George Church (Mary Altaffer/AP Images)

Bay­er backs a George Church spin­out try­ing to turn lab-in­vent­ed amino acids in­to a new class of pro­tein ther­a­pies

Six years ago, Daniel Man­dell ap­peared on NPR to talk about an in­ven­tion out of Juras­sic Park.

As Crich­ton and Gold­blum fans re­call, In­ter­na­tion­al Ge­net­ic Tech­nolo­gies, Inc.’s con­tin­gency plan to make sure di­nosaurs didn’t es­cape was to take away their abil­i­ty to make the amino acid ly­sine, forc­ing them to re­ly on ly­sine sup­ple­ments from the park staff for sur­vival.

Dan Man­dell

Man­dell, a fel­low at George Church’s Har­vard lab, took the idea a step fur­ther. He, Church and a team of sci­en­tists en­gi­neered a bac­te­ria de­pen­dent on an ar­ti­fi­cial amino acid that didn’t ex­ist any­where; sci­en­tists had in­vent­ed it.

In the­o­ry, you could ex­ploit that re­liance to make sure ge­net­i­cal­ly en­gi­neered or­gan­isms didn’t spread out­side their in­tend­ed use. For ex­am­ple, you could use the mod­i­fied bac­te­ria to clean up an oil spill and then get rid of the bac­te­ria.

“While ly­sine is a nat­ur­al amino acid that is found every­where in na­ture,” Man­dell ex­plained on Sci­ence Fri­day, “our amino acid ex­ists on­ly where we put it.”

Their bac­te­ria nev­er de­ployed to clean up oil spills, but that was on­ly one in a long list of po­ten­tial ap­pli­ca­tions for an or­gan­ism that can re­ly on and churn out ar­ti­fi­cial amino acids. And af­ter years of fine-tun­ing and in­dus­tri­al­iz­ing the aca­d­e­m­ic bac­te­ria, Man­dell has man­aged to raise mon­ey from blue chip in­vestors to use his or­gan­isms else­where: build­ing new kinds of ther­a­peu­tics.

On Wednes­day , GRO Bio­sciences, the com­pa­ny he co-found­ed short­ly af­ter the orig­i­nal work ap­peared in Na­ture, an­nounced a $25 mil­lion Se­ries A led by Leaps by Bay­er and Red­mile Group to de­vel­op ther­a­pies with ar­ti­fi­cial amino acids. The new round adds to ear­li­er seed cash from Dig­i­tal­is and In­no­va­tion En­deav­ors, for­mer Google CEO Er­ic Schmidt’s VC.

Amino acids are the ba­sic build­ing blocks of pro­teins, so it’s per­haps un­sur­pris­ing that GRO will fo­cus on pro­tein-based ther­a­pies. On­ly 20 amino acids oc­cur in na­ture, each com­ing to­geth­er in var­i­ous se­quences and con­for­ma­tions to form the pro­teins that make up all life.

By adding new types of amino acids, Man­dell and his CSO and co-founder Christo­pher Gregg — and a long list of aca­d­e­mics and a few biotechs, in­clud­ing the $2.5 bil­lion Sanofi sub­sidiary Syn­thorx — think they can make pro­teins with new prop­er­ties.

Chris Gregg

“As a de­sign­er, one is of­ten struck by a fun­da­men­tal lim­i­ta­tion of pro­teins, which is that they’re all com­prised of the same 20 amino acid build­ing blocks,” Man­dell, now CEO, said in an in­ter­view. Adding new amino acids “re­al­ly opens up an in­cred­i­bly ex­cit­ing chem­i­cal uni­verse.”

GRO claims that its ad­van­tage will come from its syn­thet­ic or­gan­isms. It can be dif­fi­cult to get bac­te­ria to man­u­fac­ture these ar­ti­fi­cial build­ing blocks; pic­ture a fac­to­ry try­ing to put to­geth­er a car from mis­shapen parts.

GRO can make bac­te­ria that are not on­ly re­liant on syn­thet­ic amino acids to sur­vive, but Man­dell said, are al­so unique­ly adept at churn­ing out pro­teins with syn­thet­ic amino acids.

“All this leads to very high ef­fi­cien­cy, pro­duc­tion and scal­a­bil­i­ty,” he said.

The first ap­proach is the most in­tu­itive. GRO will try to use the ar­ti­fi­cial amino acids, tech­ni­cal­ly known as non-stan­dard or non-canon­i­cal amino acids, to build ther­a­peu­tic pro­teins that can last longer than cur­rent pro­tein-based ther­a­pies.

Nu­mer­ous meta­bol­ic dis­eases can be treat­ed by giv­ing pa­tients ar­ti­fi­cial ver­sions of a hu­man pro­tein: re­place­ments for en­zymes pa­tients with ge­net­ic dis­or­ders such as Fab­ry dis­ease are miss­ing, or var­i­ous treat­ments for di­a­betes. These drugs, though, of­ten have to be dosed week­ly or even dai­ly.

It’s “oner­ous,” Man­dell said. And it “caus­es non-com­pli­ance in pa­tients.”

In the­o­ry, GRO’s pro­teins can be in­fused and re­main in the body at rough­ly the same con­cen­tra­tion for an ex­tend­ed pe­ri­od. That would both ease dos­ing and pre­vent the big spike and de­cline in pro­tein lev­els pa­tients of­ten see.

The sec­ond ap­proach in­volves au­toim­mune dis­eases. Syn­thet­ic amino acids can al­so be used to cre­ate pro­teins with dif­fer­ent so-called post-trans­la­tion­al mod­i­fi­ca­tions — i.e. the var­i­ous dec­o­ra­tions and ac­cou­trements that cells of­ten place on top of pro­teins to serve dif­fer­ent func­tions.

Coro­n­avirus­es, for ex­am­ple, use a coat of sug­ary mol­e­cules called gly­cans to shield them­selves from the im­mune sys­tem. Gly­cans, though, can al­so be used to train the hu­man im­mune sys­tem.

In an au­toim­mune dis­ease like mul­ti­ple scle­ro­sis, a pa­tient’s im­mune cells be­gin at­tack­ing myelin pro­teins in their ner­vous sys­tem. By giv­ing that pa­tient lab-made myelin pro­teins stud­ded with the right gly­can coat, GRO hopes to coax the im­mune sys­tem to learn to tol­er­ate myelin again.

Nei­ther of these ideas are en­tire­ly unique to GRO, al­though syn­thet­ic amino acids have most­ly been used in the past for con­ju­ga­tion.

The com­pa­ny, though, is still in its ear­ly stages. They plan to put their first ther­a­pies in the clin­ic in 2024, while al­so de­vel­op­ing new mi­crobes that po­ten­tial­ly can build pro­teins with mul­ti­ple ar­ti­fi­cial amino acids, al­low­ing for fur­ther de­sign.

Illustration: Assistant Editor Kathy Wong for Endpoints News

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