Synthetic bi­ol­o­gists are on a quest to build or­gan­isms that sat­isfy our ma­te­rial needs in a cleaner, greener way.

Cosmos - - Front Page - JAMES MITCHELL CROW ex­plains.

IMAG­INE A FU­TURE where synthetic jel­ly­fish roam wa­ter­ways look­ing for tox­ins to de­stroy, where eco-friendly plas­tics and fu­els are har­vested from vats of yeast, where viruses are pro­grammed to be can­cer killers, and elec­tronic gad­gets re­pair them­selves like liv­ing or­gan­isms.

WEL­COME TO THE WORLD of synthetic bi­ol­ogy, or ‘syn­bio’, where pos­si­bil­i­ties are limited only by the imag­i­na­tion. Its prac­ti­tion­ers don’t view life as a mys­tery but as a ma­chine – one that can be de­signed to solve a slew of press­ing global health, en­ergy and en­vi­ron­men­tal prob­lems.

It’s a plug-and-play ap­proach. Ea­ger re­searchers can order DNA se­quences on­line in much the same way elec­tron­ics en­thu­si­asts buy parts on ebay. Work­ing com­po­nents are listed in in­ven­to­ries of stan­dard­ised bi­o­log­i­cal parts. The cul­ture is highly col­lab­o­ra­tive, with synthetic bi­ol­o­gists shar­ing data and tools in the same spirit that drives the open-source, copy­left and maker move­ments.

The front man for the field would have to be the au­da­cious Craig Ven­ter. In 2010 his team cre­ated the world’s first synthetic life form – a replica of the cat­tle bac­terium My­coplasma my­coides. Dubbed ‘JCVI-SYN 1.0’, its DNA code was writ­ten on a com­puter, as­sem­bled in a test tube and in­serted into the hol­lowed-out shell of a dif­fer­ent bac­terium. Its cre­ators em­bed­ded their names in wa­ter­marks in the DNA, along with two quotes. From writer James Joyce: “To live, to err, to fall, to tri­umph, to recre­ate life out of life.” From pi­o­neer­ing quan­tum physi­cist Richard Feyn­man: “What I can­not cre­ate, I do not un­der­stand.”

For Ven­ter this was just one of many firsts. He holds joint credit for the first se­quenc­ing of the three-bil­lion­let­ter DNA code of the hu­man genome in 2001; in 2007 he be­came the first hu­man to have their in­di­vid­ual genome se­quenced.

In 2016 he an­nounced the an­swer to the mean­ing of life. It’s 473 – at least for M. my­coides. That’s the min­i­mal num­ber of genes the bac­terium needs to sur­vive. Ven­ter’s team dis­cov­ered this by strip­ping down JCVI-SYN 1.0 to cre­ate JCVI-SYN 3.0. The leaner life form has about half as many genes as its pre­cur­sor.

Ven­ter wasn’t just mo­ti­vated by in­tel­lec­tual cu­rios­ity. A pared-down life form might serve as a chas­sis on which to build some­thing use­ful to

hu­mankind. Bolt on the right hand­ful of genes and you could have an eco­log­i­cally friendly mi­crobe fac­tory to pro­duce drugs or bio­fu­els or ar­ti­fi­cial meat.

Such am­bi­tions might seem doomed in a world where peo­ple are ter­ri­fied by far more mod­estly en­gi­neered or­gan­isms such as GM crops. But synthetic bi­ol­o­gists are an op­ti­mistic lot. They are work­ing hard to win so­ci­ety over with their vi­sion of cre­at­ing a smarter, greener, more sus­tain­able world.

“To me it comes back to the idea of sus­tain­abil­ity,” says Clau­dia Vick­ers, who runs a syn­bio lab at the Univer­sity of Queens­land and heads the CSIRO’S $30 mil­lion Synthetic Bi­ol­ogy Fu­ture Science Plat­form. Ian Paulsen, whose lab at Mac­quarie Univer­sity in Syd­ney is part of a global project to cre­ate synthetic yeast, con­curs: “One could make the case that the synthetic bi­ol­ogy com­mu­nity is the most eth­i­cally en­gaged sci­en­tific com­mu­nity there has ever been.” SYNTHETIC BI­OL­OGY GETS less at­ten­tion than ge­netic en­gi­neer­ing but prac­ti­tion­ers use many of the same tech­niques. There are long-stand­ing ex­am­ples, like Golden Rice en­gi­neered to pro­duce vi­ta­min A, which could be tagged with ei­ther la­bel.

His­tor­i­cally, ge­netic en­gi­neers have tin­kered with or­gan­isms. Synthetic bi­ol­o­gists have a far bolder mind­set. As Pol­ish ge­neti­cist Wacław Szy­bal­ski put it at a con­fer­ence back in 1973: “Up to now we are work­ing on the de­scrip­tive phase of molec­u­lar bi­ol­ogy … But the real chal­lenge will start when we en­ter the synthetic phase … We will then de­vise new con­trol el­e­ments and add these new mod­ules to the ex­ist­ing genomes or build up wholly new genomes.”

Fi­nally, Szy­bal­ski pre­dicted, the work would move to building “other or­gan­isms”.

Synthetic bi­ol­o­gists, quips Vick­ers, “are largely bi­ol­o­gists mas­querad­ing as en­gi­neers or vice versa”. While they work with bi­ol­ogy – genomes (DNA codes), tran­scrip­tomes (parts of the DNA that are up­loaded) and pro­teomes (what pro­teins are be­ing made) – they like to trans­late that work into en­gi­neer­ing con­cepts and lan­guage.

In ge­net­ics speak, for ex­am­ple, reg­u­la­tory stretches of DNA are called ‘pro­mot­ers’; they are in turn reg­u­lated by ‘re­pres­sor’ or ‘in­ducer’ mol­e­cules. In syn­bio speak, pro­mot­ers are called ‘switches’ and the mol­e­cules that reg­u­late them ‘ac­tu­a­tors’. Work­ing cir­cuits of switches and ac­tu­a­tors are ‘logic gates’.

Is de­sign­ing a tai­lor-made or­gan­ism as straight­for­ward as putting to­gether some cir­cuit com­po­nents? No, says Vick­ers, life is much messier. “We would like to be able to treat bi­ol­ogy like it’s an elec­tri­cal cir­cuit, but bi­o­log­i­cal com­plex­ity is con­found­ing much of the time.”

Synthetic bi­ol­o­gists de­velop their projects through stan­dard en­gi­neer­ing cy­cles of ‘de­sign, build, test’. The de­sign phase in­volves com­puter modelling of the com­po­nents’ be­hav­iour. The build stage in­volves the ge­netic en­gi­neer­ing. The test step as­sesses if it works – and all too of­ten un­pre­dicted DNA in­ter­ac­tions and tox­i­c­i­ties mean it does not work as ex­pected.

Even the sim­plest bi­o­log­i­cal or­gan­isms have DNA se­quences no one en­tirely un­der­stands. Take Ven­ter’s min­i­mal­ist life form, JCVI-SYN 3.0, with its 473 genes. While all these genes are nec­es­sary for the bac­terium to live, the team – which has spent decades study­ing M. my­coides – has no idea what a third of them do. “As a synthetic bi­ol­o­gist I find this so hum­bling,” Vick­ers says.

If the ge­netic logic of sim­ple bac­te­ria is mys­te­ri­ous, synthetic bi­ol­o­gists are likely to en­counter far more span­ners in the works as they at­tempt to move up the evo­lu­tion­ary tree.

Here the ‘Yeast 2.0 project’ may help. This in­ter­na­tional ini­tia­tive is re­build­ing the yeast genome from scratch (see “Why syn­the­sise a yeast genome” on page 55). Think of it as building a cus­tom model racer rather than tin­ker­ing with a stock car. By start­ing with the nuts and bolts, sci­en­tists may be able to over­come the tan­gled legacy of mil­lions of years of evo­lu­tion to engi­neer a su­per-sleek genome in which they know how ev­ery gene con­trib­utes to life. At least, that’s the hope. Life may turn out to be harder to tame than the synthetic bi­ol­o­gists ini­tially thought. Nev­er­the­less, they have al­ready scored some im­pres­sive runs and their imag­i­na­tion re­mains un­fet­tered – with a wild ar­ray of projects on the draw­ing board that span the solidly util­i­tar­ian to the truly fan­tas­tic.

A pared- down life form might serve as a use­ful chas­sis. Bolt on the right hand­ful of genes and you could have an eco­log­i­cally friendly mi­crobe fac­tory to pro­duce drugs or bio­fu­els or ar­ti­fi­cial meat.


Synthetic bi­ol­ogy’s great­est suc­cess story so far is the syn­the­sis of artemisinin, the key in­gre­di­ent in to­day’s best malaria drugs. Its large-scale pro­duc­tion was made pos­si­ble by Jay Keasling and col­leagues at the Univer­sity of Cal­i­for­nia, Berke­ley, who worked out how to make it us­ing the hum­ble yeast.

Artemisinin was first iso­lated from the sweet worm­wood plant, Artemisia an­nua, in the early 1970s by Chi­nese chemist Youyou Tu – a dis­cov­ery that would ul­ti­mately win her a share of the 2015 No­bel Prize in Medicine.

When she first iso­lated artemisinin, Tu was part of a se­cret gov­ern­ment project to help China’s North Viet­namese al­lies, who weren’t just bat­tling hu­man foes but strains of malaria re­sis­tant to chloro­quine, the most widely used malar­ial medicine. Search­ing for al­ter­na­tives in tra­di­tional Chi­nese medicine, Tu found her break­through in The Hand­book of Pre­scrip­tions for Emer­gency Treat­ments, writ­ten some 1700 years ago by physi­cian Ge Hong.

The pro­hi­bi­tions of the Cul­tural Rev­o­lu­tion pre­vented Tu from pub­lish­ing her work till 1981, when it pro­vided a shot in the arm for the bat­tle against chloro­quine-re­sis­tant malaria across Asia and Africa. By the early 2000s, the World Health Or­gan­i­sa­tion was rec­om­mend­ing artemisinin-based medicines as first-line treat­ments. Its sup­ply, how­ever, was limited and er­ratic due to the va­garies of grow­ing sweet worm­wood. In 2001 Keasling and col­leagues set out to find a cheaper and more re­li­able way to make it.

The sweet worm­wood plant makes artemisinin from a pre­cur­sor mol­e­cule called far­ne­syl py­rophos­phate (FPP). Yeast cells also make FPP, which they use as the start­ing ma­te­rial for er­gos­terol, a building block of yeast cell walls.

Keasling’s team turned up the con­trols on the yeast genes that make FPP and turned down the genes that con­vert FPP into er­gos­terol. They then took a sweet worm­wood gene that turns FPP into artemisinic acid and in­serted it into the yeast genome. In the lab it was a small step to turn artemisinic acid into artemisinin.

Keasling and his col­lab­o­ra­tors es­tab­lished a com­pany called Amyris to com­mer­cialise synthetic artemisinin. In 2008 it handed the tech­nol­ogy over to French phar­ma­ceu­ti­cal gi­ant Sanofi.


Yeast-made artemisinin cap­tured hearts and minds by show­ing synthetic bi­ol­ogy could make a life-sav­ing malaria drug af­ford­able. For its fol­low-up act, Amyris wanted to turn yeast into some­thing equally com­pelling

and bio­fuel was the an­swer. The Amyris sci­en­tists en­gi­neered a synthetic path­way that con­verted FPP into the hy­dro­car­bon far­ne­sene, the only bio­fuel suf­fi­ciently en­ergy-dense to be ap­proved for use in avi­a­tion fuel. Along with be­ing a sub­sti­tute for fos­sil fu­els, far­ne­sene also has the en­vi­ron­men­tal ben­e­fit of not belch­ing par­tic­u­lates and sul­fur. When burned, it smells like green ap­ples.

Ven­ter, mean­while, has been chas­ing the holy grail of turn­ing al­gae into a com­mer­cially ro­bust source of bio­fuel. It is a dream that over the past decades has de­feated many biotech com­pa­nies. Ven­ter’s com­pany Synthetic Ge­nomics – bankrolled by the world’s largest oil and gas com­pany, Exxon­mo­bil – turned to synthetic bi­ol­ogy for the an­swer.

Al­gae pro­duce oil and re­quire only briny wa­ter and sun­light to grow. But har­vest­ing the oil is still ex­pen­sive. To make it eco­nom­i­cally vi­able re­quires ramp­ing up the al­gae’s rate of growth and the amount of oil pro­duced. Un­til now, it has been an ei­ther/or sit­u­a­tion – you can dou­ble their oil out­put if you starve al­gae of ni­tro­gen, but that crip­ples their growth.

The Synthetic Ge­nomics team iden­ti­fied the ge­netic switch for pro­duc­ing oil in the al­gae species

Nan­nochlorop­sis ga­di­tana, then tweaked it to pro­duce oil even when ni­tro­gen is plen­ti­ful. The re­sult, re­ported in the jour­nal Na­ture Biotech­nol­ogy in June 2017, was a dou­bling of the al­gae’s oil con­tent – from 20% to more than 40% – with no sig­nif­i­cant im­pact on the al­gae’s growth.

It is still not enough for com­mer­cial vi­a­bil­ity, but Ven­ter re­mains up­beat that even­tu­ally al­gae will pro­vide a vi­able al­ter­na­tive en­ergy source.


While prof­its from bio­fu­els might still be many years away, synthetic-bi­ol­ogy star­tups see more im­me­di­ate re­turns in tool­ing their liv­ing fac­to­ries to make high­mar­gin com­modi­ties.

Yeast-pro­duced far­ne­sene is be­ing used to make per­sonal-care prod­ucts such as vi­ta­min E, patchouli oil and squa­lene, a com­pound once har­vested from the liv­ers of sharks, which is prized for its at­tributes as a skin mois­turiser and other ther­a­peu­tic ben­e­fits.

The chem­istry that gives far­ne­sene the smell of green ap­ples is be­ing lever­aged at Vick­ers’ lab at the Univer­sity of Queens­land. Her team has gone back to the draw­ing board to engi­neer yeast and bac­te­ria to pro­duce hy­dro­car­bons like far­ne­sene that, among other things, emit mar­ketable fra­grances.

Length is every­thing for this class of hy­dro­car­bons, known as iso­prenoids. Vick­ers says her team pro­duces 10-15 hy­dro­car­bon chains that not only emit nice smells but can also help make bio­fu­els, in­sect re­pel­lents, vi­ta­mins and hor­mones used in agri­cul­ture to mod­ify plant struc­ture and growth.


Pare iso­prenoids down to a five-hy­dro­car­bon chain and you have iso­prene, the raw ma­te­rial for rub­ber, which was tra­di­tion­ally tapped from the rub­ber tree. Synthetic rub­ber was first made in the early 1900s, and now al­most all rub­ber comes from pro­cess­ing close to a mil­lion tonnes of iso­prene from crude oil each year.

Ge­nen­cor, a Cal­i­for­nia-based com­pany, en­gi­neered bac­te­ria to pro­duce iso­prene in a more sus­tain­able way. Dupont bought the com­pany and has pro­duced bioiso­prene to make con­cept tyres with Goodyear.

Synthetic bi­ol­ogy also of­fers a greener op­tion for plas­tics like ny­lon. Cur­rently, ny­lon pro­duc­tion from crude oil ac­counts for 10% of hu­man-made emis­sions of ni­trous ox­ide, a green­house gas about 300 times more po­tent than car­bon diox­ide. Keasling’s lab at Berke­ley has en­gi­neered a bac­terium that pro­duces adipic acid, the mol­e­cule used to make ny­lon.

While the com­pe­ti­tion with petroleum-based prod­ucts is fierce and dy­namic, these synthetic bi­ol­ogy prod­ucts – drugs, cosmetics, per­fumes and plas­tics – are al­ready trans­form­ing the way we man­u­fac­ture sta­ple com­modi­ties of mod­ern life. Synthetic bi­ol­o­gists also have more way-out prod­ucts on their draw­ing boards.


Ev­ery day an es­ti­mated 200 mil­lion peo­ple drink wa­ter poi­soned by high lev­els of arsenic. If only they had a quick test to check their wells.

En­ter synthetic bi­ol­ogy. The Arsenic Biosen­sor Col­lab­o­ra­tion in­volv­ing re­searchers from the univer­si­ties of Cam­bridge and Ed­in­burgh is de­vel­op­ing a cheap, re­li­able arsenic test that ex­ploits the nat­u­ral ca­pa­bil­i­ties of bac­te­ria. The mi­crobes can sense arsenic con­cen­tra­tions of less than 10 parts per bil­lion – WHO’S thresh­old for safe drink­ing.

The tech­nol­ogy orig­i­nates from two projects un­der­taken for the in­ter­na­tional Ge­net­i­cally En­gi­neered Ma­chines (IGEM) com­pe­ti­tion, where un­der­grad­u­ate stu­dents team up to solve global prob­lems with the help of synthetic bi­ol­ogy.

Chris French at Ed­in­burgh Univer­sity led a team that turned the E. coli bac­terium into an arsenic sen­sor by rewiring two genes. One gene senses arsenic and ac­ti­vates genes to pump it out of the cell; the other al­lows the bac­te­ria to digest the sugar lac­tose, pro­duc­ing lac­tic acid. The rewiring in­volves putting the gene for di­gest­ing lac­tose un­der the con­trol of the arsenic sen­sor. When arsenic is de­tected, the lac­tosedi­gest­ing gene switches on. The lac­tic acid it pro­duces makes the wa­ter more acidic, which can be de­tected us­ing a cheap ph in­di­ca­tor: if the read­ing is blue, the wa­ter is safe; yel­low means it is dan­ger­ous.

At the Univer­sity of Cam­bridge, a group led by Jim Ajioka turned the in­ven­tion into a credit-card-sized sen­sor for prac­ti­cal field use.

“The science is the sim­ple bit,” says French. The real hur­dle now is get­ting reg­u­la­tory ap­proval. Coun­tries that could ben­e­fit most from the tech­nol­ogy, such as Bangladesh, don’t have the reg­u­la­tory frame­work to test and ap­prove the biosen­sor. The plan is to part­ner with re­searchers in the US to get the biosen­sor tested and ap­proved there. That should smooth the path for its ac­cep­tance else­where.


Ti­mothy Lu earned a de­gree in com­puter science at MIT be­fore mov­ing on to medicine and a PHD at Har­vard Med­i­cal School. His lab at Har­vard, the Synthetic Bi­ol­ogy Group, boasts a mix of com­pu­ta­tion, med­i­cal and bi­ol­ogy spe­cial­ists. The hy­brid vigour is

re­sult­ing in some daz­zling de­vices. At the med­i­cal end of the spec­trum, the team has pro­grammed viruses to boost the im­mune sys­tem’s abil­ity to fight can­cer. So far they have fought off ovar­ian can­cer in mice, as pub­lished in a 2017 pa­per in the jour­nal Cell.

Can­cer spreads when a con­tin­gent of the im­mune army known as killer T- cells are not do­ing their job prop­erly. Some­times they don’t de­tect the can­cer cells; other times the can­cer cells dis­arm their weaponry.

To im­prove their kill rate, Lu’s group loaded a virus with a gene cir­cuit that car­ries alarm sig­nals called cy­tokines. When the virus in­fects a can­cer cell, the cir­cuit sends an alarm that alerts killer T-cells to the can­cer. It also re­leases a com­pound to stop the can­cer cell from dis­arm­ing the killer T-cell.

The gene cir­cuit only responds in the pres­ence of two can­cer-spe­cific pro­teins – myc and E2F – to en­sure nor­mal cells in­fected by the virus do not end up as col­lat­eral dam­age. The genes op­er­ate like a ‘logic gate’ in an elec­tronic cir­cuit, with the virus un­leash­ing its pay­load only when both pro­teins are de­tected. “Com­put­ing lan­guage makes the de­sign process eas­ier,” says Lu.


While Lu and other synthetic bi­ol­o­gists love to use cir­cuit metaphors to de­scribe their liv­ing ma­chines, Lu’s team has made the metaphor real by de­sign­ing bac­te­ria to pro­duce work­ing elec­tronic cir­cuit boards.

As a clin­i­cian, Lu knew bac­te­ria shield them­selves from an­tibi­otics by gang­ing up to­gether and pro­duc­ing a biofilm. This is made up of pro­teins called curli fi­bres that tan­gle like vel­cro to form a tight sheet. As a synthetic bi­ol­o­gist, Lu won­dered if the biofilm might be di­rected to form the fab­ric of a liv­ing cir­cuit.

Lu’s group re-en­gi­neered bac­te­ria DNA so some of the curli fi­bre pro­teins (Csga) would bind met­als – some­thing many pro­teins can do. They pro­grammed dif­fer­ent bac­te­ria so some pro­duced metal-bind­ing curli fi­bres while oth­ers did not. This en­abled them to pro­gram a pat­tern into the biofilm – a bit like im­print­ing a pat­tern on fab­ric. Then they sprin­kled gold atoms onto the biofilm to cre­ate path­ways of gold wires. To com­plete the cir­cuit board, the sci­en­tists equipped other curli fi­bres to bind to ‘quan­tum dots’ – nanoscale semi-con­duc­tors that emit light.

Lu de­scribes the work, pub­lished in Na­ture Ma­te­ri­als in 2014, as a proof of con­cept to in­spire what is pos­si­ble: think en­vi­ron­men­tal sen­sors for met­als, sponges to ex­tract gold from tail­ings and self-re­pair­ing so­lar pan­els.

In 2017 Ling­chong You of Duke Univer­sity was in­spired to make a nanoscale pres­sure sen­sor. He used the tech­nique to gen­er­ate biofilms that form dome­like struc­tures the size of a freckle. Each dome was con­nected to an LED light bulb through cop­per wiring. When pres­sure was ap­plied to the domes, it changed the con­duc­tiv­ity and the bright­ness of the bulbs. Hey presto: a liv­ing, self-re­pair­ing pres­sure sen­sor. Ro­bot skin, any­one?


Be­lieve it or not, Nina Pol­lak at the Univer­sity of Sun­shine Coast in Queens­land is syn­the­sis­ing jel­ly­fish to clean up toxic spills.

In 2012 the Aus­trian-born sci­en­tist was in­spired by a bold study, pub­lished by Kevin Kit Parker at Har­vard’s Wyss In­sti­tute for Bi­o­log­i­cally In­spired En­gi­neer­ing. Parker’s group had trans­formed rat heart mus­cle cells into a swim­ming crea­ture dubbed a ‘medu­soid’ (medusa be­ing the sci­en­tific name for the typ­i­cal form of a jel­ly­fish).

Be­gin­ning with a com­puter de­sign, the re­searchers laid rat heart mus­cle cells on a scaf­fold of sil­i­cone poly­mer shaped like an eight-petalled flower. The cre­ation could be made to swim with pulses of elec­tric­ity: flow­ing cur­rent caused the mus­cle to con­tract; when the cur­rent stopped it re­laxed and the medu­soid’s elas­tic sil­i­cone pulled it back to its orig­i­nal shape. The mo­tion echoed that used by jel­ly­fish to pro­pel them­selves.

Parker’s goal with the medu­soid was to model the beat­ing of a heart and test new drugs; Pol­lak en­vi­sioned the pos­si­bil­ity of cre­at­ing an aquatic rover to de­tect and clean up ocean pol­lu­tants. Her ap­proach re­lies on

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