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Analysis of the protovirus hypothesis
Medical Hypotheses18: 151-156,1985
ANALYSIS
OF THE PROTOVIRUS
HYPOTHESIS.
Godfrey Caesar, 209 west 137th. Street, New York, New York 10030, U.S.A ABSTRACT Its activity Cancer may be endogenous to all mankind. is dependent upon the absence of anti cancer gene agent or agents. INTRODUCTION I outline evidence to support the idea that cancer is an inborn phenomenon, probably commencing from birth and whose activity is primarily dependent upon the constitution of the individual, EVIDENCE 1. The author (1) proposed that (a) every human being is born with a tendency to develop cancer, i.e., to say the development of cancer is complete from birth; (5) some human beings are born with an anti cancer agent or agents in addition to this cancer tendency which causes their potential cancer(s) to be inactive and dormant at all times, while other human beings who have no anti cancer agent or agents will and do suffer from cancer at some time; (c) cancer is neither infectious nor contagious; (d) all cancers are fundamentally similar in nature, except that they may reveal their active presence at any site of the human body. 2. Temin (2) stated that (a) the oncogene theory appears to combine viral and epigenetic theories by postulating that neoplasia results from the activation of a veriically transmitted provirus. However, this oncogene theory is basically an epigenetic theory since it postulates a stable change in phenotype due to switch in a regulatory system; (b) proposed in the protovirus hypothesis that there is apparent vertical transmission of the information for cancer, even though the germ line does not contain this information on its chromosomes (proviruses or oncogenes) or off its chromosomes 151
(virions). The germ line is postulated to contain in its chromosomes the potential for genetic evolution by the somatic cells that may lead to the de Novo formation of information for cancer; (c) This apparent vertical transmission of the information for cancer differs from classical vertical transmission which involves the whole virus as an infectious particle in, for example, the milk or egg. It also differs from transfer of the DNA provirus of an RNA tumor virus, since in the protovirus hypothesis only the potential for genetic evolution of the information for cancer is transmitted in the DNA; (d) There might be times when the RNAjDNA information transfer takes place only in cell A, with or without concomittant integration thereby leading to gene amplification. However, if, as he (Temin) believes, there is great genetic instability in this type of information transfer, variants would appear and wholly new DNA sequences could be formed: (e) The time and extent of protovirus transfer would be controlled by the availability of the polymerase and integration systems, and the absence of possible inhibitory systems, especially nucleases. Selection of randomly appearing variants could also be through the properties of the polymerase, integration, and possibly, inhibitory systems. In the development of an organism, information transfer from DNAJRNA+DNA would allow variability and amplificationj information transfer from DNA-DNA would allow stability and storage; (f) The normal physiological evolution of the protovirus-derived DNA's would fall within a pattern predetermined by the rest of the cell genome and by the state of the cell and of the developing organism. Integration next to a region controlling cell multiplication could affect multiplication control of the cell; (g) The usual process leading to cancer could be a variation in the normal physiological evolution of the protovirus DNA so that variants which contain information for the cancer appeared either by mutation of the base sequences or by integration in incorrect places or both; (h) In extreme cases, one could imagine that a product of protovirus evolution would infect the germ line, become integrated Such a there, and thus also affect progeny organisms. process could provide part of a mechanism for inheritance of some acquired characters. 3. Holley suggested (a) That the crucial change in a malignant cell is an alteration in the cell surface membrane that results in increased internal concentrations of nutrients that regulate cell growth; (b) Selectivity of control of growth of different cells could be accomplished by selectively altering the availability of the nutrients inside the cells; (c) Thus, growth stimulation would result from stimulation of uptake, and growth inhibition would result from inhibition of uptake of the critical nutrients; (d) These considerations have led him (Holley) to the hypothesis that cancer results from changes in uptake mechanisms caused by changes in the cell membrane. 152
These changes would make critical nutrients which normally limit growth, available at higher In other words, it is concentrations inside the cell. suggested that the primary cause of malignant growth is the increased concentrations of these critical nutrients inside the cell. (e) This hypothesis suggests that different types of cancer cells will vary widely and will be uniform only in having altered cell membranes that affect uptake mechanisms; (f) The hypothesis is consistent with the observation that different cancers have widely different growth rates varying from very slow to completely unrestricted growth. 4. Macara et al stated that (a) the tr_;gforming protein of avian sarcoma virus UR2, p6 Ya , has an associated tyrosine-specific protein Kinase activity similar to that of p60"'SrC and several other oncogene products; (b) suggested in a hypothesis a mechanism whereby certain oncogene proteins might cause the unrestricted growth typical of transformed cells and could explain why tumor promoters mimic many of the effects of transformation: (c) suggested a mechanism by which an increased turnover of P-inositides induced by p6Bvores , other similar viral oncogene Kinases, or receptor Kinases might result in the enhanced growth of susceptible cells. 5. Haseltine et al stated (a) that although this sequence (genomes of HTLV-I and II retroviruses) occupies a position similar to the src gene in Rous Sarcoma virus, it is not homologous to conserved mammalian genes and therefore differs from the oncogenes of transforming retroviruses. There is some evidence that this region contains a functional gene; (b) A new gene? The perimeters of the 1011 nucleotide sequence of the HTLV-II genome correspond precisely with a single long open reading frame capable of encoding a polypeptide 337 amino acids long. A corresponding sequence of HTLV-I also encompasses a Single long open reading frame capable of encoding a polypeptide 357 amino acids long. They (Haseltine et al) call the nucleotide sequence containing these long open reading frames the LOR region: Cc) The degree of similarity of these two proteins is even more striking if conservative amino acid substitutions are considered (89 percent similar). The distribution of hydrophilic and hydrophobic regions of these proteins is remarkably similar; (d) These observations suggest that the 3' terminal region of HTLV contains a new gene that encodes a protein with a molecular weight of at least 38,000. Such a protein could be translated from the 2.2-Kb spliced m RNA species containing LOR sequences found in HTLV-infected cells; (e) They have also reported that transacting factors, either directly encoded by HTLV or induced by HTLV infection substantially augment gene expression directed by HTLV LTR sequences. The phenomenon of trans-activation distinguishes HTLV from other retroviruses. The unusual structure of the 3 153
terminus of HTLV also distinguishes these from most For this reason, they (Haseltine et other retroviruses. al) suggested that the protein encoded by the LOR region may mediate transcriptional changes observed in HTLV infected cells. They further suggested that the HTLV LOR product mediates both the trans-activating and transforming effects of HTLV infection; (f) Although the similarity in structure of HTLV and BLV proteins is insufficient to indicate that they have a common functional role, the overall similarity in genomic structure including the location of a 5' NCR and 3' LOR frame, and the previously described similarity in protein antigenicity of the two viruses suggests that they are functionally similar. Moreover, there is a similarity in the distribution of hydrophobic and hydrophilic regions of the HTLV and BLV polypeptides. They noted that the disease induced by BLV has characteristics similar to those associated with HTLV-I, namely a long latent period sometimes preceded by persistent lymphocytosis, an absence of chronic viremia in target organs preceding disease, and an absence of preferred integration sites in tumor cells. IMPLICATIONS
IN SUPPORT OF THE AUTHOR'S CANCER THEORY
1. The oncogene theory 2(a) implies that cancer is a The protovirus hypothesis natural biological event. 2(b) which states that the information for cancer is apparently vertically transmitted also implies that cancer is endogenous to mankind, which is also stated by the author l(a). 2(c) By suggesting that the potential for genetic evolution of the information for cancer is transmitted in DNA, is still saying, that cancer does not originate or activate itself by exogenous infection, 2(d) Great which l(a) and 2(a) states and implies. genetic instability in which variants would appear might be interpreted by l(a,b) to mean instances where there is only the cancer gene agent, i.e, minus the anti cancer gene agent or agents thus causing instability, and the variants that would result in cancer activity (information transfer for cancer activity). 2(e) Here, it is at least implied that there might be an integration and inhibitory system involved in cancer activity, selection of randomly appearing variants in its development, that cancer activity is dependent upon being born with an integrated cancer, minus the inhibitory anticancer agent or agents, possessing or not possessing the anti cancer agent or agents (variability) and being born with or without the anti cancer agent or agents in addition to cancer (development of an organism). 2(f) Again appears to suggest that cancer is a natural biological event probably occurring from birth, and which is suggested by the author in l(a). Also, integration could affect multiplication control of a cell, if and only if, there was in fact no control, 154
but the activity which could occur at any given period, occurred simultaneously but unrelated to what appeared 2(g) could be interpreted to be controlled integration. by the author l(a) to mean cancer activity will vary from non cancer activity by the fact that it (cancer) would lack the integrated presence of the anti cancer gene agent or agents. 2(h) would appear again to support at least by implication the idea suggested by the author l(a) that cancer may be a natural biological event probably occurring from birth. The author (1) suggested that since no means has been devised to prove in advance whether or not a person would suffer from active cancer, therefore, if a person dies from 'old age', the only possible conclusion that could be drawn concerning that person's susceptibility or nonsusceptibility to cancer is,that person has in his body the anti cancer agent or agents, because if he had not, some time before he died, he would in all probability have suffered from the activity of his cancer. 2. 3(a-d) may be interpreted by the author l(a,b) to mean that the cancer gene agent alone causes cancer activity, and the addition of the anti cancer gene agent or agents prevents cancerous activity: (e) Tends to support the author's l(d) proposal that all cancers are fundamentally similar in nature, except they may reveal their active presence on or in various sites of the human body; (f) is implied by the author, 6. 3. 4(a) Indicates that there is some evidence to support the possibility that all cancers are fundamentally similar in nature which was proposed by the author l(d); 4(b) The certain oncogene proteins that may cause the unrestricted growth of transformed cells, i.e., cancer, may be interpreted by the author's l(a) to mean the cancer agent in man which alone causes cancer activity. 4(c) may be interpreted as in 4(a). 4. 5(a) Tends to support the suggestion, mae by the author l(a) .fhat is, that cancer is not of exogenous origin. 5(b-c) appears to support the suggestion made by the author l(d) that all cancers are fundamentally similar in nautre. 5(d-e) appears to support the author's (1) suggestion of the use of the endogenous anticancer gene agent or agents to prevent cancer 5(f) would appear (1) to support the author's activity. suggestion l(d) that cancers are fundamentally similar in nature and (II) support the author's implication, that cancer can gradually manifest its activity (6).
155
CONCLUSION The natural prevalence of cancer in virtually all animals including man would tend to suggest that cancer is part of the body. Although there are different suggestions as to how cancer activates itself, the above evidences tend to support the idea that cancer originates from within the organism itself. REFERENCES 1. Caesar, G. A Possible Interpretation of Human Cancer, Philosophical Journal. 144-145, July, 1967, University of Edingburgh, Scotland, Notes and Review. 2. Temin, H.M. Journal, National Cancer Institute, III-VII, 1971, pp 233-238.
46,
3. Holley, W.R. A Uniifying Hypothesis concerning the nature of malignant growth. Proc. Natl. Acad. Sci. rJ.S.A., Vol. 69. No. 10, pp 2840-2841, October 1972. 4. Macara, I.G. G.V. Marietti, P.C. Balduzzi, Proc. Natl. Acad. Sci., U.S.A. Vol. 81, pp 2728-2732, May, 1984. 5.
W.A. Haseltine
et al., Science 225, 419 (1984).
6. Caesar, G., Analysis of the Oncogene Hypothesis, Medical Hypothesis, 14, 4, 379 (1984).
156
ANALYSIS
OF THE PROTOVIRUS
HYPOTHESIS.
Godfrey Caesar, 209 west 137th. Street, New York, New York 10030, U.S.A ABSTRACT Its activity Cancer may be endogenous to all mankind. is dependent upon the absence of anti cancer gene agent or agents. INTRODUCTION I outline evidence to support the idea that cancer is an inborn phenomenon, probably commencing from birth and whose activity is primarily dependent upon the constitution of the individual, EVIDENCE 1. The author (1) proposed that (a) every human being is born with a tendency to develop cancer, i.e., to say the development of cancer is complete from birth; (5) some human beings are born with an anti cancer agent or agents in addition to this cancer tendency which causes their potential cancer(s) to be inactive and dormant at all times, while other human beings who have no anti cancer agent or agents will and do suffer from cancer at some time; (c) cancer is neither infectious nor contagious; (d) all cancers are fundamentally similar in nature, except that they may reveal their active presence at any site of the human body. 2. Temin (2) stated that (a) the oncogene theory appears to combine viral and epigenetic theories by postulating that neoplasia results from the activation of a veriically transmitted provirus. However, this oncogene theory is basically an epigenetic theory since it postulates a stable change in phenotype due to switch in a regulatory system; (b) proposed in the protovirus hypothesis that there is apparent vertical transmission of the information for cancer, even though the germ line does not contain this information on its chromosomes (proviruses or oncogenes) or off its chromosomes 151
(virions). The germ line is postulated to contain in its chromosomes the potential for genetic evolution by the somatic cells that may lead to the de Novo formation of information for cancer; (c) This apparent vertical transmission of the information for cancer differs from classical vertical transmission which involves the whole virus as an infectious particle in, for example, the milk or egg. It also differs from transfer of the DNA provirus of an RNA tumor virus, since in the protovirus hypothesis only the potential for genetic evolution of the information for cancer is transmitted in the DNA; (d) There might be times when the RNAjDNA information transfer takes place only in cell A, with or without concomittant integration thereby leading to gene amplification. However, if, as he (Temin) believes, there is great genetic instability in this type of information transfer, variants would appear and wholly new DNA sequences could be formed: (e) The time and extent of protovirus transfer would be controlled by the availability of the polymerase and integration systems, and the absence of possible inhibitory systems, especially nucleases. Selection of randomly appearing variants could also be through the properties of the polymerase, integration, and possibly, inhibitory systems. In the development of an organism, information transfer from DNAJRNA+DNA would allow variability and amplificationj information transfer from DNA-DNA would allow stability and storage; (f) The normal physiological evolution of the protovirus-derived DNA's would fall within a pattern predetermined by the rest of the cell genome and by the state of the cell and of the developing organism. Integration next to a region controlling cell multiplication could affect multiplication control of the cell; (g) The usual process leading to cancer could be a variation in the normal physiological evolution of the protovirus DNA so that variants which contain information for the cancer appeared either by mutation of the base sequences or by integration in incorrect places or both; (h) In extreme cases, one could imagine that a product of protovirus evolution would infect the germ line, become integrated Such a there, and thus also affect progeny organisms. process could provide part of a mechanism for inheritance of some acquired characters. 3. Holley suggested (a) That the crucial change in a malignant cell is an alteration in the cell surface membrane that results in increased internal concentrations of nutrients that regulate cell growth; (b) Selectivity of control of growth of different cells could be accomplished by selectively altering the availability of the nutrients inside the cells; (c) Thus, growth stimulation would result from stimulation of uptake, and growth inhibition would result from inhibition of uptake of the critical nutrients; (d) These considerations have led him (Holley) to the hypothesis that cancer results from changes in uptake mechanisms caused by changes in the cell membrane. 152
These changes would make critical nutrients which normally limit growth, available at higher In other words, it is concentrations inside the cell. suggested that the primary cause of malignant growth is the increased concentrations of these critical nutrients inside the cell. (e) This hypothesis suggests that different types of cancer cells will vary widely and will be uniform only in having altered cell membranes that affect uptake mechanisms; (f) The hypothesis is consistent with the observation that different cancers have widely different growth rates varying from very slow to completely unrestricted growth. 4. Macara et al stated that (a) the tr_;gforming protein of avian sarcoma virus UR2, p6 Ya , has an associated tyrosine-specific protein Kinase activity similar to that of p60"'SrC and several other oncogene products; (b) suggested in a hypothesis a mechanism whereby certain oncogene proteins might cause the unrestricted growth typical of transformed cells and could explain why tumor promoters mimic many of the effects of transformation: (c) suggested a mechanism by which an increased turnover of P-inositides induced by p6Bvores , other similar viral oncogene Kinases, or receptor Kinases might result in the enhanced growth of susceptible cells. 5. Haseltine et al stated (a) that although this sequence (genomes of HTLV-I and II retroviruses) occupies a position similar to the src gene in Rous Sarcoma virus, it is not homologous to conserved mammalian genes and therefore differs from the oncogenes of transforming retroviruses. There is some evidence that this region contains a functional gene; (b) A new gene? The perimeters of the 1011 nucleotide sequence of the HTLV-II genome correspond precisely with a single long open reading frame capable of encoding a polypeptide 337 amino acids long. A corresponding sequence of HTLV-I also encompasses a Single long open reading frame capable of encoding a polypeptide 357 amino acids long. They (Haseltine et al) call the nucleotide sequence containing these long open reading frames the LOR region: Cc) The degree of similarity of these two proteins is even more striking if conservative amino acid substitutions are considered (89 percent similar). The distribution of hydrophilic and hydrophobic regions of these proteins is remarkably similar; (d) These observations suggest that the 3' terminal region of HTLV contains a new gene that encodes a protein with a molecular weight of at least 38,000. Such a protein could be translated from the 2.2-Kb spliced m RNA species containing LOR sequences found in HTLV-infected cells; (e) They have also reported that transacting factors, either directly encoded by HTLV or induced by HTLV infection substantially augment gene expression directed by HTLV LTR sequences. The phenomenon of trans-activation distinguishes HTLV from other retroviruses. The unusual structure of the 3 153
terminus of HTLV also distinguishes these from most For this reason, they (Haseltine et other retroviruses. al) suggested that the protein encoded by the LOR region may mediate transcriptional changes observed in HTLV infected cells. They further suggested that the HTLV LOR product mediates both the trans-activating and transforming effects of HTLV infection; (f) Although the similarity in structure of HTLV and BLV proteins is insufficient to indicate that they have a common functional role, the overall similarity in genomic structure including the location of a 5' NCR and 3' LOR frame, and the previously described similarity in protein antigenicity of the two viruses suggests that they are functionally similar. Moreover, there is a similarity in the distribution of hydrophobic and hydrophilic regions of the HTLV and BLV polypeptides. They noted that the disease induced by BLV has characteristics similar to those associated with HTLV-I, namely a long latent period sometimes preceded by persistent lymphocytosis, an absence of chronic viremia in target organs preceding disease, and an absence of preferred integration sites in tumor cells. IMPLICATIONS
IN SUPPORT OF THE AUTHOR'S CANCER THEORY
1. The oncogene theory 2(a) implies that cancer is a The protovirus hypothesis natural biological event. 2(b) which states that the information for cancer is apparently vertically transmitted also implies that cancer is endogenous to mankind, which is also stated by the author l(a). 2(c) By suggesting that the potential for genetic evolution of the information for cancer is transmitted in DNA, is still saying, that cancer does not originate or activate itself by exogenous infection, 2(d) Great which l(a) and 2(a) states and implies. genetic instability in which variants would appear might be interpreted by l(a,b) to mean instances where there is only the cancer gene agent, i.e, minus the anti cancer gene agent or agents thus causing instability, and the variants that would result in cancer activity (information transfer for cancer activity). 2(e) Here, it is at least implied that there might be an integration and inhibitory system involved in cancer activity, selection of randomly appearing variants in its development, that cancer activity is dependent upon being born with an integrated cancer, minus the inhibitory anticancer agent or agents, possessing or not possessing the anti cancer agent or agents (variability) and being born with or without the anti cancer agent or agents in addition to cancer (development of an organism). 2(f) Again appears to suggest that cancer is a natural biological event probably occurring from birth, and which is suggested by the author in l(a). Also, integration could affect multiplication control of a cell, if and only if, there was in fact no control, 154
but the activity which could occur at any given period, occurred simultaneously but unrelated to what appeared 2(g) could be interpreted to be controlled integration. by the author l(a) to mean cancer activity will vary from non cancer activity by the fact that it (cancer) would lack the integrated presence of the anti cancer gene agent or agents. 2(h) would appear again to support at least by implication the idea suggested by the author l(a) that cancer may be a natural biological event probably occurring from birth. The author (1) suggested that since no means has been devised to prove in advance whether or not a person would suffer from active cancer, therefore, if a person dies from 'old age', the only possible conclusion that could be drawn concerning that person's susceptibility or nonsusceptibility to cancer is,that person has in his body the anti cancer agent or agents, because if he had not, some time before he died, he would in all probability have suffered from the activity of his cancer. 2. 3(a-d) may be interpreted by the author l(a,b) to mean that the cancer gene agent alone causes cancer activity, and the addition of the anti cancer gene agent or agents prevents cancerous activity: (e) Tends to support the author's l(d) proposal that all cancers are fundamentally similar in nature, except they may reveal their active presence on or in various sites of the human body; (f) is implied by the author, 6. 3. 4(a) Indicates that there is some evidence to support the possibility that all cancers are fundamentally similar in nature which was proposed by the author l(d); 4(b) The certain oncogene proteins that may cause the unrestricted growth of transformed cells, i.e., cancer, may be interpreted by the author's l(a) to mean the cancer agent in man which alone causes cancer activity. 4(c) may be interpreted as in 4(a). 4. 5(a) Tends to support the suggestion, mae by the author l(a) .fhat is, that cancer is not of exogenous origin. 5(b-c) appears to support the suggestion made by the author l(d) that all cancers are fundamentally similar in nautre. 5(d-e) appears to support the author's (1) suggestion of the use of the endogenous anticancer gene agent or agents to prevent cancer 5(f) would appear (1) to support the author's activity. suggestion l(d) that cancers are fundamentally similar in nature and (II) support the author's implication, that cancer can gradually manifest its activity (6).
155
CONCLUSION The natural prevalence of cancer in virtually all animals including man would tend to suggest that cancer is part of the body. Although there are different suggestions as to how cancer activates itself, the above evidences tend to support the idea that cancer originates from within the organism itself. REFERENCES 1. Caesar, G. A Possible Interpretation of Human Cancer, Philosophical Journal. 144-145, July, 1967, University of Edingburgh, Scotland, Notes and Review. 2. Temin, H.M. Journal, National Cancer Institute, III-VII, 1971, pp 233-238.
46,
3. Holley, W.R. A Uniifying Hypothesis concerning the nature of malignant growth. Proc. Natl. Acad. Sci. rJ.S.A., Vol. 69. No. 10, pp 2840-2841, October 1972. 4. Macara, I.G. G.V. Marietti, P.C. Balduzzi, Proc. Natl. Acad. Sci., U.S.A. Vol. 81, pp 2728-2732, May, 1984. 5.
W.A. Haseltine
et al., Science 225, 419 (1984).
6. Caesar, G., Analysis of the Oncogene Hypothesis, Medical Hypothesis, 14, 4, 379 (1984).
156