Sci­en­tists cre­ate ‘de­signer’ yeast in a ma­jor step to­ward synthetic life

The Washington Post - - THE WORLD - BY SARAH KA­PLAN sarah.ka­plan@wash­post.com More at wash­ing­ton­post.com/ news/ speak­ing-of-sci­ence

In a sig­nif­i­cant ad­vance to­ward cre­at­ing the first “de­signer” com­plex cell, sci­en­tists said they are one-third of the way to syn­the­siz­ing the com­plete genome of baker’s yeast.

In seven stud­ies pub­lished in the jour­nal Sci­ence last week, the re­searchers de­scribe how they built six of the 16 chro­mo­somes re­quired for the yeast Sac­cha­romyces cere­visiae, al­ter­ing the ge­netic ma­te­rial to edit out some genes and write in new char­ac­ter­is­tics.

“A lot of synthetic bi­ol­ogy is mo­ti­vated by this idea that . . . you only un­der­stand some­thing when you can build it,” said Joel Bader, a com­pu­ta­tional bi­ol­o­gist at Johns Hop­kins Univer­sity who is one of the project’s lead­ers. “Well, now we know enough about bi­o­log­i­cal sys­tems that we can de­sign a chro­mo­some on a com­puter, syn­the­size it in a lab­o­ra­tory, put it in the cell, and it will work.”

Sci­en­tists have built de­signer cells in the past. In 2010, sci­en­tists at the J. Craig Ven­ter In­sti­tute cre­ated a bac­te­rial cell con­trolled by a syn­the­sized genome by copy­ing the DNA of one bac­terium into an­other. Last year, they took the ef­fort a step fur­ther by build­ing the first “min­i­mal cell,” an or­gan­ism never found in na­ture that had the small­est number of genes re­quired for life. Sev­eral months later, a team led by re­searchers at Har­vard Med­i­cal School suc­cess­fully re-en­gi­neered a small frac­tion of the genes of the bac­terium E. coli.

This is not the first time that sci­en­tists have writ­ten ge­netic code for yeast. Jef Boeke, direc­tor of New York Univer­sity Lan­gone’s In­sti­tute for Sys­tems Ge­net­ics and an or­ga­nizer of the project, and his col­leagues syn­the­sized their first chro­mo­some in 2014. They dubbed their project Sc2.0 (“Sc” stands for S. cere­visiae).

The new pa­pers, how­ever, sig­nal an im­por­tant ad­vance. The chro­mo­somes gen­er­ated this time rep­re­sent the largest amount of ge­netic ma­te­rial ever syn­the­sized, and the new Sc2.0 cells are sub­stan­tially dif­fer­ent from nat­u­ral chro­mo­somes. “In ad­di­tion to build­ing the thing, we’ve re­ally added new fea­tures to chro­mo­somes that weren’t there be­fore,” Boeke said.

Among the most sig­nif­i­cant of these new fea­tures is a pro­gram that al­lows sci­en­tists to re­ar­range ele­ments within the genome to gen­er­ate new and po­ten­tially use­ful per­mu­ta­tions. It’s like a ver­sion of the lot­tery in which you can con­tin­u­ously and in­stan­ta­neously roll new num­bers un­til you get a re­sult you want.

Other in­no­va­tions in the Sc2.0 genome in­clude the re­moval of du­pli­cate bits of ge­netic code and the ad­di­tion of short ge­netic se­quences that dis­tin­guish synthetic chro­mo­somes from their nat­u­ral coun­ter­parts.

“By re­build­ing chro­mo­somes, these teams are show­ing that bi­ol­ogy can be re­made such that it is eas­ier to mea­sure, model and ma­nip­u­late,” said An­drew Endy, a bio­engi­neer at Stan­ford Univer­sity who was not in­volved in the project.

Unlike other synthetic or­gan­isms, the en­gi­neered yeast is a eu­kary­ote — a com­plex cell with di­verse in­ter­nal struc­tures, just like the cells in the hu­man body.

Yeast is among the most well­stud­ied or­gan­isms on Earth, a sta­ple of bi­ol­ogy labs, mak­ing it ex­tremely use­ful for re­search. And it has myr­iad pos­si­ble in­dus­trial, med­i­cal and sci­en­tific ap­pli­ca­tions, from the pro­duc­tion of bio­fu­els to the de­vel­op­ment of vac­cines. The Sc2.0 team plans to add a 17th chro­mo­some to the de­signer cell to im­prove its pro­tein­mak­ing ma­chin­ery.

S. cere­visiae is also the yeast that bak­ers use to make bread. Some of the un­der­grad­u­ates work­ing on the Sc2.0 project crafted a gene that would cause the yeast to pro­duce beta carotene, the mol­e­cule that gives car­rots their vi­ta­min A and or­ange col­or­ing, and baked a loaf with it. The bread came out of the oven with a lovely or­ange color, but Boeke wouldn’t let the stu­dents eat it. (They didn’t have ap­proval from their In­sti­tu­tional Re­view Board, which over­sees re­search safety and ethics.)

The re­searchers worked nearly 10 years to build their first chro­mo­some — even though they were work­ing on the short­est one in the yeast’s genome. But they needed less than three years to gen­er­ate the next five chro­mo­somes, which in­clude some of the genome’s long­est. Boeke said the team will com­plete the full genome by the end of next year.

Each syn­the­sized chro­mo­some still re­quires a her­culean ef­fort on the part of more than 100 col­lab­o­ra­tors work­ing across three con­ti­nents. The blue­prints for the chro­mo­somes are writ­ten via a com­puter pro­gram and then an­a­lyzed by bi­ol­o­gists to see whether they will work. These are then bro­ken into short, man­age­able seg­ments and shipped off to com­mer­cial DNA syn­the­sis labs. The short chunks are then stitched to­gether us­ing a tech­nique de­vel­oped by Boeke and un­der­grad­u­ate stu­dents who took his “build-a-genome” course at Johns Hop­kins, and then in­jected into the cell.

The com­pli­ant yeast cells make it easy to swap in the fab­ri­cated ma­te­rial for the DNA that is al­ready there. The data for the en­tire Sc2.0 project is open­source, so any­one can bor­row from or con­trib­ute to the re­search.

“This is a progress report, it is not a fi­nal prod­uct,” said Har­vard ge­neti­cist Ge­orge Church, who led the re­search on en­gi­neered E. coli.

Church and Boeke are or­ga­niz­ers of the Genome Project-write, an heir to the Hu­man Genome Project that aims to de­velop tools to en­gi­neer and test genomes on a large scale, dra­mat­i­cally re­duc­ing the cost of such ef­forts. The ini­tia­tive drew crit­i­cism from many in the sci­en­tific com­mu­nity when it was for­mally launched last year. Fran­cis Collins, head of the Na­tional In­sti­tutes of Health and an or­ga­nizer of the ear­lier Hu­man Genome Project, told The Wash­ing­ton Post at the time that “whole-genome, whole-or­gan­ism syn­the­sis projects ex­tend far beyond cur­rent sci­en­tific ca­pa­bil­i­ties, and im­me­di­ately raise nu­mer­ous eth­i­cal and philo­soph­i­cal red flags.”

Boeke ac­knowl­edged that there are se­ri­ous eth­i­cal con­sid­er­a­tions to be made when it comes to syn­the­siz­ing the genomes of hu­mans and even other an­i­mals. But he doesn’t worry too much about the safety pro­file of Sc2.0.

“Let’s say for the sake of ar­gu­ment there could be the yeast that ate Man­hat­tan,” he said. “If such a yeast could arise in na­ture it prob­a­bly al­ready would have.”

In other words, na­ture has had bil­lions of years to per­fect the process of syn­the­siz­ing genomes. Hu­mans may have crafted a hand­ful of se­quences for a few sin­gle­cell or­gan­isms, but if our dreams — and our night­mares — in­volve some­day mas­ter­ing evo­lu­tion, we have still got a long way to go.

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