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Cell suicide gene cloned

Researchers at the Massachusetts Instituteof Technology (MIT) have cloned a sui-cide gene responsible for programmed celldeath, or apoptosis, in the roundworm

Caenorhabditis elegans, and, in a related

study, scientists at Massachusetts GeneralHospital (MGH) demonstrated that a

similar mammalian gene will cause pro-grammed cell death in rat fibroblast cells.Junying Yuan, who worked with both

research teams, said the findings shouldadvance the understanding of the role ofprogrammed cell death in embryonicdevelopment, tissue homoeostasis, inflam-mation, and disease.

In the first paper, MIT researchers

reported that they cloned ced-3, a geneessential for programmed cell death inC elegans. Then, by working with the

sequences of the cloned cDNA, theydeduced that the gene’s product is a 503aminoacid protein whose active site is

similar to that of interleukin-1-convertingenzyme (ICE). ICE, a cysteine protease,cleaves the inactive precursor of IL-1 to

generate the active cytokine. High levels ofIL-L have been detected in Alzheimer’s

disease, rheumatoid arthritis, septic shock,and head injury. The active site of the

ced-3 protein was also similar to the pro- t

tein product of the mouse gene nedd-2, 1which is expressed during embryonic !

brain development and then down-regu- (

lated in the adult. ,

In a follow-on study to the MIT lab’s 1

work, researchers at MGH joined a pro- imoter gene to the gene for murine ICE, 1

introduced it into rat fibroblasts, andfound that overexpression of ICE caused 1

stereotypical programmed cell death inthese mammalian cells. In addition, theyfound that the mammalian proto-onco-gene bcl-2 and the viral gene crm-A couldinhibit the cell death brought on by theoverexpression of ICE gene.The researchers concluded, first, that

the ced-3 protease acts to control pro-

grammed cell death in C elegans and, sec-ond, that members of the ced-3fICE/nedd-2 gene family might function in pro-grammed cell death in vertebrates. The

inhibitory effect of bcl-2 suggests that notonly does bcl-2 act to regulate cell deathbut also that the gene for ICE and other

members of the ced-3fICE family could berecessive oncogenes, whose elimination

could prevent normal cell death and pro-mote malignancy.The finding that the viral gene crm-A

inhibits ICE-induced cell death suggests

that one way an infecting virus may pro-long its host-cell’s life is by preventing itssuicide. "It is definitely to the advantageof the virus to have the cell live longer",said Yuan. ICE, therefore, in additionto eliciting immune response to viral

infection by activating IL-1, could alsobe initiating the suicide of infected cells,Yuan said, "so one stone kills two

birds".

MIT researcher Shai Shaham saidone focus of future research will be to

identify sequences crucial to the func-tion of ICE and related proteins. "Notonly would this have implications for

blocking or inactivating cell death in

humans", Shaham said, "it could alsobe very useful in designing drugs thatmight interfere with ICE in its role ininflammation".

1 Yuan J, Shaham S, Ledoux S, Ellis HM,Horvitz HR. The C elegans cell deathgene ced-3 encodes a protein similar tomammalian interleukin-1-convertingenzyme. Cell 1993; 75: 1-20.

2 Miura M, Zhu H, Rotello R, Hartwieg EA,Yuan J. Induction of apoptosis in fibroblastsby IL-1-converting enzyme, a mammalianhomolog of the C elegans cell death geneced-3. Cell 1993; 75: 653-60.

Michael McCarthy

Gene for Wilson’s disease

Wilson’s disease (hepatolenticular degen-eration) is an autosomal recessive disordercharacterised by accumulation of copperin the liver and, when binding sites thereare saturated, in the brain, cornea, andkidneys. The underlying biochemicalabnormalities are reduced incorporationof copper into caeruloplasmin and defec-tive biliary excretion of copper. The disor-der can be treated effectively with

penicillamine but is fatal if left untreated.Wilson’s disease is a classic example of aninborn error of metabolism. The gene thatcauses it has now been dissected.’-3

Linkage studies had already assignedthe Wilson’s disease locus (WD) to chro-mosome 13ql4-3, and the impetus to

define its position more precisely camepartly from the recent isolation of the genefor Menkes’ disease (MNK), an X-linkeddisorder of copper metabolism. AlthoughWilson’s disease is primarily a defect ofliver function, whereas the MNK gene is

expressed in all tissues except the liver, theidentification of the normal (wild-type) =MNK gene product as a copper-transport-ing P-type ATPase suggested that Wil-

son’s disease might also be caused by adefect in a copper transporter. Cox et alused a probe from the proposed copper-binding region of the MNK gene to searchfor a homologue on 13ql4-3. The resultwas the identification of a region some 30kb long showing nearly 60% homologywith AfA’7’C.’Tanzi et al used a different

technique to isolate the WD gene and

found a similar degree of homology withMNK.3

Tanzi’s DNA sequence analysisrevealed four disease-specific single-base-pair mutations within the WD gene, threebeing found in only one or two affectedmembers among 115 families studied.3Tanzi et al predict difficulties with DNA-based genetic diagnosis because theyexpect more mutations to be found. Forthe present, screening of patients’ familieswill continue to be based on biochemicaltests. In the short term the most likelybenefit from isolating the WD and MNKgenes will be a better understanding ofthe molecular basis of copper homoeosta-sis. One question is why two structurallysimilar genes have apparently paradoxicaleffects: the MNK gene’s normal functionappears to be to ensure that dietary cop-per is distributed to all tissues that need it,whereas the wild-type WD gene protectsagainst excessive copper accumulation.

Dorothy Bonn

1 Bull PC, Thomas GR, Rommens JM, ForbesJR, Cox DW. The Wilson disease gene is aputative copper transporting P-type ATPasesimilar to the Menkes gene. Nature Genet

1993; 5: 327-37.2 Petrukhin K, Fischer SG, Pirastu M, et al.Mapping, cloning and geneticcharacterization of the region containing theWilson disease gene. Nature Genet 1993; 5:338-43.

3 Tanzi RE, Petrukhin K, Chemov I, et al. TheWilson disease gene is a copper transportingATPase with homology to the Menkes gene.Nature Genet 1993; 5: 345-50.

Bioethics convention

Agreement on the European Bioethics

Convention, the first accord of its kind,should be clinched by the end of 1994,two years later than originally envisaged,says the Council of Europe. Latest detailswere given at the Council’s second sym-posium on bioethics in Strasbourg, Nov30-Dec 2. (This meeting coincided withWHO call for international consultationsto secure a consensus on guidelines forresearch in genetics and biotechnology.) Apragmatic approach is being taken on atext that seeks to cover a subject in whichnational divergence and technical progressappear to be running ahead of the Stras-bourg organisation’s efforts at harmonisa-tion. The latest draft is a distillation of

uncontroversial general principles such asfree and informed consent and adherenceto professional standards. Many of theseare already the subject of non-bindingCouncil of Europe recommendations.The specific issues of organ transplanta-tion and medical research will be coveredin separate protocols, although the lattertext has yet to be agreed within the Con-vention’s main steering committee. Later,the Convention may be joined by a thirdspecific protocol on the protection of thehuman embryo and fetus, but drafting hasbeen postponed.

In other areas, member states still dif-

fer. While unanimously agreeing thatinterventions on the human genomeshould have a therapeutic or diagnostic

1482

purpose, states remain divided on a pro-vivision that these interventions shouldnot interfere with the germ cell line.Therefore the steering committee has

compromised by proposing a prohibitionon the latter type of intervention and tore-examine the situation "in a few yearstime in the light of scientific develop-ments".A major dispute concerns the use of

embryos for non-therapeutic research.Some states consider the embryo to be ahuman being from the moment of its cre-ation. In others, notably the UK and Den-mark, research is authorised up to the14th day of development (see also

p 1477). Still others authorise research

only on non-viable embryos. Consequent-ly the draft text adopts a cautious ap-

proach by leaving the question of embryoresearch to national legislation. Where thisprinciple is accep-ted in nat-ional law, theAnglo-Danish 14-day limit is prescribed.

Arthur Rogers

Transplant territorial battle

An unprecedented battle between doctors :in Denmark has now been brought to anend-by the Minister of Health.The surgeons in Aarhus and Copen-

hagen have for months been discussingwhether Denmark should have two cen-tres for liver transplants or just one. Thediscussion, which at times led to mutual =

accusations, arose after a political decisionwas made to have two centres for these

transplants-at Aarhus Kommunehospitaland the Rigshospitalet in Copenhagen.However, the surgeons in Copenhagen

argued that the results in Aarhus havebeen poor, and that the small number of

patients and donor organs mean that onlyone centre is needed. The surgeons in

Copenhagen also claimed that the neces-sary skill can be achieved only if surgeonshave ample work put their way. The sur-geons in Aarhus reported that the sur-

geons in Copenhagen did a poor job on

taking out organs, and that their ownresults were "poor" because they often

put transplants in very ill patients.The Danish Medical Association

strongly urged the surgeons to make

peace, but in vain. The chief of theNational Board of Health was apparentlymore successful in urging both parties tostop the fight, when he brought the twoheads of units together face-to-face. Theboard held the view that the fight couldonly discredit the whole transplant-pro-gramme, and that it would probablyreduce the number of organ donors. TheMinister of Health stopped the dispute bydeclaring that there shall be two centres,and that the smaller centre in Aarhus shallwork as an independent centre. He saidthat the surgeons of the two centres must

cooperate to put available donor organs tothe best use-if they do not obey this

order, strong action will be taken againstthem.

Kaare Skovmand

Medical litigation and theNATO treaty

A serving member of the US Airforce wasnot entitled to pursue through the Englishcourts a personal injury action relating totreatment at a US military hospital in

England. So decided the Court of Appealin London recently. The plaintiff hadbeen treated at the US military hospital,Lakenheath, after which he claimed to

have lost the use of an arm and was dis-

charged as medically unfit. His claim tocompensation in the US was barred by adoctrine established in 1950, so he issueda writ in England against both the US gov-ernment and the UK Ministry of Defence.The latter was struck out on the basis thatan agreement on the Status of Forces ofParties to the North Atlantic Treaty 1951(SOFA) did not confer such right ofaction against the UK. What, if any, rele-vance did SOFA have to the claim, andshould the conduct of the US governmenthere be regarded as falling under

private/commercial law (in which case theUS would not be immune from suit) or asacta jure imperii, in other words the exer-cise of sovereign, immune authority?The Court of Appeal rejected the claim

unanimously. It held that SOFA was irrel-evant to the claim. Furthermore it wouldbe astonishing if the plaintiff were able toget compensation in a foreign court fromthe country in whose forces he served, inrespect of treatment provided by that

country when compensation not availableto him in that country’s own courts.Crown immunity from suit by members

of the British armed services has latelybeen removed but under US law acta jureimperii still rules, it seems.

Diana Brahams

French medicalcontracts agreedThe French government has agreed to a 1new medical contract that fixes for the ]next 4 years the agreements between most 1

general practitioners and the social securi- .ty organisations (see Lancet Oct 9, p 920). :

The new contract establishes, for the first jtime, a connection between the remunera- I

tion of general practitioners and govern- .

ment health expenditure. ,

The intended savings for 1994 of FFr I

10-7 thousand million will reduce the j

annual increase in the cost of health care ]from 6% to 3-4%. The novelty and key-stone of the agreement is the system of

I

practice guidelines. There are 24 cate-

gories of medical practice (eg, sciatica, ’

hypertension, obstetric ultrasound, hyper-cholesterolaemia, prescriptions for antibi-

’

otics) for which diagnostic and

therapeutic procedures have been precise- ’

ly defined, and what the doctor can andcannot do is spelt out. Social security willnot pay for services outside these guide-lines. The plan was not challenged by theOrdre des Medecins (equivalent to UKGeneral Medical Council), which

attached importance to the medical pro-fession’s part in drawing up the practiceguidelines.

The new contract includes the creationof "medical dossiers" for people aged over15 with severe illness and all people overthe age of 70, to be held by the patient,the purpose being to ensure continuity ofmedical care and to avoid overprescribing.The idea of these dossiers came from the

general practitioners who suggest an

annual fee of FFr 200 per dossier.

Jean-Yves Nau

News in brief

League tables in UK An "intormation

revolution" is set to sweep through thehealth services of England and Wales.From June, 1994, league tables of individ-ual hospitals’ performances will be madepublic. The hospitals will be ranked

according to their achievements in sixindicator areas, which include the number

of accident and emergency patients seenimmediately and the number of cancelledoperations. The Department of Health isdeciding whether mortality figures for

individual hospitals should also be pub-lished.

Final split in drug industry More than100 firms will leave the German federalassociation of pharmaceutical industry bythe beginning of next year; 370 will stay.A proposed reform of the association’s

statutes, which could have stopped the

departure, did not get the necessary two-thirds majority. 24 of the departing firmshave entered the Verband forschender

Arzneimittelhersteller, the association of

drug firms involved in research. Togetherthey hold about 60% of the drug marketshare.

Ethics of genetic screening The first

report of the UK Nuffield Council onBioethics was published on Dec 7.1 It dis-cusses the ethical consequences of screen-

ing programmes and recommends a seriesof safegurads. The controversial subject ofinsurance and genetic testing is high-lighted (see Lancet Jan 23, p 224). TheCouncil calls for action from government,health professionals, employers, and theinsurance industry.1 Genetic screening: ethical issues. NuffieldCouncil on Bioethics. London: NuffieldFoundation. 1993. Pp 115. 6. ISBN0-952270102.