Micro­biome Engi­neers

Ex­ploring micro­bial com­mu­ni­ties in the gut has be­come a hot to­pic in the life sciences. While bio­logists at Kiel Uni­versi­ty re­con­struct how micro­biomes inter­act with their host, bio­tech con­tract manu­factu­rer Nord­mark has step­ped into the challen­ging field of pro­du­cing live bio­thera­peu­tics.

Our bo­dies har­bor a huge array of micro­orga­nisms both inter­nally and exter­nally. While bac­te­ria are the big­gest players, we also host sin­gle-cel­led orga­nisms known as archaea, as well as fungi, viru­ses and other micro­bes – in­clu­ding viru­ses that at­tack bac­teria. To­ge­ther these are dub­bed the hu­man micro­bio­ta. The body’s micro­biome in­clu­des all the genes our microbiota contains, however colloquially the two terms are used interchangeably. Rapid advances in DNA se­quen­cing and bio­infor­matics techno­logies in the past two de­cades have substan­tially im­proved our under­stan­ding of the micro­bial world in­side our bodies.

“We’ve come to the fasci­nating con­clusion that life is multi-orga­nis­mic – we are meta­orga­nisms,” says Thomas Bosch, a de­ve­lop­men­tal bio­logist and head of “Kiel Life Science” (KLS) re­search at the Chris­tian-Al­brechts-Uni­versi­tät Kiel (CAU). Bio­logists have only star­ted to un­cover the im­portant role of micro­bial com­mu­ni­ties in hu­man physio­logy. Mi­cro­bes help to break down the ar­ray of sugars. Other key roles of our mic­ro­bes in­clude pro­gra­ming our im­mune sys­tems, pro­vi­ding nu­tri­ents for our cells and pre­ven­ting colo­niza­tion by harm­ful bac­teria and viru­ses.

In re­cent years, the gut micro­biome has been lin­ked to a ple­tho­ra of dis­eases and con­di­tions, from dia­be­tes to au­tism and an­xie­ty to obe­si­ty. Tar­ge­ting or mo­di­fy­ing the mi­cro­bi­ome has e­mer­ged as a hot to­pic in bio­medi­cal re­search. Bosch is con­vin­ced the micro­biome pro­vi­des a power­ful way to ap­proach com­plex dis­eases. He also says it is worth be­ing cauti­ous: many studies show cor­re­la­tions ra­ther than cause and ef­fect. “The field has to move from de­scri­bing the struc­ture of micro­biomes to gene­rating mecha­nistic in­sights on how these eco­systems work,” Bosch under­lines. He is con­vinced that basic re­sear­chers must now de­sign ex­peri­ments such that they find out how the micro­bio­ta and their host inter­act and com­muni­cate with each other.

Brin­ging causali­ty to micro­biome re­search is at the heart of the DFG-fun­ded Colla­bora­tive Re­search Cen­ter CRC 1182 “Origin and function of Metaorganisms” at CAU. Bosch is its spokes­person. A key is­sue for the re­sear­chers is how the com­po­sition of an orga­nism’s micro­biome forms du­ring its uni­que develop­ment. To reduce com­plexi­ty in their ana­lyses, Bosch and his team use the fresh­water polyp Hy­dra as an ex­peri­mental mo­del. The trans­pa­rent ani­mal has a tube-like bo­dy that is akin to the ver­te­bra­te in­tes­tine. And it is co­lo­ni­zed by a sim­ple micro­biome. “The in­te­res­ting thing is that we can cre­ate germ-free ani­mals,” Bosch says. “Com­bi­ned with so­phis­ti­ca­ted ge­ne­tic tech­ni­ques, this al­lows us to as­sem­ble or also to de­con­struct the meta­organism.”

This way of micro­biome engi­nee­ring has, for ex­am­ple, gene­rated no­vel in­sight into how bac­teria and the 3,000 neu­rons in the sim­ple ner­vous sys­tem of Hy­dra com­mu­ni­cate with each other. The in­tact natu­ral Hy­dra micro­biome can play an im­por­tant role in the spon­ta­ne­ous contrac­tile ac­ti­vi­ty of the po­lyp’s bo­dy co­lumn. “The mi­cro­bes al­so play a role in dys­mo­ti­li­ty of the hu­man in­tes­ti­ne, a dis­or­der seen in in­flam­ma­to­ry bo­wel dis­ease or Par­kin­son’s dis­ease. “Thus, Hy­dra is a very in­for­ma­ti­ve mo­del sys­tem that al­lows us to de­ve­lop no­vel con­cepts which we can dis­cuss with our me­di­cal col­lea­gues here in Kiel.”

Mi­cro­bi­ome re­search re­le­vant to cli­ni­cal ap­pli­ca­tion is al­so part of the new Clus­ter of Ex­cel­lence “Precision Medicine in Chronic Inflammation”, a Kiel and Lü­beck Uni­versi­ty clus­ter with part­ner ins­ti­tu­tions in Plön and Bors­tel.

Li­ving Bio­thera­peu­tics as new mo­da­li­ty

In­flu­en­cing the func­tion of the gut mi­cro­biome is re­gar­ded as a new fron­tier in phar­ma re­search and de­ve­lop­ment. That is why a gro­wing num­ber of com­pa­nies wor­king in the mi­cro­bio­me field are now de­ve­lo­ping live bio­thera­peu­tics — sin­gle or mul­ti-strain bac­te­ri­al cul­tu­res that can re­co­lo­nize in­tes­tines with ‘be­ne­fi­cial’ bac­te­ria to re­sto­re the ba­lan­ce of the mi­cro­bio­me.

How­ever, out­side of their na­tu­ral ha­bi­tat, most gut bac­te­ria are sen­si­ti­ve crea­tu­res. Be­ing strict an­ae­ro­bes they die on con­tact with oxy­gen. This is only one as­pect that ma­kes dea­ling with mi­cro­bes as drugs so chal­len­ging. It re­qui­res spe­cia­li­zed know-how which is sca­rce in the field of bio­phar­ma. Nordmark Arzneimittel GmbH & Co. KG is a bio­phar­ma com­pany that can de­li­ver this ex­per­tise.

The com­pa­ny head­quar­te­red in Ueter­sen, clo­se to Ham­burg, has suc­ces­sful­ly joi­ned the small club of manu­fac­tu­rers that can pro­du­ce live bio­thera­peu­tics tar­ge­ting the hu­man gut mi­cro­bi­ome. The drug­ma­ker em­ploys near­ly 600 peo­ple and has a lar­ge bio­tech di­vi­sion spe­cia­li­zed in the ma­nu­fac­tu­ring of the­ra­peu­tic pro­te­ins. Apart from sup­ply­ing its own bio­lo­gics pipe­line, Nord­mark also acts as a con­tract de­ve­lop­ment and ma­nu­fac­tu­ring or­ga­ni­za­tion (CDMO). “We are a ful­ly inte­gra­ted phar­ma­ceu­ti­cal com­pa­ny, pro­vi­ding ser­vi­ce and ex­per­ti­se along the en­ti­re va­lue chain,” says Jan Heyland, who is re­spon­si­ble for re­search and de­ve­lop­ment at Nord­mark’s Bio­tech di­vi­sion. “This in­clu­des pro­cess de­ve­lop­ment, GMP-com­pli­ant pro­duc­tion and for­mu­lation,” he ex­plains.

How to ma­nu­fac­tu­re a mi­cro­be cock­tail

Nord­mark can build on de­ca­des of ex­per­ti­se in mi­cro­bi­al fer­men­ta­tion and cell cul­tu­re pro­cesses. But brin­ging micro­biome-ba­sed thera­peu­tics to the cli­nic means navi­gating se­ve­ral tough pro­duc­tion chal­len­ges. Un­like tra­di­tio­nal pharma­ceu­ti­cals and bio­mole­cules, micro­bial-based thera­peu­tics con­sist of a mix of li­ving orga­nisms, mea­ning bio­techno­logists must fi­gure out how to keep their mi­cro­bes alive while also con­si­de­ring things like pro­duct sta­bi­li­ty and shelf life. “It is a steep lear­ning curve for all par­ties in­vol­ved: big phar­ma, au­thori­ties and of course for us as bio­pharma­ceuti­cal con­tract manu­factu­rers,” Heyland un­der­li­nes.

It’s not only the gut bac­teria spe­cies which must be cul­ti­va­ted un­der strict an­aerobic con­di­tions. “They also form spo­res, which can in­crease cross-con­ta­mi­na­tion risks,” Heyland says. This re­qui­res spe­cial equip­ment and ­hand­ling to keep the mi­cro­bes under an­aerobic con­di­tions as well as strin­gent hy­gie­nic con­trol. In ad­di­tion, the bio­techno­logists can­not rely on stan­dard pro­to­cols or es­ta­bli­shed pro­duc­tion plat­forms when cul­ti­va­ting their bac­te­ria. The de­ve­lop­ment of a pill in­clu­ding a mix of mi­cro­bi­al spe­cies is an­other chal­lenge, since the live bio­thera­peu­tics must be en­cap­su­la­ted and hand­led un­der oxy­­gen-free con­di­tions and need to be cha­rac­te­ri­zed in de­tail. There­by, so­phis­ti­ca­ted ana­lytic tools are nee­ded to dif­fe­ren­tia­te bet­ween close­ly re­la­ted strains, to spot li­ving and dead cells and to en­sure a ho­mo­ge­nic drug pro­duct.

“We are brea­king new ground in many as­pects,” Heyland re­su­mes. His team has suc­ces­sful­ly achie­ved the first mile­stones in mi­cro­biome engi­neering. Re­cent­ly, Nord­mark sup­plied an Ac­tive Bio­logi­cal In­gre­dient (API) in the form of a cap­sule to a part­ner with a view to con­duc­ting a clini­cal stu­dy. Al­though he can­not pro­vide de­tailed in­for­ma­tion on the con­di­tion ad­dres­sed in the stu­dy, Heyland is con­vin­ced that the the­ra­peu­tic ex­pec­ta­tions with­in the scien­ti­fic com­mu­ni­ty seem to jus­ti­fy the ef­forts. “At this stage it ap­pears that big phar­ma­ceu­ti­cal com­pa­nies pre­fer to out­source such com­plex pro­jects to spe­cia­lists,” he says.

Autor: Philipp Graf für LSN

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