Few ex­tinct an­i­mals cap­ture the imag­i­na­tion like the Tas­ma­nian tiger. Ge­neti­cists have taken the first steps to bring it back from the dead. JOHN PICKRELL ex­plains what comes next.

Cosmos - - Feature -

ON THE IS­LANDS OF the Dampier Ar­chi­pel­ago, just off the coast of north-west Western Aus­tralia, gi­ant piles of rusty, iron-rich boul­ders tum­ble into the bril­liant turquoise wa­ters of the In­dian Ocean. Six thou­sand years ago, these is­lands were hill­tops emerg­ing from a wide coastal plain teem­ing with life. Abo­rig­i­nal peo­ple recorded these an­i­mals by carv­ing pet­ro­glyphs into the deep-red rocks.

AMONG THE IM­AGES are more than 20 thy­lacines, also known as Tas­ma­nian tigers. These wolf-like, car­niv­o­rous mar­su­pi­als car­ried their young in a pouch like kan­ga­roos, sported tiger-like stripes on their backs and had jaws ca­pa­ble of an im­pres­sive 120-de­gree gape. They were once common across much of Aus­tralia and New Guinea.

The thylacine van­ished from the Aus­tralian main­land about 3,000 years ago, prob­a­bly as a re­sult of a dry­ing cli­mate and the loss of dense veg­e­ta­tion. It main­tained a toe­hold in forested Tas­ma­nia, only to be hunted to ex­tinc­tion by Euro­peans from the 1800s. The last known tiger died in Ho­bart Zoo in 1936.

Aus­tralia’s roll call of ex­tinct species in­cludes car­sized rel­a­tives of the wom­bat, lion-like preda­tors and gi­ant flight­less birds. But the thylacine holds a spe­cial place in the public con­scious­ness. Fre­quent ‘sight­ings’ and quests to find ev­i­dence of a liv­ing thylacine man­i­fest hopes it might not re­ally be lost.

In re­cent times, that hope has trans­lated into pos­si­ble ‘de-ex­tinc­tion’ through cloning.

Spec­i­mens from 450 thy­lacines are in mu­se­ums around the world. Most are skin and bones, but 13 pouch young (joeys) were pre­served in al­co­hol or formalde­hyde. The Mel­bourne Mu­seum has one so well-pre­served that a team led by An­drew Pask at the Univer­sity of Mel­bourne an­nounced, in 2017, the suc­cess­ful se­quenc­ing of its en­tire genome. It is the most in­tact genome ob­tained for an ex­tinct species.

The Mel­bourne joey’s own life might have been cut short, but its DNA may be a blue­print to res­ur­rect the en­tire species. No one thinks it will hap­pen soon but, as Univer­sity of New South Wales palaeon­tol­o­gist and incurable ‘de-ex­tinc­tion’ cham­pion Michael Archer puts it: “It’s a brave ge­neti­cist these days who’ll say what’s im­pos­si­ble in the next decade or two.”

ARCHER WAS PER­HAPS the first per­son to dare to dream of cloning the thylacine. In 1996, when Dolly the sheep made his­tory as the first mam­mal to be cloned, he de­clared do­ing the same with a thylacine was “a mat­ter of not if but when”.

Dolly’s DNA orig­i­nated from the mam­mary cell of an adult ewe. The cell’s nu­cleus, con­tain­ing the DNA, was sucked out and trans­ferred into a sheep egg whose own nu­cleus had been re­moved. The trans­ferred nu­cleus ‘re­booted’ the egg’s devel­op­ment, cre­at­ing a clone of the orig­i­nal ewe.

There is no chance of do­ing the same with a thylacine. Mu­seum spec­i­mens can de­liver thylacine DNA but not a vi­able nu­cleus or egg. So how do you clone some­thing with­out these seem­ingly es­sen­tial in­gre­di­ents? Ge­neti­cist Ge­orge Church, at Har­vard Univer­sity, has pi­o­neered a way.

It is some­what like the cloning strat­egy imag­ined in Juras­sic Park. The fic­tional ge­netic en­gi­neers source di­nosaur DNA from am­ber-pre­served mos­qui­toes that dined on di­nosaur blood. Gaps in the di­nosaur DNA are filled by rep­til­ian, bird or am­phib­ian DNA.

In a sim­i­lar man­ner, Church is head­ing an ef­fort to clone the mam­moth by us­ing the DNA of its clos­est liv­ing rel­a­tive, the Asian ele­phant, to fill in the miss­ing bits of mam­moth DNA.

What takes the sce­nario from fiction to re­al­ity is CRISPR. This lat­est tool in the ge­netic engi­neer’s kit is a set of en­zymes used by bac­te­ria to tar­get and de­stroy for­eign DNA. In 2015 ge­netic en­gi­neers co-opted CRISPR to tar­get and al­ter DNA within liv­ing cells. Church’s goal is to ‘edit’ key tracts of ele­phant code to con­vert them into mam­moth code, rather like turn­ing a mod­ern novel into me­dieval-era prose.

Church’s team have iden­ti­fied 1642 genes that dif­fer be­tween the species. In Fe­bru­ary 2017 Church an­nounced the suc­cess­ful con­ver­sion of 45 of those genes. “We al­ready know about the ones to do with small ears, sub­cu­ta­neous fat, hair and blood,” he said, pre­dict­ing a hy­brid ele­phant-mam­moth em­bryo “could hap­pen in a cou­ple of years”.

Once an edited fac­sim­ile of a mam­moth nu­cleus has been cre­ated, it could be placed into an Asian ele­phant egg and then into a womb. Church is also look­ing into tech­nolo­gies for ar­ti­fi­cial wombs.

BY THE TIME DOLLY the sheep was cloned, ac­quir­ing a thylacine’s DNA blue­print from a mu­seum spec­i­men was a tan­ta­lis­ing pos­si­bil­ity. Short se­quences of DNA were al­ready be­ing ex­tracted from mam­moths and other long-dead spec­i­mens. Archer, then at the Aus­tralian Mu­seum in Syd­ney, at­tempted to ex­tract DNA from a thylacine in the mu­seum’s col­lec­tion – a six-month-old pup pre­served in al­co­hol in 1886 – but the DNA was too frag­mented to be use­ful.

Given those dif­fi­cul­ties, Pask in Mel­bourne thought se­quenc­ing the thylacine genome would be im­pos­si­ble. His team fo­cused in­stead on se­quenc­ing the genomes of liv­ing species – the platy­pus, tam­mar wal­laby and

dun­nart. The goal was to com­pare their blue­prints to pla­cen­tal mam­mals like us and trace how genes had evolved since these mam­malian rel­a­tives had di­verged.

Suc­cess at read­ing mar­su­pial genomes em­bold­ened the sci­en­tists to take an­other shot at the thylacine. In 2008 they re­ported a mile­stone: iso­lat­ing a frag­ment of thylacine DNA so in­tact its code was still read­able. A com­puter pro­gram recog­nised the DNA as the code for a gene – Col 2A1 – that di­rects the devel­op­ment of car­ti­lage and bone. The re­searchers in­serted the gene frag­ment into a mouse em­bryo, to­gether with a chem­i­cal tag that made the gene glow blue wher­ever it was ac­tive. Blue pat­terns ap­peared in the em­bryo’s de­vel­op­ing skele­ton, mean­ing the code was good enough to work in a liv­ing crea­ture.

The find­ing was en­cour­ag­ing. Even if sci­en­tists could never read a com­plete thylacine genome, they might glean im­por­tant in­for­ma­tion from study­ing its genes – such as clues about how this cousin of the kan­ga­roo evolved the body shape of a wolf.

Pask’s team spent 10 years tak­ing sam­ples from 40 thylacine spec­i­mens world­wide. “Most of the mu­seum sam­ples had re­ally, re­ally badly dam­aged DNA,” he says. He had al­most given up hope when, in 2010, he came across a spec­i­men on his doorstep. In a dusty cab­i­net in the bow­els of the Mel­bourne Mu­seum, pre­served in a jar of ethanol, was a four-week-old joey taken from its dead mother’s pouch in 1909.

Pask’s team sam­pled its DNA. Un­like all the other spec­i­mens, the joey re­tained strings of DNA 1,000 let­ters in length – long enough to mean the en­tire three-bil­lion-let­ter genome might be puz­zled back to­gether. Pask be­lieves the DNA’S good con­di­tion might be due to the spec­i­men miss­ing the stan­dard for­ma­lin fix­a­tion, in­stead go­ing straight into ethanol.

The sam­ple not only yielded long strings of DNA but plenty of them. Cru­cially that al­lowed Pask’s team to read ev­ery bit of the DNA se­quence 60 times over us­ing dif­fer­ent strands. This en­abled them to cor­rect in­evitable er­rors in the cen­tury-old ma­te­rial.

Imag­ine find­ing an old car man­ual with many pages miss­ing. You would strug­gle to make use of it. But with 60 tat­tered in­com­plete copies you could prob­a­bly com­pile a whole man­ual. Pask is sim­i­larly con­fi­dent the blue­print is ac­cu­rate enough to in­struct the building of a thylacine. So too is Archer, who has lost none of his en­thu­si­asm for bring­ing back ex­tinct species. “It’s the roadmap for get­ting a thylacine back,” he says.

Keep­ing hopes alive: An­drew Pask re­con­structed a thylacine genome from the pup in the bot­tle in what may be the first step in res­ur­rect­ing the species.

04 | Thylacine DNA is so in­tact it can func­tion in a mouse em­bryo. The blue pat­tern shows where the DNA is try­ing to di­rect the devel­op­ment of the skele­ton.

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