On 2014 Apr 16, Claudiu Bandea commented:

What if we have totally missed the true nature of viruses? (Part II)

(Due to size limitations, this comment was entered as two parts)

Another way to react to the critical question raised by Wolkowicz and Schaechter (24) is to invoke the notion that viruses are not even living entities, and come up with “Ten reasons to exclude viruses from the tree of life” (26). As discussed in more detail elsewhere (8), many of the reasons presented by David Moreira and Purificación López-García (26) were rationalized within the framework of the misleading conventional paradigms about their nature and evolution, so their scientific validity is compromised. Interestingly, Moreira and López-García were well aware of the problems with the dogma of viruses as virus particles, as they wrote: “Claverie recently proposed a provocative redefinition of the viral identity wherein the true nature of a virus is not the virion (the infective viral particle)” (26). However, they dismissed the entire issue by justifiably arguing that the solution to the problems associated with the dogma of viruses as virus particles as proposed by Claverie, “The virus factory should be considered the actual virus organism when referring to a virus” (4), is nonsensical, as the identity of an organism should rely solely on its components and properties, not those of its environment (i.e. the host cell; for more discussion on this issue see Ref. 9); incidentally, this rationale also questions the ‘virocell concept,’ which was developed by Patrick Forterre as a novel solution to the misleading dogma of viruses as virus particles (11, 27). Moreover, in their response to a flurry of comments prompted by their article (see the published correspondence associated with Ref. 26 in the journal Nature Rev. Microbiol.), Moreira and López-García explained the reasons for much of the scientific confusion afflicting the current paradigms on the evolution of viruses: “We realize that much of this confusion comes from the fact that many virologists and other biologists are not familiar with the theory and practice of molecular phylogeny.” That might be true. However, generating correct data and observations is only half of the scientific process, the other half is their interpretation; and, as previously discussed (9), the interpretation of their own (presumably valid) molecular phylogeny data by Moreira and López-García was compromised by the current misleading paradigms on their nature and evolutionary origin.

The allegations outlined here against the conventional paradigms on the nature and evolution of viruses are strong and implicating, climaxing with the assertion that the life and welfare of tens of millions of people suffering from neurodegenerative diseases might have been affected by the constrains imposed by the dogma of viruses as virus particles on understanding the true etiology of these devastating diseases and on the development of preventive and treatment approaches (14-16). It should be expected, therefore, that scientists working in these basic and applied biomedical fields would timely and openly refute or embrace these allegations. That might not happen, though, as it is well recognized by the historians and philosophers of science (28, 29) that the scientific theories, paradigms and dogmas, even if blatantly wrong, have a life of their own, which doesn’t necessarily follow Peter Medawar’s sensible recipe for conducting science: “The scientific method is a potentiation of common sense, exercised with a specially firm determination not to persist in error” (30). However, in this particular case, there is hope that some of the millions of patients affected by neurodegenerative diseases, as well as their family members and friends, might put some pressure on the scientists working these fields to either dismiss or to embrace these allegations.

References:

(1) Edwards, RA, Rohwer F. Viral metagenomics. 2005. Nat. Rev. Microbiol. 3:504-510. Edwards RA, 2005

(2) Suttle C.A. 2007. Marine viruses--major players in the global ecosystem. Nat Rev Microbiol. 5:801-12. Suttle CA, 2007

(3) Forterre P. 2006. The origin of viruses and their possible roles in major evolutionary transitions. Virus Res. 117:5-16. Forterre P, 2006

(4) Claverie JM. 2006. Viruses take center stage in cellular evolution. Genome Biol. 7, 110. Claverie JM, 2006

(5) Koonin EV, Senkevich TG, Dolja VV. 2006. The ancient Virus World and evolution of cells. Biol Direct. 1-27. Koonin EV, 2006

(6) Bandea CI. 2009. A Unifying Scenario on the Origin and Evolution of Cellular and Viral Domains. Nature Precedings; http://precedings.nature.com/documents/3888/version/1

(7) Rohwer F, Barott K. 2013. Viral information. Biol Philos. 28:283-297. Rohwer F, 2013

(8) Bandea CI. 1983. A new theory on the origin and the nature of viruses. Journal of Theoretical Biology 105:591-602. Bândea CI, 1983

(9) Bandea CI. 2009. The origin and evolution of viruses as molecular organisms. Nature Precedings; http://precedings.nature.com/documents/3886/version/1

(10) Watson, JD. 1976. Molecular Biology of the Gene. Benjamin-Cummings, Menlo Park.

(11) Forterre P. 2010. Giant viruses: conflicts in revisiting the virus concept. Intervirology. 53:362-78. Forterre P, 2010

(12) Legendre M et al. 2014. Thirty-thousand-year-old distant relative of giant icosahedral DNA viruses with a pandoravirus morphology. Proc Natl Acad Sci U S A. 111:4274-9. Legendre M, 2014

(13) Zimmer C. 2011. A Planet of Viruses. University of Chicago Press, Chicago.

(14) Bandea CI. 1986. From prions to prionic viruses. Med Hypotheses. 20:139-142.Bândea CI, 1986

(15) Bandea CI. 2009 Endogenous viral etiology of prion diseases. Nature Precedings; http://precedings.nature.com/documents/3887/version/1

(16) Bandea CI. 2013. Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders. bioRxiv; http://biorxiv.org/content/early/2013/11/18/000604

(17) Prusiner, SB. 1998. Prions. Proc. Natl. Acad. Sci. U. S. A. 95:13363-13383. Prusiner SB, 1998

(18) Raoult D et al. 2004. The 1.2-megabase genome sequence of Mimivirus. Science. 306:1344-50. Raoult D, 2004

(19) Philippe N et al. 2013. Pandoraviruses: amoeba viruses with genomes up to 2.5 Mb reaching that of parasitic eukaryotes. Science 341:281-6. Philippe N, 2013

(20) Hoffmann R et al. 1998. Archaea-like endocytobiotic organisms isolated from Acanthamoeba sp. (Gr II). Endocytobiosis & Cell Res.12, 185.

(21) Michel R et al. 2003. Endocytobiont KC5/2 induces transformation into sol-like cytoplasm of its host Acanthamoeba sp. as substrate for its own development. Parasitol Res. 90:52-6. Michel R, 2003

(22) Scheid P et al. 2008. An extraordinary endocytobiont in Acanthamoeba sp. isolated from a patient with keratitis. Parasitol. Res.102, 945, (2008). Scheid P, 2008

(23) Scheid P, Hauröder B, Michel R. 2010. Investigations of an extraordinary endocytobiont in Acanthamoeba sp.: development and replication. Parasitol Res.106:1371-7. Scheid P, 2010

(24) Wolkowicz R, Schaechter M. 2008.What makes a virus a virus? Nat Rev Microbiol. 6:643. Wolkowicz R, 2008

(25) Raoult D, Forterre P. 2008. Redefining viruses: lessons from Mimivirus. Nat Rev Microbiol. 6:315-9. Raoult D, 2008

(26) Moreira D. & López-García P. 2009.Ten reasons to exclude viruses from the tree of life. Nature Rev. Microbiol. 7:306–311. Moreira D, 2009

(27) Forterre P. 2013. The virocell concept and environmental microbiology.ISME J. 7:233-6. Forterre P, 2013

(28) Kuhn TS. 1962. The Structure of Scientific Revolutions. University of Chicago Press, Chicago.

(29) Popper K. 1963. Conjectures and Refutations: The Growth of Scientific Knowledge. Routledge, London

(30) Medawar PB. 1969. Induction and Intuition in Scientific Thought. Methuen, London.

On 2014 Apr 16, Claudiu Bandea commented:

What if we have totally missed the true nature of viruses? (Part I)

(Due to size limitations, this comment was entered as two parts)

Viruses are the most abundant life forms on Earth and the repertoire of their genes is greater than that of cellular organisms (reviewed in 1, 2). Considering also their extraordinary medical and ecological significance as well as their critical role in shaping the evolution of cellular species and their genome (3-7), it would be expected that the paradigms about the nature and evolution of viruses were on solid scientific grounds.

However, in what might be the most enduring misconception in biology, ever since they were discovered more than a century ago, viruses have been conceptually misidentified with the virus particles and defined based on the physical, biochemical, and biological properties of these particles (8, 9). Because of the dogma of viruses as virus particles, thousands of scientific articles and books about viruses contain errors that border the pseudo-science realm. Take, for example, the following quote, which is representative of the scientific description of viruses: “all viruses differ fundamentally from cells, which have both DNA and RNA, in that viruses contain only one type of nucleic acid, which may be either DNA or RNA” (italics added to all quotes; 10). Despite common knowledge that during their life cycle many viruses have both nucleic acids, even James Watson, the eminent scientist, who arguably knows nucleic acids better than anyone, has fallen victim to the dogma of viruses as virus particles (for additional examples and quotes outlining this dogma see Ref. 9).

Although the scientific flaws associated with the dogma of viruses as virus particles were outlined more than three decades ago (8), along with a new hypothesis on their nature and evolutionary origin, these flaws have only become acute after the discovery of giant viruses (reviewed in Ref. 11). Perhaps no one has questioned the dogma of viruses as virus particles more explicitly, and in stronger terms, than Jean-Michel Claverie, the senior author of the article by Legendre et al. (12) and one of the leading researchers in the field of giant viruses, who asked: “what if we have totally missed the true nature of (at least some) viruses?” (4). Claverie answered this intriguing question in a rather revealing way: identifying viruses with the virus particles, he wrote, might “be a case of ‘when the finger points to the stars, the fool looks at the finger.”

As previously emphasized, however, questioning the dogma of viruses as virus particles is challenging (9). After all, it can be argued that, even if scientifically flawed, the dogma has ‘guided’ several generations of scientists to extraordinary discoveries in virology and in related biomedical fields. By analogy, it is also true that many scientific studies about our planet, which is increasingly thought of as “A Planet of Viruses” (13; see also Ref. 7), can be successfully performed in context of the theory that Earth is flat. So, why question the dogma of viruses as virus particles? First, this dogma is scientifically flawed and, therefore, academically unacceptable. More importantly, though, it has constrained progress not only in basic research, such as that on the origin and evolution of viruses and cells, but also in some applied biomedical fields, in which the life and welfare of many people is at stake.

For example, in the field of neurodegenerative diseases, which affect tens of millions of people and have a negative economic impact that dwarfs the entire global investment in biomedical research, the misleading dogma of viruses as virus particles led to the formulation of the prion hypothesis, which has apparently misdirected much of the thinking and research for decades (14-16). Briefly, in the context of dogma of viruses as virus particles, in order to prove or disprove the viral etiology of Transmissible Spongiform Encephalopathies (TSEs), the scientists searched for viruses (i.e. virus particles containing the viral genome) in the material used for the transmission of the disease. Hundreds of studies using this experimental approach were performed, but no TSE virus was found, which led to the triumph of the prion hypothesis and the dismissal of the virus hypothesis: “the 50-year quest for a virus has failed because it does not exist!” it was exclaimed (17). However, a decade earlier, it was proposed that the scientific rationale and the experimental approach that were used to investigate the etiology of TSEs were misleading; specifically, it was proposed that the so called ‘prion protein’ was encoded by an endogenous virus, and that this virus could not be identified by the experimental approaches that were employed or in the context of the scientific rationale imposed by the dogma of viruses as virus particles; indeed, none of the thousands of endogenous viruses can be identified using these scientifically flawed approaches. Nevertheless, the pseudoscientific aberration imposed by conventional view about the nature and identity of viruses did not stay in the way of making the prion hypothesis one of the top novelties in modern biology and promoted and rewarded accordingly (17).

Regarding P. sibericum and other giant viruses, the current dogma about the nature and evolution of viruses has delayed their identification for many years, if not decades, and have confused the interpretation of the experimental data and observations in the field. For example, the original mimivirus isolate was classified as a small Gram-positive bacterium for a decade before realized that it was a virus (18). Since then, several viruses with large genomes size have been identified, culminating with the remarkable reports on the discovery of pandoraviruses (19) and P. sibericum (12) by Claverie and his colleagues. Interestingly, it appears that some of these ‘novel’ giant viruses have also been isolated and characterized many years ago, but classified as cellular organisms. Indeed, two free-living amoeba intracellular parasites, labeled KC5/2 and KLaHel, which were discovered by a German research group in samples collected form a water-treatment-plant sample (20, 21) and the inflamed eye of a patient with keratitis (22, 23), respectively, are highly similar P. sibericum and pandoraviruses.

So, “What makes a virus a virus?” (24). Incited by a new proposal by Didier Raoult and Patrick Forterre for defining the nature of viruses (25), Roland Wolkowicz and Moselio Schaechter (24) have come to realize that the identity of viruses, as traditionally defined (i.e. virus particles), or as proposed by Raoult and Forterre (i.e. capsid-, or virus particle-encoding organisms), is missing the “the most fundamental aspect of what makes a virus a virus: it breaks up and loses its bodily integrity, with its progeny becoming reconstituted after replication from newly synthesized parts.” And, reflecting more broadly on the nature of viruses and on the field of virology, Wolkowicz and Schaechter wrote: “We are surprised from our own experience that the world of virology has not fully embraced this outlook” (24). However, this outlook, along with a comprehensive theory on their evolutionary origin, nature, and identity, has been presented more than three decade ago (8, 9), but until recently (see, for example, Ref. 11) it has received little attention.

On 2014 Apr 16, Claudiu Bandea commented:

What if we have totally missed the true nature of viruses? (Part I)

(Due to size limitations, this comment was entered as two parts)

Viruses are the most abundant life forms on Earth and the repertoire of their genes is greater than that of cellular organisms (reviewed in 1, 2). Considering also their extraordinary medical and ecological significance as well as their critical role in shaping the evolution of cellular species and their genome (3-7), it would be expected that the paradigms about the nature and evolution of viruses were on solid scientific grounds.

However, in what might be the most enduring misconception in biology, ever since they were discovered more than a century ago, viruses have been conceptually misidentified with the virus particles and defined based on the physical, biochemical, and biological properties of these particles (8, 9). Because of the dogma of viruses as virus particles, thousands of scientific articles and books about viruses contain errors that border the pseudo-science realm. Take, for example, the following quote, which is representative of the scientific description of viruses: “all viruses differ fundamentally from cells, which have both DNA and RNA, in that viruses contain only one type of nucleic acid, which may be either DNA or RNA” (italics added to all quotes; 10). Despite common knowledge that during their life cycle many viruses have both nucleic acids, even James Watson, the eminent scientist, who arguably knows nucleic acids better than anyone, has fallen victim to the dogma of viruses as virus particles (for additional examples and quotes outlining this dogma see Ref. 9).

Although the scientific flaws associated with the dogma of viruses as virus particles were outlined more than three decades ago (8), along with a new hypothesis on their nature and evolutionary origin, these flaws have only become acute after the discovery of giant viruses (reviewed in Ref. 11). Perhaps no one has questioned the dogma of viruses as virus particles more explicitly, and in stronger terms, than Jean-Michel Claverie, the senior author of the article by Legendre et al. (12) and one of the leading researchers in the field of giant viruses, who asked: “what if we have totally missed the true nature of (at least some) viruses?” (4). Claverie answered this intriguing question in a rather revealing way: identifying viruses with the virus particles, he wrote, might “be a case of ‘when the finger points to the stars, the fool looks at the finger.”

As previously emphasized, however, questioning the dogma of viruses as virus particles is challenging (9). After all, it can be argued that, even if scientifically flawed, the dogma has ‘guided’ several generations of scientists to extraordinary discoveries in virology and in related biomedical fields. By analogy, it is also true that many scientific studies about our planet, which is increasingly thought of as “A Planet of Viruses” (13; see also Ref. 7), can be successfully performed in context of the theory that Earth is flat. So, why question the dogma of viruses as virus particles? First, this dogma is scientifically flawed and, therefore, academically unacceptable. More importantly, though, it has constrained progress not only in basic research, such as that on the origin and evolution of viruses and cells, but also in some applied biomedical fields, in which the life and welfare of many people is at stake.

For example, in the field of neurodegenerative diseases, which affect tens of millions of people and have a negative economic impact that dwarfs the entire global investment in biomedical research, the misleading dogma of viruses as virus particles led to the formulation of the prion hypothesis, which has apparently misdirected much of the thinking and research for decades (14-16). Briefly, in the context of dogma of viruses as virus particles, in order to prove or disprove the viral etiology of Transmissible Spongiform Encephalopathies (TSEs), the scientists searched for viruses (i.e. virus particles containing the viral genome) in the material used for the transmission of the disease. Hundreds of studies using this experimental approach were performed, but no TSE virus was found, which led to the triumph of the prion hypothesis and the dismissal of the virus hypothesis: “the 50-year quest for a virus has failed because it does not exist!” it was exclaimed (17). However, a decade earlier, it was proposed that the scientific rationale and the experimental approach that were used to investigate the etiology of TSEs were misleading; specifically, it was proposed that the so called ‘prion protein’ was encoded by an endogenous virus, and that this virus could not be identified by the experimental approaches that were employed or in the context of the scientific rationale imposed by the dogma of viruses as virus particles; indeed, none of the thousands of endogenous viruses can be identified using these scientifically flawed approaches. Nevertheless, the pseudoscientific aberration imposed by conventional view about the nature and identity of viruses did not stay in the way of making the prion hypothesis one of the top novelties in modern biology and promoted and rewarded accordingly (17).

Regarding P. sibericum and other giant viruses, the current dogma about the nature and evolution of viruses has delayed their identification for many years, if not decades, and have confused the interpretation of the experimental data and observations in the field. For example, the original mimivirus isolate was classified as a small Gram-positive bacterium for a decade before realized that it was a virus (18). Since then, several viruses with large genomes size have been identified, culminating with the remarkable reports on the discovery of pandoraviruses (19) and P. sibericum (12) by Claverie and his colleagues. Interestingly, it appears that some of these ‘novel’ giant viruses have also been isolated and characterized many years ago, but classified as cellular organisms. Indeed, two free-living amoeba intracellular parasites, labeled KC5/2 and KLaHel, which were discovered by a German research group in samples collected form a water-treatment-plant sample (20, 21) and the inflamed eye of a patient with keratitis (22, 23), respectively, are highly similar P. sibericum and pandoraviruses.

So, “What makes a virus a virus?” (24). Incited by a new proposal by Didier Raoult and Patrick Forterre for defining the nature of viruses (25), Roland Wolkowicz and Moselio Schaechter (24) have come to realize that the identity of viruses, as traditionally defined (i.e. virus particles), or as proposed by Raoult and Forterre (i.e. capsid-, or virus particle-encoding organisms), is missing the “the most fundamental aspect of what makes a virus a virus: it breaks up and loses its bodily integrity, with its progeny becoming reconstituted after replication from newly synthesized parts.” And, reflecting more broadly on the nature of viruses and on the field of virology, Wolkowicz and Schaechter wrote: “We are surprised from our own experience that the world of virology has not fully embraced this outlook” (24). However, this outlook, along with a comprehensive theory on their evolutionary origin, nature, and identity, has been presented more than three decade ago (8, 9), but until recently (see, for example, Ref. 11) it has received little attention.

On 2014 Apr 16, Claudiu Bandea commented:

What if we have totally missed the true nature of viruses? (Part II)

(Due to size limitations, this comment was entered as two parts)

Another way to react to the critical question raised by Wolkowicz and Schaechter (24) is to invoke the notion that viruses are not even living entities, and come up with “Ten reasons to exclude viruses from the tree of life” (26). As discussed in more detail elsewhere (8), many of the reasons presented by David Moreira and Purificación López-García (26) were rationalized within the framework of the misleading conventional paradigms about their nature and evolution, so their scientific validity is compromised. Interestingly, Moreira and López-García were well aware of the problems with the dogma of viruses as virus particles, as they wrote: “Claverie recently proposed a provocative redefinition of the viral identity wherein the true nature of a virus is not the virion (the infective viral particle)” (26). However, they dismissed the entire issue by justifiably arguing that the solution to the problems associated with the dogma of viruses as virus particles as proposed by Claverie, “The virus factory should be considered the actual virus organism when referring to a virus” (4), is nonsensical, as the identity of an organism should rely solely on its components and properties, not those of its environment (i.e. the host cell; for more discussion on this issue see Ref. 9); incidentally, this rationale also questions the ‘virocell concept,’ which was developed by Patrick Forterre as a novel solution to the misleading dogma of viruses as virus particles (11, 27). Moreover, in their response to a flurry of comments prompted by their article (see the published correspondence associated with Ref. 26 in the journal Nature Rev. Microbiol.), Moreira and López-García explained the reasons for much of the scientific confusion afflicting the current paradigms on the evolution of viruses: “We realize that much of this confusion comes from the fact that many virologists and other biologists are not familiar with the theory and practice of molecular phylogeny.” That might be true. However, generating correct data and observations is only half of the scientific process, the other half is their interpretation; and, as previously discussed (9), the interpretation of their own (presumably valid) molecular phylogeny data by Moreira and López-García was compromised by the current misleading paradigms on their nature and evolutionary origin.

The allegations outlined here against the conventional paradigms on the nature and evolution of viruses are strong and implicating, climaxing with the assertion that the life and welfare of tens of millions of people suffering from neurodegenerative diseases might have been affected by the constrains imposed by the dogma of viruses as virus particles on understanding the true etiology of these devastating diseases and on the development of preventive and treatment approaches (14-16). It should be expected, therefore, that scientists working in these basic and applied biomedical fields would timely and openly refute or embrace these allegations. That might not happen, though, as it is well recognized by the historians and philosophers of science (28, 29) that the scientific theories, paradigms and dogmas, even if blatantly wrong, have a life of their own, which doesn’t necessarily follow Peter Medawar’s sensible recipe for conducting science: “The scientific method is a potentiation of common sense, exercised with a specially firm determination not to persist in error” (30). However, in this particular case, there is hope that some of the millions of patients affected by neurodegenerative diseases, as well as their family members and friends, might put some pressure on the scientists working these fields to either dismiss or to embrace these allegations.

References:

(1) Edwards, RA, Rohwer F. Viral metagenomics. 2005. Nat. Rev. Microbiol. 3:504-510. Edwards RA, 2005

(2) Suttle C.A. 2007. Marine viruses--major players in the global ecosystem. Nat Rev Microbiol. 5:801-12. Suttle CA, 2007

(3) Forterre P. 2006. The origin of viruses and their possible roles in major evolutionary transitions. Virus Res. 117:5-16. Forterre P, 2006

(4) Claverie JM. 2006. Viruses take center stage in cellular evolution. Genome Biol. 7, 110. Claverie JM, 2006

(5) Koonin EV, Senkevich TG, Dolja VV. 2006. The ancient Virus World and evolution of cells. Biol Direct. 1-27. Koonin EV, 2006

(6) Bandea CI. 2009. A Unifying Scenario on the Origin and Evolution of Cellular and Viral Domains. Nature Precedings; http://precedings.nature.com/documents/3888/version/1

(7) Rohwer F, Barott K. 2013. Viral information. Biol Philos. 28:283-297. Rohwer F, 2013

(8) Bandea CI. 1983. A new theory on the origin and the nature of viruses. Journal of Theoretical Biology 105:591-602. Bândea CI, 1983

(9) Bandea CI. 2009. The origin and evolution of viruses as molecular organisms. Nature Precedings; http://precedings.nature.com/documents/3886/version/1

(10) Watson, JD. 1976. Molecular Biology of the Gene. Benjamin-Cummings, Menlo Park.

(11) Forterre P. 2010. Giant viruses: conflicts in revisiting the virus concept. Intervirology. 53:362-78. Forterre P, 2010

(12) Legendre M et al. 2014. Thirty-thousand-year-old distant relative of giant icosahedral DNA viruses with a pandoravirus morphology. Proc Natl Acad Sci U S A. 111:4274-9. Legendre M, 2014

(13) Zimmer C. 2011. A Planet of Viruses. University of Chicago Press, Chicago.

(14) Bandea CI. 1986. From prions to prionic viruses. Med Hypotheses. 20:139-142.Bândea CI, 1986

(15) Bandea CI. 2009 Endogenous viral etiology of prion diseases. Nature Precedings; http://precedings.nature.com/documents/3887/version/1

(16) Bandea CI. 2013. Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders. bioRxiv; http://biorxiv.org/content/early/2013/11/18/000604

(17) Prusiner, SB. 1998. Prions. Proc. Natl. Acad. Sci. U. S. A. 95:13363-13383. Prusiner SB, 1998

(18) Raoult D et al. 2004. The 1.2-megabase genome sequence of Mimivirus. Science. 306:1344-50. Raoult D, 2004

(19) Philippe N et al. 2013. Pandoraviruses: amoeba viruses with genomes up to 2.5 Mb reaching that of parasitic eukaryotes. Science 341:281-6. Philippe N, 2013

(20) Hoffmann R et al. 1998. Archaea-like endocytobiotic organisms isolated from Acanthamoeba sp. (Gr II). Endocytobiosis & Cell Res.12, 185.

(21) Michel R et al. 2003. Endocytobiont KC5/2 induces transformation into sol-like cytoplasm of its host Acanthamoeba sp. as substrate for its own development. Parasitol Res. 90:52-6. Michel R, 2003

(22) Scheid P et al. 2008. An extraordinary endocytobiont in Acanthamoeba sp. isolated from a patient with keratitis. Parasitol. Res.102, 945, (2008). Scheid P, 2008

(23) Scheid P, Hauröder B, Michel R. 2010. Investigations of an extraordinary endocytobiont in Acanthamoeba sp.: development and replication. Parasitol Res.106:1371-7. Scheid P, 2010

(24) Wolkowicz R, Schaechter M. 2008.What makes a virus a virus? Nat Rev Microbiol. 6:643. Wolkowicz R, 2008

(25) Raoult D, Forterre P. 2008. Redefining viruses: lessons from Mimivirus. Nat Rev Microbiol. 6:315-9. Raoult D, 2008

(26) Moreira D. & López-García P. 2009.Ten reasons to exclude viruses from the tree of life. Nature Rev. Microbiol. 7:306–311. Moreira D, 2009

(27) Forterre P. 2013. The virocell concept and environmental microbiology.ISME J. 7:233-6. Forterre P, 2013

(28) Kuhn TS. 1962. The Structure of Scientific Revolutions. University of Chicago Press, Chicago.

(29) Popper K. 1963. Conjectures and Refutations: The Growth of Scientific Knowledge. Routledge, London

(30) Medawar PB. 1969. Induction and Intuition in Scientific Thought. Methuen, London.