Evolution without genes – prions can evolve and adapt too

By Ed Yong | December 31, 2009 2:00 pm

If you search for decent definitions of evolution, the chances are that you’ll see genes mentioned somewhere. The American Heritage Dictionary talks about natural selection acting on “genetic variation”, Wikipedia discusses “change in the genetic material of a population… through successive generations”, and TalkOrigins talks about changes that are inherited “via the genetic material”. But, as the Year of Darwin draws to a close, a new study suggests that all of these definitions are too narrow.

Prions.jpgJiali Li from the Scripps Institute in Florida has found that prions – the infectious proteins behind mad cow disease, CJD and kuru – are capable of Darwinian evolution, all without a single strand of DNA or its sister molecule RNA.

Prions are rogue version of a protein called PrP. Like all proteins, they are made up of chains of amino acids that fold into a complex three-dimensional structure. Prions are versions of PrP that have folded incorrectly and this misfolded form, called PrPSc, is social, evangelical and murderous. It converts normal prion proteins into a likeness of its abnormal self, and it rapidly gathers together in large clumps that damage and kill surrounding tissues.

Li has found that variation can creep into populations of initially identical prions. Their amino acid sequence stays the same but their already abnormal structures become increasingly twisted. These “mutant” forms have varying degrees of success in different environments. Some do well in brain tissue; others thrive in other types of cell. In each case, natural selection culls the least successful ones. The survivors pass on their structure to the “next generation”, by altering the folds of normal prion proteins.

This process follows the principles of Darwinian evolution, the same principles that shape the genetic material of viruses, bacteria and other living things. In DNA, mutations manifest as changes in the bases that line the famous double helix. In prions, mutations are essentially different styles of molecular origami. In both cases, they are selectively inherited and they can lead to adaptations such as drug resistance. In prions, it happens in the absence of any genetic material. 

If prions can evolve, and if they can show the same sort of adaptive resistance as bacteria or fungi, does this mean that they are alive? Charles Weissman, who heads up Li’s lab, doesn’t think so on the grounds that prions are completely dependent on their hosts for reproduction. They need normal proteins that are encoded within the genome of their host to make more copies of themselves.. He says, “The remarkable finding that prions can mutate and adapt to their environment imbues them with a further attribute of living things, without however elevating them to the status of being ‘alive’.”

There are many distinct strains of prion. Each is a version of PrPSc folded in a subtly different way, and new strains can arise out of the blue. Working out their exact structure has been difficult and they’re usually characterised by the symptoms and disease they cause, and how long it takes for these to become apparent.

Li found that prions taken from brain tissue are different to those grown in cells cultured in a laboratory. The brain-adapted prions are capable of infected nerve tissue and they’re resistant to a drug called swainsonine (swa) that completely blocks the growth of other strains. The cell-adapted prions lack both these abilities but they’re better at growing in cell cultures.

When Li transferred brain prions into cell cultures, she found that they gradually adapted to their new environment. By the 12th ‘generation’, they were indistinguishable from cell-adapted prions. They had lost their ability to infect nerve tissue in favour of the ability to grow faster in cultured cells. When Li returned these prions back to brain tissue, the brain-adapted forms once again rose to dominance.

Li also found that prions are capable to evolving resistance to drugs. She treated the cell-prions with swa. At first, the drug blitzed the prion population, slashing the proportion of infected cells by five times from 35% to 7%. But the rogue proteins staged a resurgence, bouncing back to infect around 25% of the cells. After just two  rounds of growth, prions from cells that were exposed to swa completely resisted the drug. If the drug was removed, they faded into the background once more as the non-resistant forms took over again.

Further experiments showed that the resistant strains were already there in the population. But their slower growth rates mean that they’re typically in the minority, accounting for just 1 in 200 prions. When swa blasted the population, these resistant few rose to dominance. Li says that prion populations consist of a multitude of strains and substrains, all of which are different ways of folding the same sequence of amino acids. Evolutionary pressures from the environment determine which of these strains is in power.

But mutants can arise out of the blue too. Even if a population consists entirely of the same strain (which you can set up through cloning), resistant or sensitive mutants develop spontaneously in a very short span of time. Prions, it seems, are very quick to adapt.

The fact that prions can evolve drug resistance so quickly is important news for scientists trying to find new treatments for prion diseases, such as Creutzfeld-Jacob Disease (CJD) and bovine spongiform encephalitis (BSE). Rather than trying to target the abnormal proteins themselves, it might be better to reduce the levels of the production of the normal PrP in the first place. The former tactic could be easily thwarted by the rise of resistant strains, while the latter tactic denies natural selection of raw materials to work with.

Reference: Li et al. 2009. Darwinian Evolution of Prions in Cell Culture. Science DOI: 10.1126/science.1183218

More on prions:

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CATEGORIZED UNDER: Evolution, Medicine & health

Comments (23)

  1. Very interesting. But I think it’s another reason to review the definition of life. If prions are capable of transmitting some quite complex information (breeding), and this information is subject to random errors (mutation) which are then selected by environmental pressure (evolution), then they are similar to viruses. And there are other parasites (like chlamydia) who depend on their host completely, yet we call them living organisms…

  2. Fascinating and somehow scary. I wonder what other things in this world are like prions, not alive, but adaptable.

  3. Quick question: What do you mean by “Darwinian evolution”? Should we say “Newtonian gravity” or “Einsteinian(?) relativity” as well?

  4. Christina

    Evolution by itself merely means “change over time”. Darwinian evolution specifically indicates change via mutation and natural selection. Although, I agree that it’s unnecessary in contexts like this to specify. It’s not like, say, anyone’s suggesting Lamarkian evolution.

  5. Naraoia

    Cool is all I can say.

  6. qbsmd

    Reducing levels of a brain protein doesn’t seem like a good idea. Has anyone ever tried to raise a mouse or something with the appropriate genes knocked out?
    Also, doesn’t evolution predict that there won’t be a clear line between life and non-life; that wherever we try to draw a line, eventually something will be found that exists in the gray area?

  7. Anon

    For a good discussion of evolution and why it does not necessarily require either RNA or DNA, see Dennett’s Darwin’s Dangerous Idea.
    Really, what you need is a stable substrate of some sort (be it 1s and 0s or biological goo); high fidelity replication (but not 100% accuracy!); and a selection function that roots out some of the resultant offspring.
    Dennett’s characterization has the advantage of working equally well for genetic algorithms in computer science and for biological systems, including prions.

  8. Sven DiMilo

    wait.

    prion populations consist of a multitude of strains and substrains, all of which are different ways of folding the same sequence of amino acids.

    That much I’ll buy. How, though, do the different strains “breed” (nearly) true? How is it that one folded protein causes another to misfold in exactly the same way, while another protein (identical amino acid sequence) that’s folded differently induces this precise different fold instead?
    Do they know that it’s not just each prion inducing a variety of slightly different folds, which are then culled (by what?) to give the differential tissue results?
    There’s an important chunk of mechanism missing here, and it’s not anything like evolution by natural selection if there is nothing like inheritance.

  9. Alex Besogonov

    Duh. What’s so fascinating in this study?
    We’ve known for ages that if you have an imperfect replicator and selective pressure, then you’ll get evolution. In fact, we routinely use genetic (sic!) algorithms in software to exploit this fact.
    Also, the word ‘genetic’ itself is NOT related in any way to genes and/or (R|D)NA. Look it up in the dictionary.
    Thus the Wikipedian definition: “change in the genetic material of a population… through successive generations” is absolutely correct. In case of prions, the genetic material is the prion itself.

  10. jon

    BSE does not mean Bovine Spongiform ENCEPHALITIS it means
    Bovine Spongiform Encephalopathy.
    Encephalitis means inflammation of the brain, encephalopathy is a broader term relating to any number of possible causations affesting the structure of the brain.
    Encephalitis could be termed as coming under the general heading of encephalopathy but the term Bovine Spongiform Encephalitis is misleading.

  11. Sven DiMilo

    Also, the word ‘genetic’ itself is NOT related in any way to genes and/or (R|D)NA. Look it up in the dictionary.

    No, YOU look it up in “the” dictionary, please, and then link to the particular dictionary definition that you think supports this assertion.
    Prions are not “genetic material.” They are not inherited in any meaningful sense.
    What is apparently/putatively/allegedly passed on is a folding pattern. So far what I understand is that there is variation in folding patterns and that different patterns tend to accumulate in diffeent tissues.
    What is missing (afaict; please set me straight if I am woti)are 1) evidence that each variant folding pattern induces an identical folding pattern in other (sequence-identical) proteins (occasional “mutation” notwithstanding). The null hypothesis here would be that initial variation in induced folding patterns is uncorrelated to the folding patterns of the inducing prions.
    2) information about the putative “selection pressures” that favor the persistence of different folding patterns in different tissues.
    Even with information about issue 2, though, the point remains that environmental sorting alone does not cause evolution by natural selection, nor true adaptation. This is why evolutionary biologists are careful to distinguish between phenotypic selection–the sorting of variant phenotypes by differential reproduction in a particular environment–and the evolutionary response to selection, which is a resultant change in population/genepool-level allele frequencies (= evolution). Without heritability (e.g. if all variation is of purely environmental cause), even strong selection does not necessarily cause any evolution in response.
    In short, the analogy to evolution by natural selection relies entirely on the analogy to inheritance, which I am still not buying.

  12. Anton Mates

    Sven, the issue you bring up was discussed over at ERV, and someone drug up a few papers on true-breeding traits in prions. Not all their “interesting” traits are heritable, of course–in fact, the drug-resistance trait discussed in ERV’s post turned out to not to be–but apparently many traits are.
    The Li et al. paper treats the existence of individual true-breeding strains as well-established:

    Prions occur in the form of distinct strains, originally characterized by the incubation time and the neuropathology they elicit in a particular host (2). Many different strains can be propagated indefinitely in hosts homozygous for the PrP gene (Prnp); the protein-only hypothesis assumes each strain is associated with a different conformer of PrPSc (3–5), implying that there are as many stable conformations of PrP as there are stable prion strains that can be propagated in a particular mouse strain, perhaps fifteen or more (6).
    The concept of “conformation templating” at the protein level was first supported by cell-free conversion experiments (7) and extended by the development of protein misfolding cyclic amplification (PMCA), which mimics PrPSc autocatalytic replication in vitro (8).

    The important bit is “in a particular mouse strain.” These are highly inbred and virtually 100% homozygous strains of mice, so if distinct true-breeding strains of prions can be bred within mice from the same lineage, the differences in prion strain are probably due to heritable properties in the prions themselves, rather than differences in the mouse hosts.

  13. Salman

    I think this is a very important demonstration of the way biomolecules probably function which is that they adopt a finite number of conformers with a further degree of conformational plasticity in key functional domains e.g. catalytic sites etc
    I favour the induced-fit model for bimolecular interactions which underlie the specificity of biological systems. In this case it would be expected that the are a finite number of strains for a particular PrP gene and thus a limited level of infectivity. it should be possible to demonstrate this with existing technology, although I do not know enough about these molecules!

  14. Alex Besogonov

    “No, YOU look it up in “the” dictionary, please, and then link to the particular dictionary definition that you think supports this assertion.”
    Sorry for ‘the’, English is not my native language and articles is my weak spot. Here’s the definition, anyway: “Genome is the entirety of an organism’s hereditary information”.
    It’s that simple. There’s no mention of DNA or RNA or folding pattern of a peptide chain. In fact, you can make artificial organism whose genome will be encoded in a bit of silicon.
    “Prions are not “genetic material.” They are not inherited in any meaningful sense.
    What is apparently/putatively/allegedly passed on is a folding pattern. So far what I understand is that there is variation in folding patterns and that different patterns tend to accumulate in diffeent tissues. ”
    Prions ARE a genetic material. It is ‘inherited’, prions pass their folding patterns to their ‘offspings’.
    Prions are a bit special in that their ‘phenotype’ is also their ‘genotype’. But it’s not that different from viriods, for example.

  15. yervand

    People for one second please wake up! Where is the proof of “prion” being a protein only infectious agent devoid of any RNA?!!

    Please see the link bellow:

    http://www.sciencemag.org/cgi/eletters/327/5967/869

    Could Prion Protein Assumptions Engender Misleading Sensational Conclusions?
    Igor V. Zaitsev (19 March 2010)
    The Backwards Evolution of Prions
    Laura Manuelidis (19 March 2010)

    E-Letter responses to:
    reports:
    Jiali Li, Shawn Browning, Sukhvir P. Mahal, Anja M. Oelschlegel, and Charles Weissmann
    Darwinian Evolution of Prions in Cell Culture
    Science 2010; 327: 869-872 [Abstract] [Full text] [PDF]
    E-Letters: Submit a response to this article
    PUBLISHED E-LETTER RESPONSES:

    Could Prion Protein Assumptions Engender Misleading Sensational Conclusions?
    Igor V. Zaitsev (19 March 2010)
    The Backwards Evolution of Prions
    Laura Manuelidis (19 March 2010)

    http://www.sciencemag.org/cgi/eletters/327/5967/869

  16. Yervand – From your name and email, I take it that you are Yervand Karapetyan from Scripps, and actually part of Weissmann’s lab. In which case, I am confused about your comment and I’d like to point you to your own group website, which says “Prions are infectious agents that consist of protein and are devoid of a nucleic acid-based genome.” If you disagree, perhaps you’d like to cite an actual peer-reviewed paper rather than a letter by a school teacher in response to a peer-reviewed paper.

  17. lester

    Yervand,

    So, instead of posting a peer-reviewed paper as proof to your point, you cite a website that states that there is something wrong with the peer-review process. My belief is that you did not read the rest of that website. I guess I will have to fill you in. Read this page about the author’s biography (written by the author himself): http://www.nov55.com/abt.html

    If reading that doesn’t raise a flag, then go to this webpage were they breakdown some of Mr. Novak’s claims: http://moonflake.wordpress.com/2006/11/10/midweek-cuckoogary-novak/

    I wonder if you – yourself – actually believe the information on the link you posted; seeing as you – yourself – use the peer-review process to publish articles:
    http://www.ncbi.nlm.nih.gov/pubmed/19478942

  18. lester

    Nice try! But, that article isn’t even published; let alone peer-reviewed. Who are you trying to fool?
    First, you reference a website whose author most likely suffers from some type of mental disorder (note his mention of his “mental pain”). Next, you reference nature precedings (Its own title stating “nature precedings Pre-publication and preliminary findings”). Are you going to cite any article that has actually been reviewed and published? Or, do you just enjoy wasting people’s time?

    Note that the first two comments on the paper you linked are from Adriano Aguzzi and Charles Weissmann. Both experts in the field of prions. Both whom say nothing positive about the study.

  19. yervand

    PEER-REWIED, PUBLISHED “FACTS”

    Ciba Found Symp. 1988;135:209-23.
    Search for a scrapie-specific nucleic acid: a progress report.
    Oesch B, Groth DF, Prusiner SB, Weissmann C.

    Comparison of RNA from healthy and scrapie-infected hamster brain.
    German TL, McMillan BC, Castle BE, Dees C, Wade WF, Marsh RF.
    J Gen Virol. 1985 Apr;66 ( Pt 4):839-44.

    Presence of mitochondrial D-loop DNA in scrapie-infected brain preparations enriched for the prion protein.
    Aiken JM, Williamson JL, Borchardt LM, Marsh RF.
    J Virol. 1990 Jul;64(7):3265-8.

    Search for a prion-specific nucleic acid.
    Safar JG, Kellings K, Serban A, Groth D, Cleaver JE, Prusiner SB, Riesner D.
    J Virol. 2005 Aug;79(16):10796-806.

    Visualization of viral candidate cDNAs in infectious brain fractions from Creutzfeldt-Jakob disease by representational difference analysis.
    Dron M, Manuelidis L.
    J Neurovirol. 1996 Aug;2(4):240-8.

    Nuclease-resistant polyadenylated RNAs of significant size are detected by PCR in highly purified Creutzfeldt-Jakob disease preparations.
    Akowitz A, Sklaviadis T, Manuelidis EE, Manuelidis L.
    Microb Pathog. 1990 Jul;9(1):33-45.

    A cellular gene encodes scrapie PrP 27-30 protein.
    Oesch B, Westaway D, Wälchli M, McKinley MP, Kent SB, Aebersold R, Barry RA, Tempst P, Teplow DB, Hood LE, et al.
    Cell. 1985 Apr;40(4):735-46.

    Cell. 1985 Apr;40(4):725-7.
    Focusing on the nature of the scrapie agent.
    Robertson HD, Branch AD, Dahlberg JE.

    Novel proteinaceous infectious particles cause scrapie.
    Prusiner SB.
    Science. 1982 Apr 9;216(4542):136-44.

  20. yervand

    Microbiol Rev. 1990 Sep;54(3):242-6.
    The search for scrapie agent nucleic acid.
    Aiken JM, Marsh RF.

    Department of Veterinary Science, University of Wisconsin-Madison 53706.

  21. cassie

    I am writing a paper for a class in college regarding the evolution of lower forms of life. Even though prions might not be considered alive I wanted to talk about how there was evidence for their evolution in vitro regardless of them not possessing a nucleic acid genome – i.e. the data published by Li et al
    My search for information let me to this blog. Confusingly, I find people arguing about prions do having a nucleic acid genome.
    I understand that my question might come several years too late. But, is there any new data that proves prions indeed have a nucleic acid genome?

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