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Animal Research IsVital to Medicine

ny j31.."1.: H. Honing and Adrian R. ~1()rri~011

E xperiments using animals haveplayed :I crucial role in the JI."-vclopmcnt of modern medical

trearrnenrs. and they will continue to benecessary as researchers seck to allevi-are existing ailments and respond to theemergence of new disease. As any rned-ical scientist will readily stare, researchwith animals is bur one of several corn-plernenrarv approaches. SOITlequestions.however, ell! he answered ;)11'" by ani-mal research. \X'e intend ro show exact-Iy where we regard animal research tohave been essential in the past and topoint to where we think ir will he viralin (he future. To derailall the progressthat rei it'd on animal experirnenrationwould require many rimes the amountof Sp:lCCallorrcd to us. Indeed, we can-nor think of an area of medical researchthar does nor owe many of its most irn-porrant advances to animal experiments.

In rhe rnid-l Pth centurv, most debili-raring diseuses resulted from bacterialor viral infections, bur at the time, mostphysicians considered these ailments tobe caused by internal derangements ofthe body. The proof rhar such diseasesdid in Iacr derive from external micro-organisms originated with work done bythe French chemist Louis Pasreur andhis conrernporaries. who studied infec-rious diseases in domestic animals. Be-cause of his knowledge of how conram-inanrs caused wine and beer to spoil,Pasteur became convinced that rnicroor-ganisrns were also responsible for diseas-es such as chicken cholera and anthrax.

To test his hypothesis, Pasteur exam-ined the contents of the guts of chickenssuffering from cholera; he isolated a pos-sible causative microbe and then grewthe organism in culrure. Samples of theculture given to healthy chickens andrabbits produced cholera, rhus provingthat Pasteur had correcrlv identified theoffending organism. By chance, he no-ticed that after 0 rime, cultures of themicroorganisms lost their ability to in-fect. But birds given the ineffective cul-tures become resistant to fresh batchesthat were otherwise lethal to untreatedbirds. Physicians had previously ob-served that among people who surviveda severe arrack of certain diseases, recur-rence of the disease W3S rare; Pasteurhad iound 3 means of producing thisresistance without risk of disease. Thisexperience suggested to him that withthe administration of 3 weakened cul-ture of the disease-causing bacteria, doc-tors might be able to induce in their pa-tients immunity to infectious diseases.

In similar studies on rabbits and gui-nea pigs, Pasteur isolated the microbethat causes anthrax and then developed

. a vaccine against the deadly disease.With the information from animal ex-periments-cobviously of In extent rharcould never have been carried our onhumans-s-he proved nor only that infec-tious diseases could be produced by mi-croorganisms but also that immuniza-tion could protect against these diseases,

Pasteur's findings hod :1 widespreadeffect, For example, they influenced the

views of the prominent British surgeonJoseph Lister, who pioneered the use ofcarbolic acid to ••rcrilize surgical insrru-mcnrs, sutures and wound dressings,rhercby preventing intc •.rnon of wounds.In 1875 QUL'l:n Victoria asked Lister toaJJTL"Ss the Royal Commission inquiryinto vivisection-cas the queen pur it, "romake some srarcrncnr in condemnationof these horrible practices. ~ As J Quak-er, Lisrerhad spoken publicly againstmanv cruelties of ViI..'tOTUnsocierv, burdespite the request of his sovereign, hewas unable to condemn vivisection. Hisresrimonv to the RO\'JI Commissionstated that animal experiments hadbeen essential to his own work on asep-sis and that to restrict research with In-imals would prevent discoveries thatwould benefit humankind.

Dozens of Vaccines and Antibiotics

(FollOWing the work of Pasteur andothers, scientists have established

causes of and vaccines for dozens of in-fectious diseases. including diphtheria,tetanus, rabies, whooping cough, ruber-culosis, poliornyelins, measles, mumpsand rubella. The investigation of theseailments indispur.ibly relied heavily onanimal experimentation: in most cases,researchers identified candidate micro-organisms and then administered themicrobes to animals to see if they con-tracted the illness in question.

Similar work continues rc this day.Just recently, scientists developed a vac-cine against Hemophilus iniluenzaetype B [Hib), 0 major cause of meningi-tis, which before 1993 resulted in deathor severe brain damage in more than800 children each vear in the US. Earlyversions of a vaccine produced onlypoor, short-lived immunity, But a newvaccine, prepared and tested in rabbitsand mice, proved to be powerfully im-monogenic and is now in routine use.Within two months of the vaccine's in-

SciENTIfiC A~iERICA!,\ February 1997 83Debate: Animal Research Is Vital to Mt:dicinl'

rroducrion in the U.S. and the U.K., Hibinfections fell by 70 percent.

Animal research nor only producednew vaccines for the treatment of infec-tious disease; it also led to the develop-ment of antibacterial and antibioticdrugs. In 1935, despite aseptic precau-tions, trivial wounds could lead to seri-ous infections that resulted in amputa-tion or death .. \t the same time, in bothEurope and the U.S., death from puer-peral sepsis (a disease that mothers cancontract after childbirth, usually as aresult of infection by hemolytic srrepto-cocci) occurred in 200 of every 100,000births. In addition, 60 of every 100,000men aged 45 to 64 died from lobar pneu-monia. \X'hen sulfonamide drugs becameavailable, these figures fell dramatically:by 1960 only five out of every 100,000mothers contracted puerperal sepsis, andonly six of everv 100,000 middle-agedmen succumbed to lobar pneumonia .. -\range of other infections could also hetreated with these drugs.

The storv behind the introduction ofsulfonamide drugs is instructive. Theream investigating these compounds-Gerhard Dornagks group at Bayer Lab-oratories in \\'urrerr:1I·Elberfeld. Ger:many-insisted that all candidate com-pounds be screened in infected mice(using the so-called mouse protectiontest) rather than against bacteria grownon agar plates, Domagk's perspicacitywas fortunate: the compound pronto-sil, for instance. prayed to he exrremelvpotent in mice. but it had no effect onbacteria in \-itw-the active antihacrer-inl substance, sulfanilamide, was formedfrom pronrosil within the body. Scien-tists svnthesized other, even more PO\I'-

erful sulfonamide drugs and used themsuccessfully against many infections. Forhis work on anribacrerial drugs, Do-magk won the ~obel Prize in 1939.

A lack of proper animal experimenta-tion unfortunately delayed for a decaderhe use of the remarkable antibiotic pen-

icillin: Alexander Fleming, working in1929, did not use mice to examine theefficacy of his cultures containing crudepenicillin (although he did show the cul-tures had no toxic effects on mice andrabbitsl.Tn 1940, however, Howard W.Florey, Ernst B. Chain and others ar theUniversity of Oxford finally showed pen-icillin to be dramatically effective as anantibiotic via the mouse protection test.

Despite the success of vaccines andantibacterial therapy, infectious diseaseremains the greatest threat to human lifeworldwide. There is no effective vaccineagainst malaria or AIDS; physicians in-creasingly face strains of bacteria resis-tant to current antibacterial drugs; newinfectious diseases continue to emerge.It is hard to envisage how new and net-rer vaccines and medicines against in-fectious disease can be developed with-out experiments involving animals. )

Research on animals has been vital tonumerous other areas in medicine. Open-heart surgery-which, saves rhe lives ofan estimated 440.000 people everv yearin the LS, alone-is now routine. thanksto 20 years of animal research hv scien-tists such as John Gihbon of JeffersonMedical College in Philadelphia. Re-placement heart valves also emergedfrom years of animal experimentation.

The development of treatments forkidney failure has relied on step-by-stepimprovement of techniques through an-imal experiments. Today kidney dialy-sis and even kidney transplants can savethe lives of patients suffering from rCD;)1failure a; a result of a variery of ailments.including poisoning, severe hemorrhage,hypertension or diabetes. Roughly200,000 people require dialysis everyrear in the U.S.; some 11,000 receive :Inew kidney. Notably, a drug essentialfor dialysis-c-heparin-cmusr be extract-ed from animal tissues and rested fursafety on anesthetized animals.

Transplantation of a kidney or anymajor organ presents a hosr of cornpli-

cations; animal research has been IIIstrumental in generating solutions ".these problems. Experiments on c.u-,helped develop techniques for sutUTlI\::blood vessels from the host to the ~h;nor organ so that the vessels would h•.,Strong enough to withstand arterial prl'~sure. Investigators working with r,l!>bits, rodents, dogs and monkeys h.~\also determined ways to suppress th,immune system to avoid rejection oi rh,donor organ.

The list continues. Before the inrr •.•·duction of insulin, patients with dialx-res typically died from the disease. Furmore than 50 years, the lifesaving hor-mone had to be extracted from the pan-creas of cattle or pigs; these batches otinsulin also had to be tested for safer.and efficacy,on rabbits or mice. '

'When we started our scientific ca-reers, the diagnosis of malignant hyper-tension carried with it a prognosis oideath within a year, often preceded h~'devastating headaches and blindness.Research on anesthetized cats in the] 9505 heralded an array of progressive-Iy improved anrihyperrensive medicines.so rhar today treatment of hypertensionis effective and relatively benign, Simi-larly, gastric ulcers often necessitatedsurgery with a marked risk of morbid-ity afterward. Now antiulcer drugs, de-veloped from tests in rats and dogs, cancontrol the condition and mar effect acure if administered with antibiotics toeliminate Helicobacter pylori infection.

Common Misconceptions

Much is made in animal-rights pro-paganda of alleged differences be-

tween species in their physiology or re-sponses to drugs that supposedly renderanimal experiments redundant or mis-leading. These claims em usually he re-futed b}' proper examination of the lit-erarure. For instance, opponents of ani-mal research frequently cite the drug

l>cb."c: Animal Research I; \'11.1/ to MC'Jicil/l'

fthalidomide :I~ :111 example of :1 II11'Ji-cine rh.ir W.1Sthoroughl\' rcsrcd on .mi-11l:II~:IIlJ vhowcd its teratogenic dil,.-tonlv in 11lIJl1:IIIS.BlI£ rhis i~ not '0, Sci-cnrisrs 1'1l'Wrrested thalidomide in prq.:-n.mr .mim.rls until after feral dcforruirieswere observed ill humans. OJK.· rhl'Y railrhl'sl' rl'~r~. researchers rccounizcd rh.uthe drui; diJ in f:1.:t cause feral ahuor-malitics in rabbits, mice. rats. hamstersand several species of monkey. Similar-Iy. some people have claimed that pcni-cillin would nor h:1W been used in pa-ricnrs h:IJ ir tirsr been administered toguinea pigs. because it is inordinatelyroxie to this species. Guinea pigs. how-ever. respond to penicillin in exactly thesame way :IS do the marry patients whocontract nnribioric-induccd colitis whenplaced on long-term penicillin therapy.In both guinea pigs and humans, thecause of the colitis is infection with thebacreri um Clostridium difficilc,

In truth, there are no basic differencesbetween the phvsiology of laboraroryanimals JnJ humans. Both control theirinrern.il biochemistry bv releasing endo-crine hormones char are all essenriallvthe same: borh humans and laboraroryanimals send out similar chemical trans-mitters from nerve cells in the centraland peripheral nervous sysrems. andboth react in the same wav to infectionor tissue injurv.

Animal models of disease are unjusrlvcriticized by assertions rhar rhev are noridentical to'rhe conditions studi~d in hu-mans. But rhev are nor designed to be so;instead such models provide a means tostudy a particular procedure. Thus. cys-tic fibrosis in mice rnay not exactly mim-ic the human condition (which variesconsiderably among patients anyway).but it does provide a way to establishthe optimal method of administeringgene therapy to cure the disease. Oppo-nents of animal experiments also allegethat most illness can be avoided by achange of lifestyle; for example, adop-

rion oi :l \'I.'gall diet that avoids all .mi-mal products. Whl.'rl.':ls we ••upport thepromulgarion 01' healrhv pracnccs, WI.'

llo not consiJl.'r rhar our examples couldI'll' prevented by such measures.

A Bb.:k Hole

O IIr opponents in this debate claimthat even it animal experiments

have plavcd :I part in the developmentoi medical advances, this docs nor meanrhar rhev were essential. H;}J such tech-niques lx'Cn outlawed, the argumentgoes, researchers woulJ have been forcedto be more creative and thus would haveinvented superior technologies. Othershave suggested that there would not beJ gaping black hole in place of animalresearch hut instead more careful andrespected clinical and cellular research,

In fact, there WJS a gaping black hole,);0 oursranding progress in the treat-ment of disease occurred until biomedi-cal science was placed on a sound. em-pirical basis through experiments onanimals. Early researchers, such as Pas-teur and rhe l Trh-centurv scientist Wil-liam Harvev, who studied blood circu-larion in animals, were nor drawn to.mirnal experiments JS an easv option,Indeed. they drew 011JII the techniquesavailable at the time to answer theirquestions: sometimes dissection at a ca-daver, sometimes observations oi a pa-tient, sometimes examination of bacte-ria in culture, At other times. though,rhev considered experimentation on an-imals to be necessary.

W'e would like ro suggest an interest-ing exercise for those who hold the viewthat animal experiments, beca use of theirirrelevance. have retarded progress: takeIn example of an advance dependent onanimal experiments and detail how analternative procedure could have pro-vided the same material benefit. A suit-able example would be treatment of thecardiac condition known as mitral valve

illsuihci,'nc\', C:1l1'l'J hv ,I JCil'l.i in lhc'hl';lrt\ mirf:,1 valve. Th" rroJlI~llol1 IIIprosthetic hc.irt v.ilv c-, vtcmmcd !fomYl':\rSoi dcvclopmcnr .ind rl'Stlll!-!ior d-ti.:acy ill do~, .IIIJ C,I"C~, The "rtin':I.11valve can I'll.' inwrtcd 1111"into.1 lIIIIC"'-cent hl';lrt rh.ir h.i-, IX'\:11hyp.I~'\(.'J 1,,- .1

heart-lung Ill;lchlllc'-,III mvrrumcur rh.rritSl.-Ifhas been rx-rll'\.'lc'J .irrcr 20 \LIl"expcrimcnrarion ill J(~, lf, Jc.••pirc rhl'benefit of 35 yl':ll"i ot hmdsighr, ..:riri.:~of animal research caruux present .1 COIl-vincing scenario to \ho\\' how dll'l.'rIH·trearmcnt of mitral valve insutticll'n~'\'could have developed anv other W.I;-.their credibiliry i~ suspect,

Will animal experiments continue tobe necessary to resolve extant rnedic.ilproblems: Transgenic animals with Jsingle mutant !;cnc have already provid-ed a wealth 01 new intorrnanon on thefunctions of proteins and their roles indisease; no doubt rhev wr]] connnue todo so, 'V;'ealso .inricip.ire major pr~tl-ssin the rre.irrneru of rraurnanc iruurv rothe central nervous svsrern. ThO' Jo;;m.1that it is impossible to restore tuncnonto damaged nerve cells in the rn.irnrn.i-lian spinal cord hJS to be reassessed III

the light ot recent animal research indi-cating rhar nerve regenerarion is indeedpossible, It is only a matter ot time be-fore treatments begin to work. \\'e findit diffi..:ulr to envision how progress inthis field-and so many others in bio-logical and medical science-em beachieved in rhe future without animalexperiments. CI

JACK H, BOITING .111d ADRl.-L\fR, MORRISO,\' luu-e been actu-e i17

the defense O{.l11illlJI research since the19805. Botting, a retired unirersity lec-turer, is the [ormer scientific adviser tothe Research DL'{I!II5e Society ill LOII-don. Morrisol/ is director of the Labo-ratory for Study of tb« Brain ill Sleep atthe University of Pennsylvania Scboo!ofYetmllaTJ' Medicil1(.',

Debate: Animal Research Is Vital to Mrdicine ScIENTIFIC AMEltJCAN February 1997 85