CAN WE END

AN­I­MAL TEST­ING?

BBC Earth (Asia) - - Front Page - WORDS BY ALLA KAT­SNEL­SON

There are many dis­agree­ments in the world of re­search, but few de­bates will get as heated as those sur­round­ing an­i­mal test­ing. Many sci­en­tists and re­search ad­vo­cates con­tend that an­i­mal ex­per­i­ments are cru­cial for learn­ing about ba­sic bi­ol­ogy and dis­ease mech­a­nisms, and are nec­es­sary for test­ing the safety and ef­fi­cacy of new medicines and chem­i­cals. They point to many po­tent medicines that ex­ist thanks to an­i­mal test­ing. Op­po­nents, mean­while, con­tend that sub­ject­ing an­i­mals to ex­per­i­ments for hu­man gain is eth­i­cally un­jus­ti­fied. What’s more, many ar­gue, such re­search is of­ten mis­lead­ing be­cause it com­pares ap­ples and or­anges: re­sults from an­i­mal stud­ies of­ten don’t trans­late to hu­mans be­cause the an­i­mals are just too dif­fer­ent.

NEW METH­ODS

An­i­mal wel­fare ac­tivists have long in­sisted that re­searchers jet­ti­son re­search on an­i­mals for al­ter­na­tive meth­ods, such as hu­man stem cells grown in a dish, com­puter mod­el­ling, or ex­panded clin­i­cal tri­als. But it’s only in the past few years that most of these tools have be­come truly good enough for prime-time use. Now, many re­searchers are em­brac­ing these al­ter­na­tives. As Dr Don­ald Ing­ber, direc­tor of Har­vard Univer­sity’s Wyss In­sti­tute for Bi­o­log­i­cally In­spired En­gi­neer­ing, says, “It’s com­ing to a tip­ping point.”

Tal­ly­ing the pre­cise num­ber of an­i­mals used in re­search is dif­fi­cult, be­cause coun­tries record an­i­mal ex­per­i­ments dif­fer­ently. But es­ti­mates sug­gest that the count is more than 100 mil­lion an­i­mals each year world­wide. The ma­jor­ity are used in ba­sic re­search and breed­ing to cre­ate spe­cific ge­netic mod­i­fi­ca­tions. A smaller per­cent­age of an­i­mals are used to test the ef­fects of drugs or chem­i­cals. More than 95 per cent of all an­i­mals used in re­search are mice, rats, birds and fish, but other species en­ter the mix, too. For ex­am­ple, some 60,000 mon­keys like macaques are used in ex­per­i­ments in the US, Europe and Aus­tralia.

It’s hard to deny that re­search on an­i­mals has ad­vanced hu­man health. In the 19th Cen­tury, for ex­am­ple, French bi­ol­o­gist Louis Pas­teur used an­i­mal ex­per­i­ments to un­der­stand how micro­organ­isms can cause dis­ease, and later to de­velop a vac­cine for ra­bies. An­i­mal stud­ies were also cru­cial in un­der­stand­ing how in­sulin is pro­duced and in de­vel­op­ing ways to sup­ple­ment it in peo­ple with di­a­betes. Peni­cillin was proven ef­fec­tive in mice, blood trans­fu­sions were per­fected in rab­bits, and kid­ney trans­plants were tested in dogs and pigs.

There’s no short­age of re­cent ex­am­ples, ei­ther. Ex­per­i­ments in which macaques were in­fected with SIV, the mon­key ver­sion of the AIDS-caus­ing HIV virus, were cru­cial in cre­at­ing an­tiretro­vi­ral medicines and in de­vel­op­ing strate­gies for a po­ten­tial HIV vac­cine. Deep brain stim­u­la­tion, used by some

20,000 peo­ple with Parkin­son’s dis­ease, re­lied on rat and mon­key mod­els to un­der­stand how the dis­ease af­fects a part of the brain called the basal gan­glia and how sur­gi­cally im­plant­ing a stim­u­la­tor could im­prove pa­tients’ mo­tor symp­toms. And brain-ma­chine

in­ter­faces that al­low paral­ysed peo­ple to per­form ev­ery­day tasks, such as bring­ing a cof­fee cup to their lips, are be­ing de­vel­oped with the help of ex­per­i­ments in mon­keys.

A DY­ING BREED?

Yet many sci­en­tists would now agree that for some stud­ies, an­i­mal ex­per­i­ments are no longer the best way for­ward. “An­i­mal test­ing is an im­por­tant tool – it has made our world safer and it has helped to de­velop cer­tain drugs – but at the same time it has very of­ten been mis­lead­ing,” says Prof Thomas Har­tung, a tox­i­col­o­gist and the direc­tor of the Cen­ter for Al­ter­na­tives to An­i­mal Test­ing at Johns Hop­kins Univer­sity in Bal­ti­more, Mary­land. He says that in just the past few years, there has been more agree­ment on the lim­i­ta­tions of an­i­mal test­ing and “the be­lief that this is some type of gold stan­dard is fad­ing”.

Among re­searchers and the public, sup­port for lim­it­ing an­i­mal re­search where pos­si­ble seems to be growing. In the past few years, the Euro­pean Union, Is­rael and

In­dia have banned an­i­mal test­ing for cos­met­ics, and other coun­tries are con­sid­er­ing sim­i­lar laws. (The UK led the way with the first such ban back in 1989.) Coun­tries through­out the world have largely phased out re­search on Old World pri­mates such as chim­panzees, and in many re­gions the use of other non-hu­man pri­mates – as well as some other mam­malian species – is also on the de­cline. Mean­while, reg­u­la­tory bod­ies like the US Food and Drug Ad­min­is­tra­tion (FDA), which have long in­sisted on an­i­mal stud­ies, are be­gin­ning to eval­u­ate whether al­ter­na­tive tech­nolo­gies can show sim­i­lar or bet­ter re­sults, says Ing­ber, and com­pa­nies are try­ing to im­ple­ment these tools into their pipe­line.

CHANG­ING TIMES

It’s not just eth­i­cal con­cerns spurring this change. Switch­ing to stud­ies that use hu­man tis­sue in­stead of an­i­mals may of­ten make for bet­ter science. Ex­per­i­men­tal medicines that seem to be ef­fec­tive in an­i­mals (usu­ally ro­dents) of­ten fail in hu­man tri­als; 9 out of 10 can­cer drugs, and 98 out of 100 neu­ro­log­i­cal and psy­chi­atric drugs that show prom­ise in an­i­mal tests don’t turn out to work when tested in hu­mans. An­i­mal stud­ies cer­tainly don’t de­serve the full blame for this dis­con­nect, but find­ing bet­ter and more pre­dic­tive dis­ease mod­els might help, re­searchers say.

There are also cases where a hu­man dis­ease sim­ply

can’t be mod­elled in an­i­mals. For ex­am­ple, Alysson Muotri, a neu­ro­sci­en­tist at the Univer­sity of Cal­i­for­nia, San Diego, stud­ies a rare but dev­as­tat­ing neu­ro­log­i­cal dis­ease called Ai­cardi-Goutieres Syn­drome (AGS). The mu­ta­tions caus­ing AGS are well-known, but when Muotri stud­ied mice that had been ge­net­i­cally en­gi­neered to carry these mu­ta­tions, he found that they had no symp­toms. When his team grew cell struc­tures called organoids from stem cells de­rived from tis­sues of pa­tients with the dis­ease, they recre­ated the nerve cells’ glitch. They learned that what causes the dis­ease is an im­mune re­sponse to an el­e­ment of DNA that is spe­cific to hu­mans. “It’s a case where we have a truly hu­man dis­or­der,” Muotri says. “We couldn’t see it in the mouse, and very likely we wouldn’t see it in a pri­mate.”

One es­pe­cially promis­ing hu­man cell-based al­ter­na­tive to an­i­mal re­search is so-called ‘or­gan-on-a-chip’ tech­nol­ogy, in which spe­cific types of hu­man stem cells are grown with mem­branes on a mi­crochip to mimic the func­tion of spe­cific or­gans. “There are lots of things you can do on these chips that you can’t do in an­i­mal test­ing,” says Ing­ber, who has de­vel­oped about 15 such de­vices, along with his col­leagues, for mim­ick­ing the func­tion of or­gans in­clud­ing the lungs, in­tes­tine, kid­ney and bone mar­row. Each chip, the size of a com­puter mem­ory stick, is en­graved with tiny chan­nels that are lined with hu­man cells and ar­ti­fi­cial blood ves­sel tis­sue. The tools also cap­ture phys­i­o­log­i­cal fea­tures such as blood pres­sure and me­chan­i­cal forces that act on cells. Re­searchers can link up to 10 chips to­gether with vas­cu­lar chan­nels con­tain­ing hu­man blood in or­der to study how or­gan sys­tems in­ter­act.

“We’ve been able to mimic amaz­ing things – dis­eases of all types, pul­monary oedema, asthma, chronic ob­struc­tive pul­monary dis­ease, in­flam­ma­tory bowel dis­ease, vi­ral in­fec­tion, drug tox­i­c­i­ties – and we’ve been able to make chips with cells from pa­tients,”

Ing­ber says. These de­vices re­veal drug tox­i­c­i­ties that don’t show up in an­i­mal mod­els, and can also probe ques­tions that can’t be asked in clin­i­cal tri­als for eth­i­cal rea­sons. His team is us­ing them to model the ef­fects of ra­di­a­tion ex­po­sure, as well as child­hood ill­nesses and mal­nu­tri­tion.

But or­gans-on-a-chip aren’t just for univer­sity sci­en­tists. Roche Phar­ma­ceu­ti­cals, one of the top five drug com­pa­nies world­wide, em­braced the tech­nol­ogy three years ago and al­ready uses it to test the safety of new com­pounds. “It opens a to­tally new field of op­por­tu­ni­ties to us in bi­ol­ogy and drug dis­cov­ery, and all of them are much bet­ter than an an­i­mal ever can be,” says Thomas Singer, Roche’s global head of phar­ma­ceu­ti­cal sciences. As this and other tools im­prove fur­ther, more com­pa­nies have adopted them, bank­ing on them be­ing more re­pro­ducible and pre­dictable than an­i­mal tests. “In the be­gin­ning we were very much on our own,” Singer says. “But I am con­vinced this tech­nol­ogy will see a huge boost in de­vel­op­ment.”

TINY OR­GANS

Other hu­man cell-based al­ter­na­tives to an­i­mal mod­els are be­com­ing avail­able too. Prof An­thony Atala, direc­tor of the Wake For­est In­sti­tute for Re­gen­er­a­tive Medicine in North Carolina, is cre­at­ing tis­sues and or­gans such as blad­ders and kid­neys us­ing a 3D printer that spits out dif­fer­ent types of hu­man cells. “You are minia­tur­is­ing a hu­man or­gan, re­ally,” he says. Ini­tially, his team built these or­gans for sur­gi­cal use in the body, but he soon re­alised that they could be stan­dard­ised

“THERE ARE LOTS OF THINGS YOU CAN DO ON THESE CHIPS THAT YOU CAN’T DO IN AN­I­MAL TEST­ING”

and mass-pro­duced in min­utes – ideal specs for screen­ing new medicines and test­ing their safety. Ini­tially, he says, such tech­nolo­gies will just sup­ple­ment the an­i­mal stud­ies, but even­tu­ally they can re­place them.

Tox­i­col­ogy stud­ies, for medicines as well as for all sorts of other chem­i­cals, are a low-hang­ing fruit for switch­ing to al­ter­na­tive meth­ods, ex­plains Har­tung. Many an­i­mal tests are par­tic­u­larly bad at pre­dict­ing tox­i­c­ity in hu­mans, not to men­tion slow and ex­pen­sive to con­duct, and in many cases, more mod­ern, cel­lor com­puter-based as­says have been de­vel­oped. Push­ing the is­sue, a Euro­pean law passed a decade ago re­quires thou­sands of chem­i­cals to be as­sessed for safety. Har­tung and other tox­i­col­o­gists in academia and in­dus­try have de­vel­oped a com­puter model that can pre­dict the tox­i­c­ity of a com­pound based on its sim­i­lar­ity to oth­ers. “This is as­ton­ish­ingly pow­er­ful,” he says.

But de­spite the prom­ise of all these tech­niques, ex­perts say, change will prob­a­bly come slowly, and it’s likely that some forms of an­i­mal mod­els will never be elim­i­nated at all. As Ing­ber puts it, “I think we are go­ing to re­place an­i­mal test­ing one model at a time.”

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“AN­I­MAL TEST­ING IS AN IM­POR­TANT TOOL, BUT AT THE SAME TIME IT HAS OF­TEN BEEN MIS­LEAD­ING”

LEFT: A re­searcher tests the ef­fects of ul­tra-high fre­quency ra­di­a­tion on a rab­bit in the 1980s

LEFT: This ear was cre­ated us­ing a 3D printer by Prof An­thony Atala at Wake For­est In­sti­tute for Re­gen­er­a­tive Medicine. Once it’s been im­planted, it de­vel­ops func­tional tis­sue and blood ves­sels, so could be used to re­place dis­eased or dam­aged tis­sue in pa­tients. The team used the same tech­nol­ogy to cre­ate bone and mus­cle, on which to test novel treat­mentsBE­LOW: Stem cells, which can be used in med­i­cal test­ing, can be har­vested from young hu­man em­bryos, like the one pic­tured here on the end of a nee­dle

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