Medical Hypotheses I Medica/ Hypofhaes 0 Longman Group
(1990) 33, 241UK Ltd 1990
0306-9877/90/0033-0241610.00
244
Fever: Thermodynamics
Applied to the Leucocyte
V.A. NGU
Sciences, B.P. 1364 Yaounde, Cameroon
Cancer Research Laboratory, University Centre Health
Abstract - A fever, by raising the temperature of leucocytes, accelerates and so enhances their antimicrobial action against infections. This is in keeping with thermodynamic principles which apply to chemical and biochemical reactions. In keeping with the same thermodynamic principles, when the temperature of matter is raised, at certain critical temperatures its form and behaviour change dramatically and radically. Visible water, for example, boils at 100°C into invisible steam. By analogy to such dramatic changes of behaviour it has been proposed as a hypothesis, that when the temperature of the leucocyte is raised in vitro to the extreme limit just before it dies, its behaviour will also change in a radical and dramatic manner to produce a totally new class of antimicrobial substances or antibiotics, called leucocyte derived antibiotics, LDA. The new LDA should have a wide spectrum of action against infecting micro-organisms including viruses that provoke a fever in the body. They should also have some anti-tumour effects in patients providing such leucocytes. Preliminary observations suggest that when the temperature of leucocytes is raised in vitro to the point of near cell death they can indeed produce new antimicrobial and antitumoral substances.
Introduction
Fever constitutes one of the commonest symptoms in clinical medicine. In tropical climates, fevers are so common as to be considered by the local population as normal! Few are those in any part of the world who would not have had a fever in their lives. Clinicians are preoccupied with the causes and how the symptoms of fever are produced or related to the underlying causes. They are also preoccupied with the suppression of fevers. It is thanks to this preoccupation that the aspirin industry has flourished. Date received
Date accepted
7 November 16 February
As scientists, clinicians should also be concerned with a third question. Why is there a fever? An answer to this question could provide new insight into the body’s response to disease and serve as the starting point from which to improve our mastery of the disease process. Fevers may have a beneficial effect on infections Before attempting to suggest a purpose for the fever, it is worthwhile recalling that fevers are produced when the body is invaded by micro-organisms of all sorts - parasites, bacteriae, fungi and
1988 1990
241
242 viruses. A fever therefore represents the body’s response to infection and together with leucocytosis constitutes a defence mechanism against the infection. How do infections cause fever? How does a Staphylococcus aureus infection, for example, in’s carbuncle cause a fever? The explanation offered was that the toxins produced by the S. aureus or infecting micro-organism acted on, or poisoned, the temperature centre or the thermostat of the body situated in the brain stem. This disturbed its functioning which in consequence became set at a higher setting. In response to this new thermostat setting, the body carried out, at an increased rate, a series of metabolic activities in the liver, muscle etc-whose net effect was to raise the temperature of the body to the new level set by the thermostat. It should be noted that in the presence of almost all microbial toxins, the thermostat is always set for a rise in temperature or fever. If mere dysfunction or malfunction of the temperature centre or thermostat were the sole explanation, one would expect, on a purely chance basis, that the malfunctioning thermostat would be set at a lower temperature in about half or in at least some of the cases. Clinical experience confirms, however, that fit healthy persons always react to an infection with a fever and that only in feeble, old, malnourished or debilitated persons with diminished metabolic activity is hypothermia sometimes seen as a terminal event in the presence of overwhelming infection. A fever in a fit person with an infection is not therefore a chance event due to a malfunctioning thermostat, but a deliberate and purposeful response of the body to infection. In brief, if it is being proposed that a fever, in application of thermodynamics to leucocytes, is meant to enhance the anti-microbial action of leucocytes in dealing with infections. The actions of leucocytes change profoundly during high fever In order to understand the full meaning and implications of the proposal set forth above, it would be necessary first to examine some of the effects of heat on matter and on chemical reactions and secondly to apply the conclusions reached to leucocytes whose numbers in the body normally increase in response to infection. The effects of heat on matter and on chemical reactions are well-known and are embodied in the
MEDICAL HYPOTHESES
principles of thermodynamics (1). When water, one of the elements in the leucocyte, is heated, its molecules move about with extreme rapidity and become agitated, so to speak. At the critical temperature of 100°C at sea level, and at lower temperatures at higher altitudes, water boils. It is no longer a liquid but a gas, changing its visible liquid form for an invisible gaseous one. Our prehistoric ancestors who saw water boiling for the first time must have concluded that water became something new. Whilst we may take it for granted, the boiling of water is indeed a marvellous event! It is also common knowledge, to consider iron, another element present in the cell, that when iron is heated, at the critical temperature of 1535 “C it melts. It has passed from the solid to the liquid state and now flows like any other liquid. If instead of raising the temperature, it is lowered, physical matter behaves in new ways and assumes new and interesting forms also. Water freezes into ice at 0°C rubber expands, some metals become super-conductors offering no resistance at all to the flow of electrical current. Physical matter and its characteristics or behaviour depend on the temperature to which it is subjected. At certain critical temperatures its form or behaviour change radically and dramatically. These are such daily occurrences that it would have been unnecessary to repeat them but for the fact that we propose to attempt to apply the same principles to the behaviour of the leucocyte, as a biological unit. The leucocyte - polymorph, lymphocyte, eosin ophil etc - is made of physical matter and, as physical matter, would react in the way in which all physical matter reacts when subjected to a rise of temperature. But the leucocyte is also a biological unit, and its behaviour will depend on temperature also. Is there a critical temperature at which its behaviour as a biological unit will also change in a radical or dramatic manner? If there is indeed such a critical temperature at which the leucocyte behaviour changes totally, by analogy to that of physical matter, that temperature should be at, or close to, that which precedes the death of the leucocyte, that is, the temperature at which the cell passes from one state to another, from a living state to a dead state! At such a temperature a new biological substance may be produced, different from and yet related to the other substances that the leucocyte produced before this critical temperature was reached.
FEVER:
THERMODYNAMICS
APPLIED
243
TO THE LEUCOCYTE
The hypothesis From the foregoing, it is being proposed that the leucocyte, as a biothermodynamic unit, will produce increasing amounts of certain antimicrobial substances as the temperature of the cell rises as a result of microbial attack. If the rise of temperature is maintained by artificial means at a certain critical temperature just before the cell dies, it will produce a new biological substance with greater and perhaps totally new antimicrobial action, a new kind of leucocyte derived antibiotic, LDA. The proposed new substance of LDA produced will depend on the specific type of leucocytes concerned-polymorph, lymphocyte or eosinophil, etc. There could thus be several species of the new LDA, one related to polymorphs, another to lymphocytes and a third to eosinophils etc. That an antimicrobial substance or action is produced or enhanced in leucocytes with a rise of temperature or fever, is deduced from the fact that most infections produce fever, and that these infections are not invariably fatal. As regards the new biological substance of LDA postulated above, its presence in the living body must be a very rare occurrence indeed because the body temperature regulating systems would not willingly allow a temperature that led to the death of its cells in vivo. The new biological substance of LDA would thus be an artificial product of an artificial in vitro manipulation where the temperature could be raised to the point of, or near, leucocyte death. Because different infecting micro-organisms bacteriae, viruses, parasites and fungi - cause a fever in the body and provoke the multiplication of the different members of the leucocyte series - polymorphs, lymphocyte, eosinophil etc. - the LDA produced by the different types of leucocytes subjected to temperatures near cell death should, between them, have an action on all the classes of micro-organisms mentioned above. It should thus be possible to produce for the first time leucocyte derived antibiotics with antiviral activity. This should be in marked contrast to the traditional fungal derived antibiotics such as penicillin (2) and others which do not have any antiviral action. One would predict also that LDA should have some useful antitumoral action especially in those tumours such as Hodgkins disease (3), hepatomas (4, 5), cervical carcinoma (6), Burkitts lymphoma (7) etc., where a virus and/or a fever is usually present. Since lymphocytes are believed to play
a useful overall role in controlling malignant tumours including those that are not associated with fever, LDA produced by them should have an effect on such tumours as well. Fungal produced antibiotics such as mitomycin C and actinomycin D have antitumour effects but have toxic side effects (g,Y). Since LDA is produced by the body, its antimicrobial and antitumour effect should not, hopefully, be toxic. There are of course many unanswered questions concerning LDA. For example, what is its biochemical nature? Is it produced only when a specific microbe is present in contact with leucocyte and is therefore directed against that microbe, or is it produced in a non-specific response to a raised temperature? If its production is related to a specific microbe, will there be as many types of LDA as there are microbes, or will LDA produced against one microbe react against a group of microbes? If LDA were produced in a non-specific response to raised temperature, will there be different species of LDA as suggested earlier according to the leucocyte type-polymorphs, lymphocytes, eosinophils etc? Future studies will be able to answer these and other questions. There are preliminary results to be published elsewhere that suggest that leucocytes when subjected to a raised temperature in vitro can indeed produce antimicrobial and antitumour effects in the body. It should be admitted, however, that leucocyte derived antibiotics, LDA, when the time comes, will not be easy to produce commercially using human leucocytes. Nevertheless, its biochemical identification should allow its synthesis using genetic engineering and thus introduce a new era in the management of all microbial and viral infection as well as that of some malignant tumours. Acknowledgements I wish to thank Dr Enil Tutuwan Ph.D of the Department of Chemistry and Dr Vincent Titanji Ph.D of the Biochemistry Department, University of Yaounde for ciarifying thermodynamic principles and for very helpful criticisms of the manuscript, and Cecilia Arrey for excellent secretarial services.
References Arrhenius S. Z Physick Chem 1887, 4, 226 Quoted in chemical kinetics p. 50. 2nd edition Laidler Keith ed. McGraw Hill Company, (New York) 1965. Fleming A. British Journal of Experimental Pathology IO, 226, 1929. Gutensohn N and Cole P. Epidemiology of Hodgkins disease in the young. Int. J. Cancer 19: 595. 1977.
244 4. Zucherman A.J. The association of hepatitis B with pri-
mary hepatocellular carcinoma. J. Infect. Suppl. 1 73, 1983. 5. Olweny C.L. Etiology of hepatocellular carcinoma in Africa. IARC Sci. Pub]. 63: 84, 1984. 6. Rawls W.E.F. and Melnick J.L. The association of herpes virus type 2 and carcinoma of the uterine cervix. Amer. J. Epidem. 89, 547, 1969. 7. Epstein M.A. Achong B.C. and Barr Y.M. Virus parti-
MEDICAL HYPOTHESES
cles in cultured lymphoblasts from Burkitts lymphoma. Lancet i 702, 1964. 8. Hammer R.W. Verani R and Weinman E.J. Mitomycin associated renal failure. Case reports and review. Arch. Intern. Med. Vol 143 (4) 803, 1983. 9. Petrilli E.S. and Morrow C.P. Actinomycin D toxicity in the treatment of trophobtastic disease. A comparison of the five day course to single dose administration. Gynecol. Oncol. Vol9 (1) p. 18, 1980.
(1990) 33, 241UK Ltd 1990
0306-9877/90/0033-0241610.00
244
Fever: Thermodynamics
Applied to the Leucocyte
V.A. NGU
Sciences, B.P. 1364 Yaounde, Cameroon
Cancer Research Laboratory, University Centre Health
Abstract - A fever, by raising the temperature of leucocytes, accelerates and so enhances their antimicrobial action against infections. This is in keeping with thermodynamic principles which apply to chemical and biochemical reactions. In keeping with the same thermodynamic principles, when the temperature of matter is raised, at certain critical temperatures its form and behaviour change dramatically and radically. Visible water, for example, boils at 100°C into invisible steam. By analogy to such dramatic changes of behaviour it has been proposed as a hypothesis, that when the temperature of the leucocyte is raised in vitro to the extreme limit just before it dies, its behaviour will also change in a radical and dramatic manner to produce a totally new class of antimicrobial substances or antibiotics, called leucocyte derived antibiotics, LDA. The new LDA should have a wide spectrum of action against infecting micro-organisms including viruses that provoke a fever in the body. They should also have some anti-tumour effects in patients providing such leucocytes. Preliminary observations suggest that when the temperature of leucocytes is raised in vitro to the point of near cell death they can indeed produce new antimicrobial and antitumoral substances.
Introduction
Fever constitutes one of the commonest symptoms in clinical medicine. In tropical climates, fevers are so common as to be considered by the local population as normal! Few are those in any part of the world who would not have had a fever in their lives. Clinicians are preoccupied with the causes and how the symptoms of fever are produced or related to the underlying causes. They are also preoccupied with the suppression of fevers. It is thanks to this preoccupation that the aspirin industry has flourished. Date received
Date accepted
7 November 16 February
As scientists, clinicians should also be concerned with a third question. Why is there a fever? An answer to this question could provide new insight into the body’s response to disease and serve as the starting point from which to improve our mastery of the disease process. Fevers may have a beneficial effect on infections Before attempting to suggest a purpose for the fever, it is worthwhile recalling that fevers are produced when the body is invaded by micro-organisms of all sorts - parasites, bacteriae, fungi and
1988 1990
241
242 viruses. A fever therefore represents the body’s response to infection and together with leucocytosis constitutes a defence mechanism against the infection. How do infections cause fever? How does a Staphylococcus aureus infection, for example, in’s carbuncle cause a fever? The explanation offered was that the toxins produced by the S. aureus or infecting micro-organism acted on, or poisoned, the temperature centre or the thermostat of the body situated in the brain stem. This disturbed its functioning which in consequence became set at a higher setting. In response to this new thermostat setting, the body carried out, at an increased rate, a series of metabolic activities in the liver, muscle etc-whose net effect was to raise the temperature of the body to the new level set by the thermostat. It should be noted that in the presence of almost all microbial toxins, the thermostat is always set for a rise in temperature or fever. If mere dysfunction or malfunction of the temperature centre or thermostat were the sole explanation, one would expect, on a purely chance basis, that the malfunctioning thermostat would be set at a lower temperature in about half or in at least some of the cases. Clinical experience confirms, however, that fit healthy persons always react to an infection with a fever and that only in feeble, old, malnourished or debilitated persons with diminished metabolic activity is hypothermia sometimes seen as a terminal event in the presence of overwhelming infection. A fever in a fit person with an infection is not therefore a chance event due to a malfunctioning thermostat, but a deliberate and purposeful response of the body to infection. In brief, if it is being proposed that a fever, in application of thermodynamics to leucocytes, is meant to enhance the anti-microbial action of leucocytes in dealing with infections. The actions of leucocytes change profoundly during high fever In order to understand the full meaning and implications of the proposal set forth above, it would be necessary first to examine some of the effects of heat on matter and on chemical reactions and secondly to apply the conclusions reached to leucocytes whose numbers in the body normally increase in response to infection. The effects of heat on matter and on chemical reactions are well-known and are embodied in the
MEDICAL HYPOTHESES
principles of thermodynamics (1). When water, one of the elements in the leucocyte, is heated, its molecules move about with extreme rapidity and become agitated, so to speak. At the critical temperature of 100°C at sea level, and at lower temperatures at higher altitudes, water boils. It is no longer a liquid but a gas, changing its visible liquid form for an invisible gaseous one. Our prehistoric ancestors who saw water boiling for the first time must have concluded that water became something new. Whilst we may take it for granted, the boiling of water is indeed a marvellous event! It is also common knowledge, to consider iron, another element present in the cell, that when iron is heated, at the critical temperature of 1535 “C it melts. It has passed from the solid to the liquid state and now flows like any other liquid. If instead of raising the temperature, it is lowered, physical matter behaves in new ways and assumes new and interesting forms also. Water freezes into ice at 0°C rubber expands, some metals become super-conductors offering no resistance at all to the flow of electrical current. Physical matter and its characteristics or behaviour depend on the temperature to which it is subjected. At certain critical temperatures its form or behaviour change radically and dramatically. These are such daily occurrences that it would have been unnecessary to repeat them but for the fact that we propose to attempt to apply the same principles to the behaviour of the leucocyte, as a biological unit. The leucocyte - polymorph, lymphocyte, eosin ophil etc - is made of physical matter and, as physical matter, would react in the way in which all physical matter reacts when subjected to a rise of temperature. But the leucocyte is also a biological unit, and its behaviour will depend on temperature also. Is there a critical temperature at which its behaviour as a biological unit will also change in a radical or dramatic manner? If there is indeed such a critical temperature at which the leucocyte behaviour changes totally, by analogy to that of physical matter, that temperature should be at, or close to, that which precedes the death of the leucocyte, that is, the temperature at which the cell passes from one state to another, from a living state to a dead state! At such a temperature a new biological substance may be produced, different from and yet related to the other substances that the leucocyte produced before this critical temperature was reached.
FEVER:
THERMODYNAMICS
APPLIED
243
TO THE LEUCOCYTE
The hypothesis From the foregoing, it is being proposed that the leucocyte, as a biothermodynamic unit, will produce increasing amounts of certain antimicrobial substances as the temperature of the cell rises as a result of microbial attack. If the rise of temperature is maintained by artificial means at a certain critical temperature just before the cell dies, it will produce a new biological substance with greater and perhaps totally new antimicrobial action, a new kind of leucocyte derived antibiotic, LDA. The proposed new substance of LDA produced will depend on the specific type of leucocytes concerned-polymorph, lymphocyte or eosinophil, etc. There could thus be several species of the new LDA, one related to polymorphs, another to lymphocytes and a third to eosinophils etc. That an antimicrobial substance or action is produced or enhanced in leucocytes with a rise of temperature or fever, is deduced from the fact that most infections produce fever, and that these infections are not invariably fatal. As regards the new biological substance of LDA postulated above, its presence in the living body must be a very rare occurrence indeed because the body temperature regulating systems would not willingly allow a temperature that led to the death of its cells in vivo. The new biological substance of LDA would thus be an artificial product of an artificial in vitro manipulation where the temperature could be raised to the point of, or near, leucocyte death. Because different infecting micro-organisms bacteriae, viruses, parasites and fungi - cause a fever in the body and provoke the multiplication of the different members of the leucocyte series - polymorphs, lymphocyte, eosinophil etc. - the LDA produced by the different types of leucocytes subjected to temperatures near cell death should, between them, have an action on all the classes of micro-organisms mentioned above. It should thus be possible to produce for the first time leucocyte derived antibiotics with antiviral activity. This should be in marked contrast to the traditional fungal derived antibiotics such as penicillin (2) and others which do not have any antiviral action. One would predict also that LDA should have some useful antitumoral action especially in those tumours such as Hodgkins disease (3), hepatomas (4, 5), cervical carcinoma (6), Burkitts lymphoma (7) etc., where a virus and/or a fever is usually present. Since lymphocytes are believed to play
a useful overall role in controlling malignant tumours including those that are not associated with fever, LDA produced by them should have an effect on such tumours as well. Fungal produced antibiotics such as mitomycin C and actinomycin D have antitumour effects but have toxic side effects (g,Y). Since LDA is produced by the body, its antimicrobial and antitumour effect should not, hopefully, be toxic. There are of course many unanswered questions concerning LDA. For example, what is its biochemical nature? Is it produced only when a specific microbe is present in contact with leucocyte and is therefore directed against that microbe, or is it produced in a non-specific response to a raised temperature? If its production is related to a specific microbe, will there be as many types of LDA as there are microbes, or will LDA produced against one microbe react against a group of microbes? If LDA were produced in a non-specific response to raised temperature, will there be different species of LDA as suggested earlier according to the leucocyte type-polymorphs, lymphocytes, eosinophils etc? Future studies will be able to answer these and other questions. There are preliminary results to be published elsewhere that suggest that leucocytes when subjected to a raised temperature in vitro can indeed produce antimicrobial and antitumour effects in the body. It should be admitted, however, that leucocyte derived antibiotics, LDA, when the time comes, will not be easy to produce commercially using human leucocytes. Nevertheless, its biochemical identification should allow its synthesis using genetic engineering and thus introduce a new era in the management of all microbial and viral infection as well as that of some malignant tumours. Acknowledgements I wish to thank Dr Enil Tutuwan Ph.D of the Department of Chemistry and Dr Vincent Titanji Ph.D of the Biochemistry Department, University of Yaounde for ciarifying thermodynamic principles and for very helpful criticisms of the manuscript, and Cecilia Arrey for excellent secretarial services.
References Arrhenius S. Z Physick Chem 1887, 4, 226 Quoted in chemical kinetics p. 50. 2nd edition Laidler Keith ed. McGraw Hill Company, (New York) 1965. Fleming A. British Journal of Experimental Pathology IO, 226, 1929. Gutensohn N and Cole P. Epidemiology of Hodgkins disease in the young. Int. J. Cancer 19: 595. 1977.
244 4. Zucherman A.J. The association of hepatitis B with pri-
mary hepatocellular carcinoma. J. Infect. Suppl. 1 73, 1983. 5. Olweny C.L. Etiology of hepatocellular carcinoma in Africa. IARC Sci. Pub]. 63: 84, 1984. 6. Rawls W.E.F. and Melnick J.L. The association of herpes virus type 2 and carcinoma of the uterine cervix. Amer. J. Epidem. 89, 547, 1969. 7. Epstein M.A. Achong B.C. and Barr Y.M. Virus parti-
MEDICAL HYPOTHESES
cles in cultured lymphoblasts from Burkitts lymphoma. Lancet i 702, 1964. 8. Hammer R.W. Verani R and Weinman E.J. Mitomycin associated renal failure. Case reports and review. Arch. Intern. Med. Vol 143 (4) 803, 1983. 9. Petrilli E.S. and Morrow C.P. Actinomycin D toxicity in the treatment of trophobtastic disease. A comparison of the five day course to single dose administration. Gynecol. Oncol. Vol9 (1) p. 18, 1980.
