelter’s syndrome Defec

Autosomal recessive Cystic fibrosis Wide rto excespeci

Phenylketonuria MentaSickle cell anaemia Chron

or haeTay-Sachs disease DeafnThalassaemias Severe

Autosomal dominant Familial hyper- High ccholesterolaemia early cHuntington’s disease InvoluPolycystic kidney disease Cysts

X-linked Haemophilias Failureexcess

Duchenne musculardystrophy MusclLesch-Nyhan syndrome Menta

Multifactorial

(often with a high Asthma Difficgenetic contribution) Coronary heart disease Arteri

can lea

e of the 4,000 known genetic conditions. Mendelian conditi pattern of inheritance, whereas it is less easy or impossiblefactorial conditions.

Finding disease-causing genesLinkage 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 largenumbers 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 producecorresponding gene probes that allow conclusiveidentification of those who carry potentiallyharmful genes.

Many other disorders, whose genes have notyet been isolated, have been mapped to theirapproximate locations in a chromosome.These genes too can be identified by usinggene probes, although with less certainty.One recent success involved Huntington’sdisease, a devastating condition that usuallyappears between the ages of 30 and 50 andleads to uncoordinated limb movements, mentaldeterioration and death. In 1983, Jim Gusella and


Time of onsetes of symptoms

of mental retardation, etc. Birtht in sexual differentiation Birth

ange of complications dueessively thick mucus secretion,ally in the lungs/digestive system 1–2 yearsl deficiency Birthic anaemia/infections/painfulmolytic crises 6 months onwardsess/blindness/seizures/spasticity 3–6 months anaemia/skeletal deformity Six months onwards

holesterol level leads tooronary heart disease 20–30 yearsntary movements/dementia 35–45 years

in liver/pancreas/spleen/kidney 40–60 years

of blood to clot. Bruising andive bleeding after injury 1 year onwards

e wasting 1–3 yearsl retardation/self-mutilation Birth

ulty breathing Birthes become narrowed,d to heart failure Middle age

ons (recessive, dominant and X-linked) follow a to predict the occurrence of sporadic and

EIBE

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.

Steroidsulphatasedeficiency

Duchennemusculardystrophy

Ornithinetranscarbamoylasedeficiency

Androgen insensitivity

Lowe syndrome

Lesch-Nyhan syndrome

Haemophilia B

Haemophilia A

Fragile Xsyndrome

Chronicgranulomatousdisease

colleagues at the Massachusetts GeneralHospital, Boston, reported that they hadpinpointed a marker gene close to theHuntington’s disease allele on chromosome 4.Then, in 1993, following a decade ofpainstaking research, they and collaborators atother U.S. centres and the University of WalesCollege of Medicine in the UK announced theprecise position of the Huntington’s 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 Huntington’s 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.

Screening and counsellingGenetic 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 theoption 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 complicationarises because genetic conditions may affectrelatives of the individual who is directlyaffected, so it may not be easy to apply normalrules of medical confidentiality.

11 European Initiative for Biotechnology Education 1995 UNIT 4: ISSUES IN HUMAN GENETICS

......

.

....

...

12 UNIT 4:

Amniocentesis

Biochemicalstudies

DNAanalysis

Chromosomeanalysis

Prenataltesting

Chorionic villussampling

Screening in early pregnancyThere 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 Down’ssyndrome). It can provide results that eitherreassure the parents or give them evidenceupon which to make a decision.

Amniocentesis is carried out from 10 weeks’gestation. 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 Down’s syndrome.

Chorionic villus 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 atKing’s 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, althoughrelatively untried as yet, is thought topresent significantly less risk to the safety ofthe unborn child than either amniocentesisor chorionic villus sampling.


EIBE

SouthSouthdiagnanaewhiteenzymglutahaemcell hfragmprobe

If the splitsthe geand bradiotwo bhaemby the

‘Normal’ βglobin allele

Sickle cellβ globinallele

GTG(Val)

1 300 base pairs

1 100 base pairs GAG(Glu)

‘Normal’Carrier

200 bp

1 100 bp

1 300 bp

Movement of DNAfragments

Sickle

Human bl oodsampl e

DNA is extracted fromthe white blood cells

The DNA is cut into fragments...

...which are separatedby size...

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 byone 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.

Screening for haemoglobin disordersThe World Health Organisation forecaststhat by the year 2 000 approximately 7% ofthe world’s 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 thehaemoglobin 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, β-thalassaemia.

13 European Initiative for Biotechnology Education 1995 UNIT 4: ISSUES IN HUMAN GENETICS

......

.ern blotting (named after its inventor Edern) is one simple test which illustrates theosis of a condition such as sickle cellmia. First, DNA is extracted from the patient’s blood cells. This is then exposed to an

e that recognises the site coding for themic acid (glu) that is present in normaloglobin but replaced by valine (val) in sickle

aemoglobin. The resulting mixture of DNAents are separated by size, and treated with a for the normal gene.

patient’s haemoglobin is normal, the enzyme it into two fragments, each containing part ofne. The probe DNA binds to each of these,

ecause the probe has been made slightlyactive the two fragments can be detected aslack bands on a photographic film. If theoglobin is the sickle cell variety, it is not cut enzyme, and only one black band appears.

...and transferredto a nylon membrane

A radioactiveprobe binds tothe DNA...

...revealing apattern ofbands on X-rayfilm

....

...

14 UNIT 4:

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 testsshow 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.

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 ofhaemoglobin 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 β-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 suchadvances, 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.

Pinpointing the cystic fibrosis geneIn 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 itpossible to identify 85–95% of carriers,depending on racial and ethnic background.This begins to make population screeningseem more feasible.


Preimplantation diagnosisRecently, genetic screening was extended toembryos produced by in vitro fertilization —by adding spermatozoa to egg cells growing inlaboratory glassware. This method ofproducing embryos was originally developedto allow certain infertile couples to have ‘testtube’ 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 (6–10 cell)embryos and then to sex them by examiningspecific 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 byamniocentesis 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 musculardystrophy. 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.



Samplecell

tested

Selected embryoimplanted in

womb, where itdevelops normally

Fertilized celldivides to form anembryo of 6–10

cells

Remainder ofembryo frozenuntil tests are

complete

Egg fertilizedin vitro

Principles of gene therapyUntil 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 ofdisease-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 thedysfunctional 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 cellcultured in 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. Forexample, it may not be desirable to removecarrier potential from the population, since insome circumstances apparently deleteriousalleles may be beneficial.


......

.

....

...

16 UNIT 4:

Belowin theResegene

BothLo

Thin

ge

ThwetoNe

First steps in gene 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 didso by squirting into the lungs copies of a genecalled CFTR encased in liposomes (tinyglobules of fat). The liposomes fused with theanimal’s 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


: Gene therapy to combat Severe Combined Immunodefi following year, at London’s Great Ormond Street Hospital,arch Institute in Delft. The treatment involved the replacem was placed in the stem cells of the bone marrow, so that bl

ne marrow stem cells were taken frome affected baby by Dr Gareth Morgan atndon’s Great Ormond Street Hospital.

The baby’s stem cells wereinfected by the modified virus

The cells were cultured for several daysthen returned to London

e modified virusserted the ADAne into the stem

cells

At thDelftthe mbone

e cellsre flown

thetherlands

introduced a normal allele to compensate forthe abnormal one responsible for 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 thepatient’s 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


ciency (SCID) was carried out in Italy in 1991 and with the help of colleagues from the TNOent of a missing gene for an enzyme (ADA). The

ood cells derived from them would produce ADA.

,

The virus was renderedharmless by removing thegenes which allowed it to

reproduce

e TNO Research Institute in, Professor Tinco Valerio isolatedissing ADA gene from the

marrow of a healthy donor

The modified stem cellswere injected into thebaby’s bone marrow,where they producedhealthy blood cells

complete with the ADAgene

The ADA genewas insertedinto a virus

EIBE

Normalmusclefrom ahealthydonor

Early stagemuscle cells(myoblasts)carrying normaldystrophingene

Cellstransferredto dystrophicmuscle

Rescuedmuscle, nowmakingdystrophin

Above: How cell therapy might be used to alleviatethe symptoms of Duchenne muscular dystrophy.

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 patient’s 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); Hurler’s syndrome (involving anenzyme called α-iduronisase); thalassaemiasand sickle cell anaemia (where the β-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 Hurler’ssyndrome 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 bythe disease. The modified cells will bebound together with collagen, thenreimplanted into the peritoneum (the bodycavity that contains the gut and other


organs). It is hoped that the implanted cellswill secrete α-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 patient’smuscles. 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 UNIT 4: IS

INST

RU

CT

ION

S
Using thesematerials★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★
This activity involves rôle-play and aims toinform students about three serious geneticdiseases (Cystic fibrosis, Duchenne musculardystrophy and Huntington’s disease).

Students adopt the rôle 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 andother choices that are now becomingavailable.

The exercise can foster an awareness thatscientific developments must be viewedwithin wider social, ethical and politicalcontexts. It should also help students tolearn more about their own and others’values 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.

Dealing with sensitive issuesIt 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 answersto which may indicate if anyone is affectedpersonally. Consider whether to discuss someconditions at all and if so, be prepared toproceed with caution and sensitivity.

SUES IN HUMAN GENETICS

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.

AimsTo 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 preparationStudents should read and understand theBriefing notes about the three genetic diseasesdescribed in this Unit.Teachers should 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 (see Dealing withsensitive issues).

OrganisationA minimum of 60 minutes should beallowed for this activity, in addition to thepreparatory work.

MaterialsRequired by each class of students

● Sufficient Genetics cards (in male andfemale pairs) for all the studentsinvolved (from the photocopy master inthis Unit)

● Sufficient copies of the Worksheets andBriefing notes for each student (from thephotocopy masters in this Unit)

Optional

● Background information from this Unit● Resource materials from various

associations and groups (see Appendix 3)● If they are available, video recordings

explaining Cystic fibrosis, Duchennemuscular dystrophy and Huntington’sdisease might prove useful.


EIB

Procedure in brief1. Do whatever Advance preparation is

necessary.2. Give out the Genetics cards to individuals.

Allow the students to organisethemselves to work in pairs.

3. Give out Worksheet 1.4. Give out the Briefing notes and use the

other resource materials as appropriate.5. Give out Worksheet 2.6. Show video recordings if they are

available and appropriate.

ExtensionFor biology students in particular thegenetics and the DNA technology involvedmay be extended to relate to other parts ofthe curriculum. (The Background informationin this Unit may be useful here.)

Procedure in detailThe accompanying Genetics cards should 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 withthe 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 that every couple willbe at risk of having children who areaffected. Card 1 for Cystic fibrosis, Card 2for Duchenne muscular dystrophy and Card3 for Huntington’s disease. These diseaseshave been chosen to represent a range ofmodes of inheritance and to raise a variety

E European Initiative for Biotechnology Education 1995

of issues associated with genetic disease.

Participants should be told that Briefing noteson the diseases are available forconsultation so that they can answer thequestions on the worksheets.

The cardsThere 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 = Huntington’sdisease.

Worksheet 1The couple has to decide which geneticdisease 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.Huntington’s diseaseIf one of the parents is affected then theoffspring are at risk of developing thedisease.

Worksheet 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 anydecisions for the ‘parents’. Instead, theteacher should adopt the rôle 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 1Even if a couple chooses not to havechildren at this stage, they should continueto Question 2. The Briefing notes should helphere.


......

.

....

...

20 UNIT 4:

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 particular‘parents’ 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 discussionaround 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.



......

.

GE

NE

TIC

S C

AR

DS

Photocopy these cards onto coloured card for use inthe rôle play. Each participant will need a card.

CARD 1 : MALE

CF CARRIER

DMD NORMAL

HD NORMAL

CARD 1: FEMALE

CF CARRIER

DMD NORMAL

HD NORMAL

CARD 1 : MALE

CF CARRIER

DMD NORMAL

HD NORMAL

CARD 1: FEMALE

CF CARRIER

DMD NORMAL

HD NORMAL

CARD 1 : MALE

CF CARRIER

DMD NORMAL

HD NORMAL

CARD 1: FEMALE

CF CARRIER

DMD NORMAL

HD NORMAL

....

...


CARD 2 : MALE

CF NORMAL

DMD NORMAL

HD NORMAL

CARD 2 : FEMALE

CF NORMAL

DMD CARRIER

HD NORMAL

CARD 2 : MALE

CF NORMAL

DMD NORMAL

HD NORMAL

CARD 2 : FEMALE

CF NORMAL

DMD CARRIER

HD NORMAL

CARD 2 : MALE

CF NORMAL

DMD NORMAL

HD NORMAL

CARD 2 : FEMALE

CF NORMAL

DMD CARRIER

HD NORMAL

GE

NE

TIC

S C

AR

DS



......

.

GE

NE

TIC

S C

AR

DS


CARD 3 : MALE

CF NORMAL

DMD NORMAL

HD AFFECTED

CARD 3 : FEMALE

CF NORMAL

DMD NORMAL

HD NORMAL

CARD 3 : MALE

CF NORMAL

DMD NORMAL

HD AFFECTED

CARD 3 : FEMALE

CF NORMAL

DMD NORMAL

HD NORMAL

CARD 3 : MALE

CF NORMAL

DMD NORMAL

HD AFFECTED

CARD 3 : FEMALE

CF NORMAL

DMD NORMAL

HD NORMAL

....

...

24 UNIT 4: IS

UN

IT4European Initiative for Biotechnology Education

Cysticfibrosis

BRIE

FIN

G N

OT

ES

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.

FrequencyIn 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 severethan 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 person’s healthdeteriorates. Vigorous chest physiotherapy (toremove the mucus) and treatment withantibiotics helps to control the infections.

The pancreas becomes blocked by the stickysecretions 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 basisThis condition is caused by a single gene,which was localised to chromosome 7 in1985. 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

★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★

SUES IN HUMAN GENETICS

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 symptomsAll 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 mighthave 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 causeIn 1989 the CF gene was identified. A largenumber of mutations (about 450 are known)can occur which alter the structure of a largeprotein called the Cystic Fibrosis TransmembraneConductance Regulator (CFTR) which carries


EIBE

chloride ions across the membrane of cellslining the lungs and digestive tract. The alteredprotein doesn’t do its job properly, so that toomuch chloride ion is secreted.

Predictive testsFor most carriers of CF (about 75% of thoseaffected in Britain) the cause is the same — amutation called ∆F508. 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 resultsare 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.

Primary careThis 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.


cf

Carriermother

N= dominant ‘normal’ allelecf= recessive CF allele

Inheritance ofCystic fibrosis

(Autosomal recessive)

NUnaffected

child

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 theincidence of CF in the population.

A recent development is the genetic screeningof very early stage embryos resulting from invitro fertilization. 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 CFTRgene 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.


......

.

N N cf

Carrierfather

N N cf cf cfcfCarrierchild

Carrierchild

Affectedchild

....

...

26 UNIT 4: I

UN


Duchennemuscular dystrophy

BRIE

FIN

G N

OT

ES

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.

SymptomsDuring 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 meansof 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 awheelchair, and after this their arms growslowly weaker. Pushing their ownwheelchair becomes impossible, so theybecome dependent on others (or an electric

★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★

SSUES IN HUMAN GENETICS

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 childrens’muscles 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 basisThis disease is caused by a recessive allele onthe 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 theindividual 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 unaffecteddaughter, 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


EIBE

mean that exactly half 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 firsttime 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 causeIn 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, andforms part of the structure of the tissue thatsurrounds muscle fibres.

Predictive testsAt 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


Carriermother

n= ‘normal’ allele on Xchromosome

Inheritance ofDuchenne musculardystrophy

(X-linked)

nCarrier

daughter

D= DMD allele on Xchromosome

✱= no allele on Ychromosome

D

D

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.

Primary carePrimary care can be provided by:

● Family membersgood 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 therapistsspecial equipment to maintain independence;

● Surgeonssurgical 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 ofgene 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.


......

.

Unaffectedfather

✱Affected

sonUnaffecteddaughter

Unaffectedson

D

n n

nnn

✱

✱

....

...

28 UNIT 4: I

UN


Huntington’sdisease

BRIE

FIN

G N

OT

ES

In 1872 George Huntington, a 22 year-oldAmerican doctor from Long Island, NewYork, presented his scientific paper ‘on

Chorea’ to the medical academy inMiddleport, Ohio. The paper, the onlyone Huntington ever had published,appeared later in the Medical and Surgical

Reporter 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 asHuntington’s chorea (a term meaningpurposeless movements) — today it ismore commonly called Huntington’sdisease (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 Huntington’sdisease. 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.

SymptomsHuntington’s 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 yearsremains 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

★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★


pronounced than, the normal process ofageing. Early signs of the illness, which startaround 35–45 years of age, are mild andincrease very slowly and gradually with achange in the person’s 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 10–20 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 ofHuntington’s sufferers.

Hereditary basisIn 1968 it was discovered that Huntington’sdisease 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. Huntington’s never ‘skips ageneration’. If a parent with HD has a childwho 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.


EIBE

Predictive testsIn 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 locatedon 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 with HDThe 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 geneticcharacteristics 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


Unaffectemother

H= dominant HD allelen= recessive ‘normal’

Inheritance ofHuntington’s disease

(Autosomal dominant)

Affectedchild

n

nH

grief to a complex situation for all concerned.Other important worries about HD are inrelation to insurance, employment, mortgagesand so on.

Primary 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 basiccare;

● Community psychiatric nursesadvise the family on patient’s 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 Huntington’s disease.


......

.

Affectedfather

d

Affectedchild

Unaffectedchild

Unaffectedchild

nn

nnnnn

H

H

....

...


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 yoursbut 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 dystrophyand HD = Huntington’s 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.

Worksheet 1IS

SUE

S IN

HU

MA

N G

EN

ET

ICS


......

.

Worksheet 21 Having identified the genetic disease in your ‘at-risk’ family and found out as much as

you 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 normalway, 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...

ISSU

ES

IN H

UM

AN

GE

NE

TIC

S

....

...


Worksheet 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 thepregnancy.

DECISION 5 Look again at all the information, but this time considercarefully 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?

ISSU

ES

IN H

UM

AN

GE

NE

TIC

S


......

.

PROSPECTIVE PARENTS

somatic (body) cells eg white blood cells

KARYOTYPEchromosomeirregularities

To have children

or not; or choose

to adopt childrengene irregularities

(carriers)

sperm

production of sex cells

fertilisation (normal or in vitro ) prevention bycontraception

ovum (egg)

fertilised egg(zygote)

divides divides

divides

PCR DNA analysis

DNAregular

DNAirregular

implant

discard

divides

8 -12 weekembryo

one cellremoved

DNAisolated

chorionic villus samplingkaryotyping

16 weekembryo amniocentesis

abortion

PCR DNAanalysis

abortion

continuepregnancy

continuepregnancy

BIRTH

ADOLESCENTOR ADULT

PRIMARY CARE minimising the effectsof the disorder

CELL THERAPY introducing normal cells into the body to produce the particular proteins required

relief ofsymptoms

introducing functional genesinto body cells

cure (partial)

replacing or augmenting the non-functional gene with a

functional gene

cure(inherited)

If parents ‘at risk’

CONDITION IDENTIFIED

2-cell stage

4-cell stage

DNA multipliedfor analysis

8-cell stage

chromosomesirregular

chromosomesnormalgenes

irregular(markersidentified)

genesnormal

SOMATICGENE THERAPY

GERM LINEGENE THERAPY

partialrelief of

symptoms

Genetic disorders : prevention and cure?

(PolymeraseChain

Reaction :PCR)

EMBRYO SELECTION

POSSIBLEDECISION

....

...

34 UNIT 4: I

UN


Appendix 1Eugenics

EU

GE

NIC

S

★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★

Some people associate developments in

modern human genetics with the type of

eugenics that occurred in Nazi Germany.

Such anxieties are probably unjustified,

but there is a need for wider public debate

and education to put current

developments into perspective and to

ensure that abuses do not occur in the

future. For this reason, some historical

information about the eugenics

movement and associated issues has been

included here. This treatment is of

necessity, superficial; those who are

interested should consult the references

listed both here and in Appendix 3.

In the late nineteenth century Francis Galton, amathematician and younger cousin of CharlesDarwin, suggested that human beings might be‘improved’ in the same way as varieties of plantsor farm animals. He coined the word ‘eugenics’ todescribe this process.

Galton’s ideas quickly became popular andeugenic research establishments were set upthroughout the world. The first eugenicists wereencouraged by the newly-rediscovered work ofMendel, which focused on characteristics in plantsthat were controlled by single genes. Most of theearly geneticists were seduced by the ideas of theeugenicists. They tried to explain humancharacteristics, including temperament andintelligence, in terms of the inheritance of singlegenes. From their statistical studies of families,researchers claimed to have identified genesgoverning behaviours such as ‘holding a grudge’ and‘pauperism’. One prominent American eugenicisteven searched for a gene for ‘love of the sea’ (thishe believed, would be common amongst navalofficers!).

While behaviour was difficult to assess,intelligence, apparently, was not. Tests of 1.75million American army recruits during World War I


seemed to show marked differences in innateability between those from various countries.Charles Davenport, director of the EugenicsRecord Office at Cold Spring Harbor on LongIsland, New York, feared that an influx of easternand southern Europeans would make theAmerican population “darker in pigmentation, smallerin stature, more mercurial... more given to crimes of larceny,kidnapping, assault, murder, rape and sex-immorality.”

The IQ ‘evidence’ helped to persuade the USCongress to pass an Immigration Restriction Actin 1924, limiting entry of people from southernand eastern Europe. Tragically, this law kept outan estimated six million people, many of whomwere fleeing persecution by the Nazis. Today, theIQ tests’ cultural bias (in favour of white, middleclass, northern Europeans) and the unfairmanner in which they were administered seemobvious (see for example, Gould, 1981).

In the first decade of this century, surgicalprocedures permitting human sterilization wereperfected. Before the advent of antibiotics, asignificant proportion of operations led to furthercomplications and even death, but the newsurgical techniques were welcomed by theeugenicists. By 1931 compulsory sterilization lawshad been passed in 31 of the United States ofAmerica. These laws applied to ‘hereditary defectives’,including ‘drug fiends’, ‘epileptics’, ‘drunkards’ and‘diseased and degenerate persons’. The families of theunemployed who were drawing money fromsocial welfare were also encouraged to acceptvoluntary sterilization. Although the laws werenever enforced comprehensively, by January 1935some 25 000 people had been forcibly sterilized,nearly half of them in California.

During the 1920s and ’30s many prominentpeople of widely-differing political persuasionsadvocated compulsory sterilization of certaingroups. Towards the end of his life the socialistplaywright George Bernard Shaw wrote (withdeliberate irony, one assumes) “If we desire a certaintype of civilization, we must exterminate the sort of peoplewho do not fit into it... Extermination must be put on a


EIBE

scientific basis if it is ever to be carried out humanely andapologetically as well as thoroughly”.

In 1910, when he was Home Secretary, WinstonChurchill opined “The unnatural and increasingly rapidgrowth of the feeble-minded and insane classes constitutes anational and race danger which is impossible to exaggerate.I feel that the source from which the stream of madness is fedshould be cut off and sealed off before another year is past.”Churchill’s comments were considered soinflammatory, especially in the light of subsequentevents, that they were not made public until 1992.

Despite the enthusiasm of some people,proposals for sterilization were fiercely rejected inBritain, The Netherlands and several centralEuropean countries. Marie Stopes, a member ofthe Eugenics Society in the United Kingdom,advocated family planning through contraceptioninstead. However, throughout northern Europe,particularly in Scandinavia, sterilization was widelypractised. The socialist K.K. Steincke (who isaccredited with founding the Danish WelfareState) justified this action as follows: “When theliberty of the individual is detrimental to the common good itmust recede, especially when this liberty will lead toimmeasurable suffering of future generations.”

The worst extremes of the eugenics movementoccurred in Nazi Germany. Funds were pouredinto eugenic research institutes by the Nazis in aneffort to find scientific backing for their racistpolicies. Influenced by the American model, theNazis passed their own ‘racial hygiene’ law in1933. By 1945 about 2 million young Germanshad been forcibly sterilized — most of them werebetween 15 and 17 years old. Compulsorysterilization was soon to be supplemented bysystematic mass murder of the mentally andphysically disabled and eventually, by the horrorsof the death camps.

During the 1940s, scientific opinion started toturn against eugenics. The Nazi atrocities hadmuch to do with this. In addition, evidence fromconventional plant and animal genetics wasbeginning to reveal the complex nature ofinheritance. The eugenicists had neglectedpolygenic characteristics — those characteristics,such as height, which are controlled by theinteraction of many genes. Eugenicists, influencedby notions of class and race, also failed to takeadequate consideration of cultural, economic andother influences on human development.Beckwith (1993) has also identified the key rôlethat the eugenicists played in making their subject


appeal to the general public (especially in theUnited States), which helped to secure politicalsupport for their cause. By the time geneticistsbegan to speak out openly against the abuse oftheir field, it was too late (Crew et al., 1939).

To some extent, the modern researcher still bearsthe stigma of the irresponsible scientist. AsBeckwith (1993) states: “The image of the scientist assomeone who carries out ill-considered experiments, oftenwith claims of benefits to humanity, is one of the mostcommon representations of scientists in film and fiction.Less common is the image of the scientist who takes actionto prevent damaging results of scientific discoveries. ...Scientists were among the most vocal spokespersons askingfor bans or restrictions on nuclear weapons in the 1950sand 1960s. In the 1970s, a group of molecular biologistscalled successfully for a moratorium on recombinant DNAresearch until the potential health hazards were fullyaddressed.”

In recent years, especially since the advent of theHuman Genome Project, there has been aresurgence of genetic determinism (see forexample the analysis by Lewontin, 1993). Apositive sign is that a significant proportion of thefunds for the Human Genome Project have beenallocated to ethical, legal and social implications ofthe research. If developments in modern geneticsare to benefit rather than harm people there mustbe an awareness of the lessons of history amongstthe scientific community and society at large.

Additional information(see Appendix 3 also)Crew, F.A.E. et al. (1939) Men and mice atEdinburgh. Journal of Heredity 30 371–373.Beckwith, J. (1993) A historical view of socialresponsibility in genetics BioScience 43, 327–333.The racial state. Germany 1933–1945 by M. Burleighand W. Wipperman (1991) Cambridge University Press,Cambridge. ISBN: 0 521 39802 9.The mismeasure of man by S. J. Gould (1981)Penguin, London. ISBN: 0 14 02 2501 3.The doctrine of DNA. Biology as ideology by R.C.Lewontin (1993) Penguin Books, London.ISBN: 0 14 023219 2.Murderous science. Elimination by scientific selection ofJews, gypsies an others, Germany 1933–1945 by B.Müller-Hill (1988) Oxford University Press,Oxford. ISBN: 0192615556. [Out of print]Müller-Hill, B. (1993) The shadow of geneticinjustice. Nature 362, 491–492.Postgate, J. (1995) Eugenics returns. Biologist 42, 96.

★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★


......

.

....

...

36 UNIT 4:

UN


Appendix 2Cultural contexts

Cultural contexts of geneticscreening and counsellingThe field of clinical genetics is expandingrapidly. New methods of detecting geneticabnormalities offer the potential to identifyand to change what might be consideredundesirable traits.

Many people welcome these developmentsas part of medical progress and wish toseize the opportunities they promise. Someother individuals and groups voice theirdissent, though often for different religiousor secular reasons.

Fundamental anxieties surrounding the useof genetic technologies regularly involveconcern over the sanctity of life and theintegrity of nature. Disquiet over thepossible threat to the rights of the embryo,foetus, women and the disabled repeatedlyact as foci of concern.

However, on the whole, it is probably bothtoo simple and unproductive to placepeople in ‘for’ or ‘against’ camps whenconsidering the issues involved. The oftencomplex factors such as, the techniqueused, the form and severity of the disease,the wider social context, and not least, theindividuals and families concerned with thedecision-making processes, deserve a moresensitive analysis.

Some points that are pertinent to thecurrent debate around genetic screeningprogrammes are outlined below.

The rights to knowledge, refusal,privacy and confidentialityThe geneticist’s aims for screening forgenetic disorders include the prevention ofdisease and the utility of offering informedchoice about reproductive decisions. Yet,past experience of some programmes show


that they have led to discrimination andstigmatisation against identified carriers ofcertain traits (Markel 1992).

For instance, in the 1970s a screeningprogramme for sickle-cell anaemia in theU.S. and for thalassaemia in Greece haveboth had adverse, albeit unintendedconsequences, on the screened population.In Greece, once identified, carriers weresometimes isolated, socially ostracised, andconsidered to be undesirable marriagepartners. In the U.S, many African-Americans were stigmatised by their carrierstatus by being denied health and lifeinsurance, employment opportunities, andeven acceptance into the US Air ForceAcademy.

The screening procedures described weremeant to be beneficial to the populationscreened, but in fact, caused various formsof distress to the people identified ascarriers. Clearly, technical capability is anecessary but insufficient means forcarrying out successful screeningprogrammes. Social implications may needto be more carefully thought out andshould be integral to any screeningprogramme.

Networks of supportA genetic counsellor in the U.S.(Walshvockley, 1991) has raised the need foradequate counselling to back up the rapidrise in demand created by the newtechnologies. She explores how knowledgeof carrier status can result in negativepsychological consequences and/or havedetrimental practical results. By drawing onexamples of the newborn, children offeredfor adoption and those identified as carriersof cystic fibrosis, Walshvockleydemonstrated the far-reaching effects suchprogrammes can create in their wake.


EIBE

These problems centre on the right ofrefusal, the right to knowledge, the right toprivacy and the right to confidentiality. Thequestion of who should make thesedecisions becomes problematic as concernrises over the growing recognition thatmany questions cannot be reduced toexpert opinion when they overspill into thesocial arena.

Adequate counsellingGood counselling as part of anaccompanying social response to the thrustof genetic screening techniques isadvocated. Ideally, the counsellor shouldgive clear and undirected information to awoman whose choice should then besupported. Yet this is difficult to achieve inpractice (Birke, Himmleweit, Vines, 1990).

Billings argues for equitable civil rights,equal access to health care, the right towork, optional rather than mandatoryscreening, and discussion of the processesof discrimination and stigmatisation.Speaking from his experience as a clinicalgeneticist he concludes that geneticcounselling is not always successful (Billings1991)

A renaissance of eugenics?This perennial issue is frequently seen to bepertinent to the debate. When consideringthe eugenic potential inherent in thecombined use of the new reproductivetechnologies and genetic engineering,Holtzman writes: “To avoid a renaissance ofeugenics... interferences with individuals procreativechoices... every effort should be made to preserve theautonomy of the individuals in deciding whether ornot to be tested.” (Holtzman, 1992)

The British Medical Association (1992),similarly noted fears that the power tocontrol our genetic constitution could alsogive rise to a new eugenics. They stressedthe need to clearly keep in view, thedistinction between diagnosis and treatmentof disease and the selection of desirabletraits.

However, although this may present alaudable principle it suffers from problems.Historical and cultural definitions of whatconstitutes a ‘desirable trait’, tends to be a


moveable target. This is germane to theapplication of gene therapy, particularly togerm-line therapy.

ConclusionThough by no means comprehensive, theabove indicates that technical capability isonly one factor of genetic screeningprogrammes. Human gene technology isnot merely a medical matter, it is embeddedin social, political, economic and ethicalcontexts. Different screening programmeswill always have distinct consequences forindividuals and perhaps for populations,which may not always be immediate,predictable or intended.

New opportunities for screening andpreventing disease therefore, present achallenge to meet them with tolerant,sensitive and adequately-funded socialpolicies.

ReferencesBillings, P.R. (1991) The context of geneticscreening.Yale Journal of Biology and Medicine.64 (1) 47-52.Tomorrow’s Child. Reproductive Technologiesin the 90s by L. Birke, S. Himmelweit, G.Vines (1990) Virago Press, London.Our genetic future. The science and ethics ofgenetic technology. British Medical Association(1992) Oxford University Press, Oxford.Holtzman, N. The diffusion of new genetictests for predicting disease. FASEB Journal.6 (10) 2806-2812.Markel, H. (1992) The stigma of disease:Implications of genetic screening. AmericanJournal of Medicine. 93, 209-215.Walshvockley, C. (1991) Counselling issuesin genetic screening. Yale Journal of Biologyand Medicine. 64 (3) 255-257.


......

.

....

...


BooksUnless otherwise indicated, these are popularaccounts intended for a general readership.Where one is available, a paperback edition isreferred to.

Our genetic future. The science and ethics of genetictechnology Anonymous (1992) OxfordUniversity Press, Oxford.ISBN: 0 19 286156 5. Report for theinterested lay reader, produced by theBritish Medical Association.

The book of man. The quest to discover our geneticheritage by Walter Bodmer and RobinMcKie (1994) Little, Brown andCompany, London. ISBN: 0 316 90520 8.Hardback. Popular account of the genomeproject by the former director of HUGO, theHuman Genome Organisation.

Wonderwoman and superman. The ethics ofhuman biotechnology by John Harris (1992)Oxford University Press, Oxford.ISBN: 0 19 217754 0. Hardback. Anacademic discussion of ethical issues.

Genetics and society by Barry Holland andCharalambos Kyriacou (Eds.) (1993)Addison-Wesley, London. ISBN: 0 20156515 3. A collection of short papers, byscientists, describing some of thedevelopments that raise wider concerns.

Exploding the gene myth by R. L. Hubbardand E. Wald (1993) Beacon Press, Boston.ISBN: 0 8070 0419 7. A critique ofbiological determinism, the genome projectand much of the biotechnology business.

Genetics for beginners by Steve Jones andBorin van Loon (1993) Icon Books,London. ISBN: 1 874166 12 9.A cartoon presentation of genetics.

The language of the genes. Biology, history andthe evolutionary future by Steve Jones (1993)Flamingo, London. ISBN: 0 00 654676 5.A highly acclaimed popular account ofhuman genetics.

The code of codes. Scientific and social issues in thehuman genome project by Daniel Kevles andLeroy Hood (Eds.) (1992) Harvard

University Press, Massachusetts. ISBN: 0674 136462. A broad, balanced collectionof articles by scientists and non-scientists.

The doctrine of DNA. Biology as ideology byR.C. Lewontin (1993) Penguin Books,London. ISBN: 0 14 023219 2. A series ofshort articles that are critical of biologicaldeterminism.

The new human genetics. How gene splicing helpsresearchers fight inherited disease by Maya Pines(1984) U.S. Department of Health andHuman Services. A concise andauthoritative guide to basic moleculargenetics, with particular reference tohuman genetic disease and the genomeproject. (National Institute of HealthPublication Nº 84-662).

Genethics. The ethics of engineering life by DavidSusuki and Peter Knudtson (1989) UnwinHyman, London. ISBN: 0 04 440623 1.Despite the title, predominantly a popularaccount of the techniques of modernbiotechnology, with an attempt to identifysome general ‘ethical’ principles.

The new genetics and clinical practice byDavid J. Weatherall (1993) (3rd edn.)Oxford University Press, Oxford.ISBN: 0192619055. Authoritative referencefor a medical/scientific readership.

Perilous knowledge. The human genome projectand its implications by Tom Wilkie (1993)Faber and Faber, London.ISBN: 057117051X.

Exons, introns and talking genes byChristopher Wills (1992) OxfordUniversity Press, Oxford.ISBN: 0 19 286154 9. Popular account ofthe genome project.

Born imperfect by Richard West (1993) Officeof Health Economics, London. Slim, yetcomprehensive and authoritative bookletdescribing inherited diseases and some ofthe issues raised, especially for themedical community: don’t be put off by thetitle. Available from: Office of HeathEconomics, 12 Whitehall, London, SW1A2DY. (Booklet Nº 110, Price £5.00).

UN


Appendix 3Additional resources


......

.

Support organisationsThere are numerous organizations that supportthose directly affected by serious geneticconditions. Some of these fund medicalresearch, and all are a valuable source of up-to-date information about the conditions.Although many of them produce magazines,booklets and leaflets these support groups aresmall charities and they are generally run byvolunteers. Teachers and students should bearthis in mind should they request information.

Educational materials for schoolsGenes, diseases and dilemmas Anonymous (1993)Hobson’s Publishing, Cambridge. ISBN: 185324 898 3. Sponsored by the Association ofthe British Pharmaceutical Industry. Bookletaimed at 16-19 year-old students (notnecessarily those who are studying biology).Includes questions for debate and a teacher’sguide.

SATIS 16-19Unit 87: Cystic fibrosis.Materials for classroom use, aimed at 16–19year-olds. Available from:The Association for Science Education,College Lane, Hatfield, Hertfordshire AL109AA. The United Kingdom.

Mapping and sequencing the human genome: Science,ethics and public policy by M.A.G. Cutter, et al(1992) Biological Sciences Curriculum Study/American Medical Association. This packagecontains classroom activities and case studies.It is available from:BSCS, 830 North Tejon Street, Suite 405,Colorado Springs, Colorado 80903-4720.United States of America.

GeneralGeneral information about modern geneticsand some of the issues associated with it isavailable from:

The British Medical AssociationTavistock SquareLondonWC1H 9JRTelephone: + 44 (0)171 387 4499

The Medical Research Council20 Park CrescentLondonW1N 4ALTelephone: + 44 (0) 171 636 5422

The Nuffield Council on Bioethics28 Bedford SquareLondonWC1B 3EGTelephone: + 44 (0)171 631 0566

The Information CentreWellcome Centre for Medical Science183 Euston RoadLondonNW1 2BETelephone: + 44 (0)171 611 8722

In the United Kingdom, there is an ‘umbrella’organization which represents the interests ofover 100 charities set up to support thoseaffected by genetic disease. This is:

The Genetic Interest GroupFarringdon Point29–35 Farringdon RoadLondonEC1M 3JBTelephone: + 44 (0) 171 430 0090

The individual organizations that deal with theconditions mentioned in this Unit are:

The Cystic Fibrosis Research TrustAlexandra House5 Blyth RoadBromleyBR1 3RSTelephone: +44 (0) 181 464 7211

The Muscular Dystrophy Group ofGreat Britain and Northern IrelandNattrass House35 Macaulay RoadLondonSW4 0QPTelephone: + 44 (0) 171 720 8055

The Huntington’s DiseaseAssociation108 Battersea RoadLondonSW11 3HPTelephone: + 44 (0) 171 223 7000

....

...


UN

IT


Appendix 4

Question 4Do you believe that it is right to select or alter the genes forspecific hereditary characteristics in the next generation ofchildren? (More than one answer accepted.)Response % of respondents

Yes, to relieve suffering or disability 51Yes, to prolong the life of someoneotherwise destined for an early death 29Yes, to breed socially useful behaviour 4Yes, to remove socially undesirablecharacteristics 7No, all of these are wrong 35Don’t know 7

Question 5Doctors may soon be able to treat some inherited fataldiseases, such as cystic fibrosis, by a process oftransplanting genes to repair the body’s own processes.How willing would you be to accept this treatment if itwould save your life? (Tick one box only.)Response % of respondents

Very willing 70Somewhat willing 17Not very willing 3Not at all willing 4Don’t know 6

Question 6Insurance companies could use genetic information froma blood test to target their policies, for instance byensuring that only those who will develop a disease willpay a higher premium. Employers could screen theworkforce, for instance to ensure that those at risk ofcancer are not taken on to work with chemicals. In whatcircumstances should insurers and employers be allowedto have access to genetic information?Response % of respondents

Whenever they consider it necessary 8Only when the individual is known to becarrying the gene for a serious disease 10Only so long as a government-appointedbody monitors the way the information is used 9In no circumstances at all 68Don’t know 8

Question 7Faulty genes can cause diseases such as musculardystrophy and some cancers. If genetic tests on yourunborn child showed that it would suffer from a cripplingdisease at the age of 16, as a parent what would you do?(Tick one box only.)Response % of respondents

Choose abortion 38Take no action and hope that a treatmentwould be developed 24Take no action because I consider abortion to beunacceptable 14Don’t know 23

In August 1993, The Daily Telegraph newspaperin London commissioned a national poll ofthe population’s attitudes towards variousissues associated with human genetics. 1 024people over the age of 16 were surveyed. Thequestions and results of the poll are given here.

A blank questionnaire is supplied, so that itmay be photocopied and used by students.Note that although Question 7 refers toabortion, an increasing range of options isnow becoming available, so that in the futurethis may not be the only choice. (seeBackground information).

The questionnaire and the statistics remaincopyright. © The Telegraph, 1993.

HU

MA

N G

EN

ET

ICS

★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★

Question 1How knowledgeable do you consider yourself to be aboutgenetics? (Tick one box only.)Response % of respondents

Very knowledgeable 5Reasonably knowledgeable 42Not very knowledgeable 34Not at all knowledgeable 20

Question 2Some diseases run in the family. A particular person may notsuffer from that disease but may pass it on to their ownchildren. Before having a child would you (and your partner)be willing to take a test to discover whether you are going topass on a crippling or fatal disease to your child?Response % of respondents

Yes, but only to discover whether I mightsoon show symptoms of the disease 12Yes, for my child’s sake 47Yes, so I know where we both stand 25No 11Don’t know 1

Question 3Suppose you have a strong chance of contracting heartdisease at the age of 40. If doctors diagnosed this when youwere 21, would you want them to tell you? (More than oneanswer accepted.)Response % of respondents

Yes, because I have the right to know 56Yes, but only if I could adjust my lifeto reduce the risks 39No 11Don’t know 3

Human geneticsquestionnaire

4


......

.

Question 1How knowledgeable do you consider yourselfto be about genetics? (Tick one box only.)

Very knowledgeable ❏Reasonably knowledgeable ❏Not very knowledgeable ❏Not at all knowledgeable ❏

Question 2Some diseases run in the family. A particularperson may not suffer from that disease butmay pass it on to their own children. Beforehaving a child would you (and your partner)be willing to take a test to discover whetheryou are going to pass on a crippling or fataldisease to your child?

Yes, but only to discover whether I mightsoon show symptoms of the disease ❏Yes, for my child’s sake ❏Yes, so I know where we both stand ❏No ❏Don’t know ❏

Question 3Suppose you have a strong chance ofcontracting heart disease at the age of 40. Ifdoctors diagnosed this when you were 21,would you want them to tell you?(More than one answer accepted.)

Yes, because I have the right to know ❏Yes, but only if I could adjust mylife to reduce the risks ❏No ❏Don’t know ❏

Question 4Do you believe that it is right to select or alterthe genes for specific hereditary characteristicsin the next generation of children?(More than one answer accepted.)

Yes, to relieve suffering or disability ❏Yes, to prolong the life of someoneotherwise destined for an early death ❏Yes, to breed socially useful behaviour ❏Yes, to remove sociallyundesirable characteristics ❏No, all of these are wrong ❏Don’t know ❏

★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★

QuestionnaireH

UM

AN

GE

NE

TIC

S

★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★ ★

Thank you for completing this questionnaire.

Question 5Doctors may soon be able to treat someinherited fatal diseases, such as cysticfibrosis, by a process of transplanting genesto repair the body’s own processes. Howwilling would you be to accept thistreatment if it would save your life?(Tick one box only.)

Very willing ❏Somewhat willing ❏Not very willing ❏Not at all willing ❏Don’t know ❏

Question 6Insurance companies could use geneticinformation from a blood test to targettheir policies, for instance by ensuring thatonly those who will develop a disease willpay a higher premium. Employers couldscreen the workforce, for instance to ensurethat those at risk of cancer are not taken onto work with chemicals. In whatcircumstances should insurers andemployers be allowed to have access togenetic information?

Whenever they consider it necessary ❏Only when the individual isknown to be carrying thegene for a serious disease ❏Only so long as a government-appointed body monitors theway the information is used ❏In no circumstances at all ❏Don’t know ❏

Question 7Faulty genes can cause diseases such asmuscular dystrophy and some cancers. Ifgenetic tests on your unborn child showedthat it would suffer from a crippling disease atthe age of 16, as a parent what would you do?(Tick one box only.)

Choose abortion ❏Take no action and hope that atreatment would be developed ❏Take no action because I considerabortion to be unacceptable ❏Don’t know ❏

Documents

Issues in human genetics