Mighty Dons Of Science News

Sci­en­tists have found that pri­ons in­fec­tious mol­e­cules that cause fa­tal brain dis­eases can evolve in a Dar­win­i­an fash­ion, though they lack any DNA or si­m­i­lar ma­te­ri­al.

The study from Scripps Re­search In­sti­tute in Ju­pi­ter, Fla. found that pri­ons can de­vel­op many muta­t­ions. Muta­t­ions that help the pri­ons to with­stand threats then tend to per­sist in a “popula­t­ion” of pri­ons, while oth­er pri­ons are de­stroyed. This even­tu­ally leads the pri­ons to de­vel­op adapta­t­ions such as drug re­sist­ance.

The pro­cess in oth­er words would seem to be analogous to the way that liv­ing things evolve, ac­cord­ing to Dar­win­ist prin­ci­ples. Vi­rus­es, too which are of­ten con­sid­ered non-liv­ing can evolve. But un­like pri­ons, vi­ruses have in com­mon with life forms that they con­tain DNA or closely re­lat­ed mol­e­cule, RNA.

The prion study was pub­lished in the Dec. 31 is­sue of the re­search jour­nal Sci­ence Ex­press, an ad­vance, on­line edi­tion of the jour­nal Sci­ence.

Pri­ons con­sist of pro­teins, large mol­e­cule com­posed of many smaller mo­lec­u­lar sub­units of so-called ami­no acids. Pro­tein mol­e­cules have dif­fer­ent char­ac­ter­is­tics de­pend­ing on the pre­cise ar­range­ment of their sub­units. This in­cludes dif­fer­ent ways the pro­tein’s parts can be folded about with re­spect to each oth­er.

Many of the pri­on “muta­t­ions” boil down to dif­fer­ent fold­ing ar­range­ments, said Charles Weiss­mann, head of Scripps Flori­da’s De­part­ment of In­fec­tol­ogy, who led the stu­dy. These var­i­ous fold­ings play an anal­o­gous ev­o­lu­tion­ary role in pri­ons to dif­fer­ent DNA se­quences, or codes, in the ev­o­lu­tion of liv­ing things.

“On the face of it, you have ex­actly the same pro­cess of muta­t­ion and adaptive change in pri­ons as you see in vi­rus­es,” he ex­plained.

In­fec­tious pri­ons short for pro­tein­a­ceous in­fec­tious par­t­i­cles are as­so­ci­at­ed with some 20 dif­fer­ent dis­eases in hu­mans and an­i­mals, in­clud­ing mad cow dis­ease and a rare hu­man form, Creutzfeldt-Jakob dis­ease. All are un­treat­able and even­tu­ally fa­tal. Pri­ons, which are com­posed solely of pro­tein, are clas­si­fied by dis­tinct strains, orig­i­nally char­ac­terized by their in­cuba­t­ion time and the dis­ease they cause.

Pri­ons ex­ist in a nor­mal, healthy form, pro­duced nat­u­rally in mam­ma­li­an cells, called cel­lu­lar pri­on pro­tein or PrPC. The dis­ease pro­cess be­gins when pri­ons take on an abnor­mal, mis­folded form. A nor­mal pri­on that comes in­to con­tact with a mis­folded one may as a re­sult be­come mis­folded it­self. This zom­bie-like pro­cess may even­tually lead to the creation of huge as­sem­blies of these mis­folded pro­teins. They stick to­geth­er and cause mas­sive dam­age.

“It was gen­er­ally thought that once cel­lu­lar pri­on pro­tein was con­vert­ed in­to the abnor­mal form, there was no fur­ther change,” Weiss­mann said. “But there have been hints that some­thing was hap­pen­ing. When you trans­mit pri­ons from sheep to mice, they be­come more vir­u­lent over time. Now we know that the abnor­mal pri­ons rep­li­cate, and cre­ate vari­ants, per­haps at a low lev­el in­i­tial­ly. But once they are trans­ferred to a new host, nat­u­ral se­lec­tion will even­tu­ally choose the more vir­u­lent and ag­gres­sive vari­ants.”

Weiss­mann and his col­leagues trans­ferred pri­on popula­t­ions from in­fected brain cells to cul­ture cells. When trans­planted, cell-a­dapted pri­ons de­vel­oped and out-competed their brain-a­dapted coun­ter­parts, con­firm­ing pri­ons’ abil­ity to adapt to new sur­round­ings, ac­cord­ing to the sci­en­tists. When re­turned to brain, brain-a­dapted pri­ons again took over the popula­t­ion.

Weiss­mann said the find­ings have im­plica­t­ions for the de­vel­op­ment of treat­ments. In­stead of de­vel­oping drugs to tar­get abnor­mal pro­teins, it could be more ef­fi­cient to try to lim­it the supply of nor­mally pro­duced pri­ons – in es­sence, re­duc­ing the amount of fu­el for the fire, he pro­posed. Weiss­mann and his col­leagues found some 15 years ago that ge­net­ic­ally en­gi­neered mice de­void of the nor­mal pri­on pro­tein de­vel­op and func­tion quite nor­mally and are re­sist­ant to pri­on dis­ease.

“Find­ing a way to in­hib­it the pro­duc­tion of nor­mal pri­on pro­tein is a proj­ect cur­rently be­ing pur­sued in col­la­bora­t­ion with Scripps Flor­i­da Pro­fes­sor Co­rinne Las­mezas in our de­part­ment,” he said.