"Long before it's in the papers"
January 27, 2015


“Lifeless” molecules found to evolve, adapt

Jan. 4, 2009
Courtesy Scripps Re­search In­sti­tute
and World Science staff

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.

Weiss­mann and col­leagues de­ter­mined that pri­on vari­ants con­stantly arise in a par­tic­u­lar popula­t­ion. And pri­on popula­t­ions are in fact com­prised of mul­ti­ple sub-strains.

This, Weiss­mann not­ed, is rem­i­nis­cent of some­thing he helped de­fine some 30 years ago – the ev­o­lu­tion­ary con­cept of quasi-species. The idea was first con­ceived by Man­fred Eigen, a Ger­man bio­phys­i­cist who won the No­bel Prize in Chem­is­try in 1967. Bas­ic­ally, a quasi-species is a com­plex, self-per­pet­u­ating popula­t­ion of di­verse and re­lat­ed ent­i­ties that act as a whole.

“The proof of the quasi-species con­cept is a disco­very we made over 30 years ago,” with vi­rus­es, he said. “We found that an RNA vi­rus popula­t­ion, which was thought to have only one se­quence, was con­stantly cre­at­ing muta­t­ions and elim­i­nat­ing the un­fa­vor­a­ble ones. In these quasi-popula­t­ions, much like we have now found in pri­ons, you beg­in with a sin­gle par­t­i­cle, but it be­comes very het­er­o­ge­neous as it grows in­to a larg­er popula­t­ion.”

“It’s amus­ing that some­thing we did 30 years has come back to us,” he said. “But we know that muta­t­ion and nat­u­ral se­lec­tion oc­cur in liv­ing or­gan­isms and now we know that they al­so oc­cur in a non-liv­ing or­gan­ism. I sup­pose an­ything that can’t do that would­n’t stand much of a chance of sur­vival.”

* * *

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Scientists have found that prions—bits of 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. Those mutations that help the prions to withstand threats in in their immediate surroundings 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 is in other words very much parallel to the way that living things evolve, according to Darwinist principles. Viruses, too—which are often considered non-living—can evolve, but unlike prions, they contain DNA or closely related molecule, RNA. The 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. Eventually huge assemblies of these misfolded proteins can develop. They stick together and cause massive tissue and cell 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 therapeutic targets for prion disease. 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. 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. “It will likely be very difficult to inhibit the production of a specific natural protein pharmacologically,” Weissmann said, “You may end up interfering with some other critical physiological process. But nonetheless, 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.” Weissmann and colleagues determined that prion variants constantly arise in a particular population. And prion populations are in fact comprised of multiple sub-strains. This, Weissmann noted, is reminiscent of something he helped define some 30 years ago – the evolutionary concept of quasi-species. The idea was first conceived by Manfred Eigen, a German biophysicist who won the Nobel Prize in Chemistry in 1967. Basically, a quasi-species is a complex, self-perpetuating population of diverse and related entities that act as a whole. “The proof of the quasi-species concept is a discovery we made over 30 years ago,” with viruses, he said. “We found that an RNA virus population, which was thought to have only one sequence, was constantly creating mutations and eliminating the unfavorable ones. In these quasi-populations, much like we have now found in prions, you begin with a single particle, but it becomes very heterogeneous as it grows into a larger population.” “It’s amusing that something we did 30 years has come back to us,” he said. “But we know that mutation and natural selection occur in living organisms and now we know that they also occur in a non-living organism. I suppose anything that can’t do that wouldn’t stand much of a chance of survival.”