WHY SYN­THE­SISE A YEAST GENOME?

Cosmos - - Synthetic Biology -

THE SYNTHETIC YEAST Genome Project – Sc2.0 for short – is a world- first at­tempt to build from scratch the genome of the yeast used by bak­ers and brew­ers, Sac­cha­romyces cere­visiae.

It’s no small feat. So far a team of about 200 peo­ple in 11 re­search groups in six coun­tries have been work­ing for six years to build 16 synthetic chro­mo­somes en­com­pass­ing about 12 mil­lion base pairs of DNA. Sakkie Pre­to­rius, whose team at Mac­quarie Univer­sity has signed on to build two chro­mo­somes, es­ti­mates close to $ US50 mil­lion has al­ready been spent on the project.

The strat­egy for building Sc2.0 is sim­i­lar to the one used by Craig Ven­ter to make synthetic bac­te­ria.

Pore over the DNA se­quence on a com­puter and re­design it to stream­line and op­ti­mise the way the code is read. Old code, as any soft­ware engi­neer will tell you, gets ad­dled by re­dun­dan­cies and glitches. Then punch the new code into a state- of- the- art DNA syn­the­siser and de­liver the synthetic DNA into a liv­ing yeast. At first you will have a hy­brid cell: synthetic DNA in the shell of a nat­u­ral yeast. Within a few gen­er­a­tions, though, ev­ery com­po­nent of the yeast will be re­pro­grammed by the synthetic yeast code. There are still some glitches to iron out, but the project ex­pects to un­veil its com­plete synthetic genome by late 2018.

Why do it? Sci­en­tists can tinker with na­ture’s yeast to make all man­ner of use­ful things. Pre­to­rius and his col­lab­o­ra­tors, for ex­am­ple, have tweaked wine- mak­ing yeast to make red wine more but­tery ( thanks to yeast and bac­te­rial genes that con­vert malic to lac­tic acid) and white wine fruitier ( thanks to a bac­te­rial gene that makes the en­zyme beta lyase).

The end game is to cre­ate a stream­lined chas­sis or­gan­ism on which to bolt other synthetic mod­ules. For one thing, a more stream­lined and ef­fi­cient chas­sis might give yeast- made bio­fuel the edge it needs to com­pete with petro­chem­i­cals. “If you in­herit a sub­op­ti­mal fac­tory, all you can do is change a few taps,” Pre­to­rius says. “But if you pur­pose- build it from the ground up, you can de­sign the pipe­lines and op­ti­mise flow- rates the way you want.”

How do you make a yeast chro­mo­some? First syn­the­size 10,000- let­ter chunks of DNA code in the lab. Join five chunks to make a ‘ megachunk’. Tip the megachunks into a flask of grow­ing yeast with chem­i­cals to sol­u­bilise the yeast cell mem­branes. Some of the megachunks will slip into the cells. Thanks to a nat­u­ral process of DNA swap­ping called ‘ re­com­bi­na­tion’, they will in­sert them­selves like a cas­sette into a match­ing piece of chro­mo­some, eject­ing the nat­u­ral frag­ments.

Us­ing this process, the project has swapped out DNA bit by bit. It has re­moved about 20% of so­called ‘ junk DNA’ – stut­ters in the DNA code that seem to have no func­tion – and pared back the large num­ber of iden­ti­cal copies of so- called RRNA genes. The cod­ing has been ar­ranged more log­i­cally – in­clud­ing col­lect­ing the dis­persed set of so- called TRNA genes, which link code with amino acids, and putting them on a new 17th chro­mo­some.

The synthetic yeast also boasts some state- ofthe- art de­sign fea­tures. Pro­teins are made by link­ing amino acids. More than 100 amino acids are found in na­ture, but only 20 are nat­u­rally used to make pro­teins. Sc2.0 will cre­ate novel, dis­tinctly ‘ un­nat­u­ral’ func­tions by cod­ing for some of these amino acids that don’t nor­mally make pro­teins.

More novel func­tions are ex­pected from a switch­able fea­ture built in to the chro­mo­somes called SCRAM­BLE. It is a form of ac­cel­er­ated evo­lu­tion that uses a trig­ger – say feed­ing the yeast a chem­i­cal – to scram­ble the chro­mo­somes. This shuf­fling of DNA may also gen­er­ate use­ful new traits.

“The cell’s tol­er­ance for mas­sive change is quite re­mark­able,” Pre­to­rius says.

“We’ve learned so much from Yeast 2.0,” he en­thuses. “Bi­ol­ogy is where chem­istry was 70 years ago. Any­thing we can dream up, we can write the DNA to pro­duce.”

coax­ing mouse em­bry­onic stem cell to form heart cells whose beat should pro­vide lo­co­mo­tion. The stem cells will also be en­gi­neered to carry a gene that senses toxic organophos­phate – a pes­ti­cide common in agri­cul­tural run-off – and other genes that can then break toxic chem­i­cals down. The end re­sult: a jel­ly­fish-like or­gan­ism that can hunt and de­stroy pol­lu­tants.

The am­bi­tious project seems set to con­sume the rest of Pol­lak’s work­ing ca­reer – a worth­while cause, she says, if it de­liv­ers a so­lu­tion for toxic spills. “There is heaps go­ing on in synthetic bi­ol­ogy. It’s about com­bin­ing what we al­ready know to make some­thing new and great.”

ECO­NOMICS

So will the glow­ing vi­sion of the fu­ture of­fered by synthetic bi­ol­ogy be­come a re­al­ity? A large part of the an­swer de­pends on how read­ily so­ci­ety will ac­cept ar­ti­fi­cial life forms in our midst. An­other part comes down to sim­ple eco­nomics.

The his­tory of artemisinin and bio­fu­els is in­struc­tive. Large in­vest­ments in syn­bio com­pa­nies to com­mer­cialise these prod­ucts have failed to de­liver the ex­pected re­turns.

The price of nat­u­ral artemisinin in 2011 was more than US$800 a kilo­gram. With the cost of pro­duc­ing synthetic artemisinin about US$350 a kilo­gram, phar­ma­ceu­ti­cal maker Sanofi in­vested big in fa­cil­i­ties for large-scale pro­duc­tion. Then in­creased cul­ti­va­tion of sweet worm­wood and a se­ries of bumper har­vests saw the cost of mak­ing nat­u­ral artemisinin crash to less than US$200 a kilo­gram.

The same forces of sup­ply and de­mand have hin­dered bio­fu­els. In 2008 the fu­ture looked bright as crude oil hit US$140 a bar­rel, with all signs the price would only go up. Then the global fi­nan­cial cri­sis hit, fol­lowed by the nat­u­ral gas frack­ing boom, which slashed US de­mand for oil im­ports. By 2016 the price of crude was less than $40 a bar­rel, oblit­er­at­ing the busi­ness case for al­ter­na­tive fuel pro­duc­tion.

As Vick­ers puts it: “The most im­por­tant -omics is eco­nomics.”

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