The acute-phase response (APR) is a systemic response to severe trauma, infection, and cancer, al... more The acute-phase response (APR) is a systemic response to severe trauma, infection, and cancer, although many of the numerous cytokine-mediated components of the APR are incompletely understood. Some of these components, such as fever, reduced availability of iron and zinc, and nutritional restriction due to anorexia, appear to be stressors capable of causing harm to both the pathogen and the host. We review how the host benefits from differences in susceptibility to stress between pathogens and the host. Pathogens, infected host cells, and neoplastic cells are generally more stressed or vulnerable to additional stress than the host because: a) targeted local inflammation works in synergy with APR stressors; b) proliferation/growth increases vulnerability to stress; c) altered pathogen physiology results in pathogen stress or vulnerability; and d) protective heat shock responses are partially abrogated in pathogens since their responses are utilized by the host to enhance immune resp...
Although fever is one of the main presenting symptoms of COVID-19 infection, little public attent... more Although fever is one of the main presenting symptoms of COVID-19 infection, little public attention has been given to fever as an evolved defense. Fever, the regulated increase in the body temperature, is part of the evolved systemic reaction to infection known as the acute phase response. The heat of fever augments the performance of immune cells, induces stress on pathogens and infected cells directly, and combines with other stressors to provide a nonspecific immune defense. Observational trials in humans suggest a survival benefit from fever, and randomized trials published before COVID-19 do not support fever reduction in patients with infection. Like public health measures that seem burdensome and excessive, fevers involve costly trade-offs but they can prevent infection from getting out of control. For infections with novel SARS-CoV-2, the precautionary principle applies: unless evidence suggests otherwise, we advise that fever should be allowed to run its course.Lay summary...
Proceedings of the Royal Society B: Biological Sciences, 2016
Therapies with increasing specificity against pathogens follow the immune system's evolutiona... more Therapies with increasing specificity against pathogens follow the immune system's evolutionary course in maximizing host defence while minimizing self-harm. Nevertheless, even completely non-specific stressors, such as reactive molecular species, heat, nutrient and oxygen deprivation, and acidity can be used to preferentially harm pathogens. Strategic use of non-specific stressors requires exploiting differences in stress vulnerability between pathogens and hosts. Two basic vulnerabilities of pathogens are: (i) the inherent vulnerability to stress of growth and replication (more immediately crucial for pathogens than for host cells) and (ii) the degree of pathogen localization, permitting the host's use of locally and regionally intense stress. Each of the various types of non-specific stressors is present during severe infections at all levels of localization: (i) ultra-locally within phagolysosomes, (ii) locally at the infected site, (iii) regionally around the infected s...
The immune brinksmanship conceptual model postulates that many of the non-specific stressful comp... more The immune brinksmanship conceptual model postulates that many of the non-specific stressful components of the acute-phase response (e.g. fever, loss of appetite, iron and zinc sequestration) are host-derived systemic stressors used with the "hope" that pathogens will be harmed relatively more than the host. The concept proposes that pathogens, needing to grow and replicate in order to invade their host, should be relatively more vulnerable to non-specific systemic stress than the host and its cells. However, the conceptual model acknowledges the risk to the host in that the gamble to induce systemic self-harming stress to harm pathogens may not pay off in the end. We developed an agent-based model of a simplified host having a local infection to evaluate the utility of non-specific stress, harming host and pathogen alike, for host defense. With our model, we explore the benefits and risks of self-harming strategies and confirm the immune brinksmanship concept of the poten...
The Canadian veterinary journal. La revue vétérinaire canadienne, 2002
Every medical phenomenon has both a mechanistic explanation and an evolutionary explanation. Vete... more Every medical phenomenon has both a mechanistic explanation and an evolutionary explanation. Veterinarians are accustomed to dealing with the mechanistic, the "what" or the "how", of various disease conditions, and applying treatment accordingly. Darwinian medicine is a field that addresses the evolutionary explanation, the "why" for various medical conditions. This review focuses on these Darwinian explanations and is divided into 4 main categories--host defenses, virulence, genetic conflict, and incomplete adaptation to a changing environment. Each of these areas is reviewed, with examples of evolutionary reasons for disease conditions. Consideration of adaptationist reasons for many of these disease phenomena should make veterinarians better clinicians, educators, and researchers.
While using the diabetic C57BL/KsJ db/db mouse as a wound healing model, we encountered several r... more While using the diabetic C57BL/KsJ db/db mouse as a wound healing model, we encountered several repair patterns which affect its suitability as a predictive screening model for certain indications. For example, wound contraction, albeit impaired, was found to be particularly dependent on bandaging technique and vehicle type. Wounds which had been continuously occluded with Opsite dressings had a high relative variability in contraction, and there was a tendency toward reduced contraction, suggesting that the dressings were acting as a splint. Viscous dosing vehicles inhibited contraction of occluded wounds but appeared to enhance contraction of nonoccluded wounds. In contrast to many other models, occlusion in these studies did not enhance reepithelialization when compared with air exposure (the rate of reepithelialization in db/db mice appeared normal, typically growing 2 mm from each edge in 10 days). Also in contrast to other wound healing models, viscous dosing vehicles when used under occlusion inhibited reepithelialization. However, as seen in other wound healing models, granulation tissue thickness was reliably increased in response to treatment with recombinant human platelet-derived growth factor-BB. Our experience with the db/db diabetic mouse model has led us to recommend the use of this animal model only after its limitations have been identified and accepted.
Monocyte function in rhesus monkeys with simian acquired immune deficiency syndrome (SAIDS) was c... more Monocyte function in rhesus monkeys with simian acquired immune deficiency syndrome (SAIDS) was compared with that in age-matched normal juvenile rhesus monkeys. The functional tests were 1) chemotaxis, 2) phagocytosis of opsonized Candida albicans, 3) killing and/or growth inhibition of Candida albicans, 4) generation of respiratory burst, and 5) monocyte-derived macrophage response (morphology and/or respiratory burst) to stimulating agents such as lymphokines, gamma interferon, endotoxin, and phorbol myristate acetate. The monkeys tested had either clinical SAIDS (alive with lymphadenopathy, splenomegaly, and lymphopenia or neutropenia) or had terminal SAIDS (moribund due to the disease). Responses of monocytes from 14 monkeys with clinical SAIDS were indistinguishable from those of 9 normal juvenile rhesus monkeys, whereas monocytes from 3 monkeys with terminal SAIDS had enhanced phagocytosis and respiratory burst capacity. Chemotaxis, candidacidal/stasis activity, and response to stimulating agents were normal in these terminal cases. Plasma from the SAIDS monkeys was as capable of opsonizing yeasts and of being able to generate chemotactic factors by endotoxin as was control plasma. SAIDS retrovirus (SRV) was detected by co-cultivation of pure monocyte-derived macrophage cultures with Raji cells, an indicator cell line which forms syncytia in the presence of SRV. Four terminal SAIDS cases and one late-stage clinical SAIDS case were virus-positive when the number of macrophages in the cultures ranged from less than 50 to about 500. Terminal SAIDS monocyte-derived macrophages in culture as long as 17 days produced SRV. These data show that in monkeys with SAIDS the major effector functions of monocytes and macrophages involved in host defense are intact (even up until death). Additionally, some of the monocytes are productively infected, and these infected monocytes are viable and adherent in culture.
This is a ground-breaking book. Randolph Nesse, a physician interested in what evolutionary biolo... more This is a ground-breaking book. Randolph Nesse, a physician interested in what evolutionary biology has to offer the medical sciences, has teamed up with George Williams, one of the deans of evolutionary biology, to present a subject with something for everyone. The simplicity of the title, Why We Get Sick, shows that it was written in a highly readable style suitable for a lay audience. The subtitle, The New Science of Darwinian Medicine, points to the excitement and importance of the synthesis of evolutionary thought with medicine. Nesse and Williams seek to give medical science the same tremendous boost that the ecological and behavioral sciences have received from embracing evolutionary biology. Williams’ leadership role in the Darwinian synthesis is based on his 1957 paper on the evolutionary basis for senescence, his 1975 book, Sex and Evolution, and his early insistence on the gene (or the individual) as the unit of selection, rather than the group or species. As editor of The Quarterly Review of Biology, he has been promoting researchers who apply an evolutionary approach to medical problems. There is a fascinating discussion of David Haig’s application of parental-offspring conflict theory to maternal-fetal interactions. This induced me to read Haig’s original paper (Haig D, Quarterly Review of Biology 68: 495-532, 1993), which Williams says will revolutionize the practice of obstetrics in the next century. Haig discusses why both the ovary and placenta secrete many of the same hormones and why the pregnant female is flooded with hormones with opposing actions, thus helping me make sense of reproductive endocrinology. Another evolutionary hypothesis that Nesse and Williams spotlight that is directly applicable to toxicologic pathologists is Margie Profet’s explanation for pregnancy (morning) sickness. While working with Bruce Ames on the toxic arsenals that plants use for their defense, she suspected that pregnancy sickness might help protect the embryo from plant-derived teratogens. In reviewing the literature, she found a number of studies documenting the higher incidence of miscarriages and birth defects in women who are relatively free of pregnancy sickness. The authors of several of these papers expressed surprise with their findings and could offer no explanation. Like Haig, Profet invokes matemal-fetal genetic conflict, with the suggestion that pregnancy sickness is the embryo making the mother sick, through secretion of placental hormones, for its benefit. Almost all of the book has direct relevance for pathologists. I guarantee new insights on a variety of subjects. The book has an outstanding introduction to the latest in evolutionary theory and how it can be used effectively. For pathologists looking to see their field in a new and exciting light, this is the book.
A cell's decision whether to undergo apoptosis (cell suicide) is examined herefrom an adaptationi... more A cell's decision whether to undergo apoptosis (cell suicide) is examined herefrom an adaptationist perspective, rather than a mechanistic one. External and internal inputs to the cell's protein-based information processing network are used in making this decision, with the cell factoring in its replaceability. A system in which each cell takes primary responsibility for deciding its own fate has great adaptive value because it harnesses each cell's self-knowledge rather than waitingfor external cues to be recognized by other cells. Cell self-destruction can be an important selective mechanism, potentially leading to better performance of tissues over time. However, reliance on cells to monitor themselves has aflaw, since cells may incur selfish mutations that impair their apoptotic responsibility. The tight control exerted over somatic cells serves to check selfish genes involved in neoplasia and viral infections. Germ cells appear to be similarly monitored, both by other germ cells and by supportingfollicular or Sertoli cells, thus maintaining the advantages offered by an apoptotic system. The adaptationist approach views the limited replacement of neurons and cardiac myocytes as likely to have net survival value. The linkage of these cells into a network with their neighbors throughout a lifetime allows for a precisely functioning team of cells expected to compensateforgradual declines in individual cellfunctionality. Replacement of apoptotic cells with naive cells might decrease brain functionality and might risk upsetting the conduction of cardiac impulses. The evolutionary viewpoint lends itself to new hypotheses, but only the boldestspeculatorwould havepredicted a system in which cells aregiven primary responsibility for deciding whether to kill themselves when they deem it beneficial to the organism.
Advances in molecular biology have made possible the production of highly purified recombinant hu... more Advances in molecular biology have made possible the production of highly purified recombinant human proteins, and recombinant human growth factors have emerged as potential therapeutic wound healing agents. Becaplermin (recombinant human platelet-derived growth factor-BB [rhPDGF-BB]) quickly emerged as one of the leading candidates for clinical trials. Before the expected therapeutic potential of rhPDGF-BB and other growth factors could be realized, a number of concerns had to be addressed (eg, would growth factors show effects in normal animals, what parameters of wound healing would be affected, and would quality of healed wounds be normal?). In animal models, rhPDGF-BB demonstrated wound healing activity, predominantly by enhancing the formation of granulation tissue, but it was not known whether this effect on granulation tissue would translate into enhanced healing of chronic skin ulcers in humans. The objective of this article is to review how the study of rhPDGF-BB in animal wound healing models has assisted in addressing the potential clinical utility of rhPDGF-BB. Results of animal studies are summarized, and the advantages and limitations of the animal models are discussed.
The benefits of apoptosis in the removal of unnecessary, damaged, or dangerous cells are dependen... more The benefits of apoptosis in the removal of unnecessary, damaged, or dangerous cells are dependent on the altruism resulting from the absence of genetic conflict between genes in cells. However, this altruism can be exploited by self-promoting or ultra-selfish genes.These self-promoting genes can be endogenous, as with neoplasia or germ cell mutations, or exogenous, as with cellular pathogens. The fundamental flaw of apoptosis is that its development and maintenance as a system is constantly opposed by the emergence of self-promoting genes. Since apoptotically impaired cells cannot be relied on to kill themselves, apoptotic input from other cells is required for controlling self-promoting genes. Certain unique features of germ cell development, such as linkage by cytoplasmic bridges and the requirement for granulosa or Sertoli cells, appear to serve this requirement for control of self-promoting genes. G ENETIC CONFLICT CAN OCCUR whenever the survival "interests" of genes differ. Because it leads to competing evolutionary spirals, genetic conflict is an area of major interest to evolutionary biologists. This discussion examines cell suicide/apoptosis, not in the usual strictly mechanistic approach but in the strategic light of genetic conflict, with the aim of exploring perspectives otherwise not readily apparent. The basic unit of selection is at the level of the gene (Dawkins 1976; Williams 1992). The genetic composition observed at any time is a legacy of the differential effects of genes on their own survival and reproduction. Genetic conflict
A medically important paradox is why the body's own cytokines lead to reduced appetite and appare... more A medically important paradox is why the body's own cytokines lead to reduced appetite and apparently inefficient metabolism as part of the acute-phase response. This self-induced nutrient restriction occurs just when the body must maintain a fever and other defensive functions. This paradox is often ignored or considered a metabolic derangement. Others, recognizing it to be a programmed response which must have net beneficial effects, consider the nutrient restriction to be an attempt to deny resources to infectious organisms. However, this explanation fails to address how the pathogen can be harmed more than the host. The hypothesis presented here offers an explanation. Apoptosis, or cell suicide, is becoming recognized as a useful defense against intracellular parasites, and nutrient restriction promotes apoptosis. Thus, nutrient restriction may encourage apoptosis of infected cells. Nutrient restriction can thereby offer protection by simultaneously limiting nutrients to both the host cells and the infectious organisms.
Apoptosis is widely recognized as being a host defense against viral infections, since viruses re... more Apoptosis is widely recognized as being a host defense against viral infections, since viruses require live cells. There has been increasing acceptance of the view that apoptosis is also a defense against other intracellular pathogens and even against pathogens that adhere to host cells. An implication of apoptosis being a host defense is a need to reassess to what extent the cell death at infection sites may constitute a protective host response. A concept stressed here is that infected cells are a hazard to other cells and to the individual, so the benefits of early apoptosis are emphasized. Therefore, promoting the survival of infected cells, even though still functional, may carry risks. A further consideration is the possibility that the apoptotic stimulus of nutrient restriction may be acting in infection-induced anorexia to promote apoptosis of infected cells, thereby serving as a non-specific host defense.
In the evolutionary view of endotoxin presented here, endotoxin is the primary signal animals use... more In the evolutionary view of endotoxin presented here, endotoxin is the primary signal animals use to detect gram negative (Gr-) bacteria. Since endotoxin, or lipopolysaccharide (LPS), is an integral part of the surface of all Gr- bacteria, it was excellent evolutionary 'choice' for the signal. The concept of an 'endotoxin response system' (ERS) is introduced. The ERS protects against Gr- bacteria by employing many of the body's defenses to both detect and react against LPS. The intensity of the response has evolved to maximize protection while minimizing the biological cost and self-damaging effects. The setting of the response, here termed the 'endostat', is programmed by natural selection and fine tuned by feedback mechanisms. Other potentially invasive organisms are detected by different signals, but the effector components of the defenses are similar. This evolutionary view of LPS offers a framework for the seemingly contradictory findings on endotoxin and suggests new avenues of productive research.
Tolmetin sodium's efficacy in preventing primary adhesions was evaluated in two adhesion ... more Tolmetin sodium's efficacy in preventing primary adhesions was evaluated in two adhesion models each in two species: (1) rabbit uterine horn, (2) rat uterine horn, (3) rabbit peritoneal side wall, and (4) rat peritoneal side wall. In each model a single instillation of tolmetin sodium solution into the peritoneal cavity at the time of surgery effectively reduced adhesion formation. This efficacy extended over a wide range of concentrations, volumes, and total dosages, and was similar in rabbits and rats. An aqueous solution of 1 mg/ml tolmetin sodium in 5-15 ml in rabbits and in 3 ml in rats was consistently efficacious in reducing postoperative adhesion formation.
A variety of nonsteroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit postsurgical... more A variety of nonsteroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit postsurgical peritoneal adhesion formation in a number of animal models. A rabbit uterine horn adhesion model was used to directly compare several commonly used NSAIDs of different chemical classes in a single animal study to evaluate their ability to prevent adhesion formation. The effect of thromboxane inhibitors on adhesion prevention was also evaluated. Each of the NSAIDs tested (tolmetin, ibuprofen, aspirin, and indomethacin) showed significant and comparable efficacy. In this same study, imidazole, a thromboxane synthetase inhibitor, also showed significant efficacy. In a second study, ridogrel, an inhibitor of thromboxane synthetase as well as a thromboxane A2 receptor blocker, also showed significant efficacy in reducing peritoneal adhesion severity. These results further support the view that NSAIDs act to prevent adhesions through a common mechanism. In addition, thromboxane A2 inhibitors were also shown to be efficacious in adhesion prevention, suggesting that platelets may play a substantial role in adhesion formation.
The acute-phase response (APR) is a systemic response to severe trauma, infection, and cancer, al... more The acute-phase response (APR) is a systemic response to severe trauma, infection, and cancer, although many of the numerous cytokine-mediated components of the APR are incompletely understood. Some of these components, such as fever, reduced availability of iron and zinc, and nutritional restriction due to anorexia, appear to be stressors capable of causing harm to both the pathogen and the host. We review how the host benefits from differences in susceptibility to stress between pathogens and the host. Pathogens, infected host cells, and neoplastic cells are generally more stressed or vulnerable to additional stress than the host because: a) targeted local inflammation works in synergy with APR stressors; b) proliferation/growth increases vulnerability to stress; c) altered pathogen physiology results in pathogen stress or vulnerability; and d) protective heat shock responses are partially abrogated in pathogens since their responses are utilized by the host to enhance immune resp...
Although fever is one of the main presenting symptoms of COVID-19 infection, little public attent... more Although fever is one of the main presenting symptoms of COVID-19 infection, little public attention has been given to fever as an evolved defense. Fever, the regulated increase in the body temperature, is part of the evolved systemic reaction to infection known as the acute phase response. The heat of fever augments the performance of immune cells, induces stress on pathogens and infected cells directly, and combines with other stressors to provide a nonspecific immune defense. Observational trials in humans suggest a survival benefit from fever, and randomized trials published before COVID-19 do not support fever reduction in patients with infection. Like public health measures that seem burdensome and excessive, fevers involve costly trade-offs but they can prevent infection from getting out of control. For infections with novel SARS-CoV-2, the precautionary principle applies: unless evidence suggests otherwise, we advise that fever should be allowed to run its course.Lay summary...
Proceedings of the Royal Society B: Biological Sciences, 2016
Therapies with increasing specificity against pathogens follow the immune system's evolutiona... more Therapies with increasing specificity against pathogens follow the immune system's evolutionary course in maximizing host defence while minimizing self-harm. Nevertheless, even completely non-specific stressors, such as reactive molecular species, heat, nutrient and oxygen deprivation, and acidity can be used to preferentially harm pathogens. Strategic use of non-specific stressors requires exploiting differences in stress vulnerability between pathogens and hosts. Two basic vulnerabilities of pathogens are: (i) the inherent vulnerability to stress of growth and replication (more immediately crucial for pathogens than for host cells) and (ii) the degree of pathogen localization, permitting the host's use of locally and regionally intense stress. Each of the various types of non-specific stressors is present during severe infections at all levels of localization: (i) ultra-locally within phagolysosomes, (ii) locally at the infected site, (iii) regionally around the infected s...
The immune brinksmanship conceptual model postulates that many of the non-specific stressful comp... more The immune brinksmanship conceptual model postulates that many of the non-specific stressful components of the acute-phase response (e.g. fever, loss of appetite, iron and zinc sequestration) are host-derived systemic stressors used with the "hope" that pathogens will be harmed relatively more than the host. The concept proposes that pathogens, needing to grow and replicate in order to invade their host, should be relatively more vulnerable to non-specific systemic stress than the host and its cells. However, the conceptual model acknowledges the risk to the host in that the gamble to induce systemic self-harming stress to harm pathogens may not pay off in the end. We developed an agent-based model of a simplified host having a local infection to evaluate the utility of non-specific stress, harming host and pathogen alike, for host defense. With our model, we explore the benefits and risks of self-harming strategies and confirm the immune brinksmanship concept of the poten...
The Canadian veterinary journal. La revue vétérinaire canadienne, 2002
Every medical phenomenon has both a mechanistic explanation and an evolutionary explanation. Vete... more Every medical phenomenon has both a mechanistic explanation and an evolutionary explanation. Veterinarians are accustomed to dealing with the mechanistic, the "what" or the "how", of various disease conditions, and applying treatment accordingly. Darwinian medicine is a field that addresses the evolutionary explanation, the "why" for various medical conditions. This review focuses on these Darwinian explanations and is divided into 4 main categories--host defenses, virulence, genetic conflict, and incomplete adaptation to a changing environment. Each of these areas is reviewed, with examples of evolutionary reasons for disease conditions. Consideration of adaptationist reasons for many of these disease phenomena should make veterinarians better clinicians, educators, and researchers.
While using the diabetic C57BL/KsJ db/db mouse as a wound healing model, we encountered several r... more While using the diabetic C57BL/KsJ db/db mouse as a wound healing model, we encountered several repair patterns which affect its suitability as a predictive screening model for certain indications. For example, wound contraction, albeit impaired, was found to be particularly dependent on bandaging technique and vehicle type. Wounds which had been continuously occluded with Opsite dressings had a high relative variability in contraction, and there was a tendency toward reduced contraction, suggesting that the dressings were acting as a splint. Viscous dosing vehicles inhibited contraction of occluded wounds but appeared to enhance contraction of nonoccluded wounds. In contrast to many other models, occlusion in these studies did not enhance reepithelialization when compared with air exposure (the rate of reepithelialization in db/db mice appeared normal, typically growing 2 mm from each edge in 10 days). Also in contrast to other wound healing models, viscous dosing vehicles when used under occlusion inhibited reepithelialization. However, as seen in other wound healing models, granulation tissue thickness was reliably increased in response to treatment with recombinant human platelet-derived growth factor-BB. Our experience with the db/db diabetic mouse model has led us to recommend the use of this animal model only after its limitations have been identified and accepted.
Monocyte function in rhesus monkeys with simian acquired immune deficiency syndrome (SAIDS) was c... more Monocyte function in rhesus monkeys with simian acquired immune deficiency syndrome (SAIDS) was compared with that in age-matched normal juvenile rhesus monkeys. The functional tests were 1) chemotaxis, 2) phagocytosis of opsonized Candida albicans, 3) killing and/or growth inhibition of Candida albicans, 4) generation of respiratory burst, and 5) monocyte-derived macrophage response (morphology and/or respiratory burst) to stimulating agents such as lymphokines, gamma interferon, endotoxin, and phorbol myristate acetate. The monkeys tested had either clinical SAIDS (alive with lymphadenopathy, splenomegaly, and lymphopenia or neutropenia) or had terminal SAIDS (moribund due to the disease). Responses of monocytes from 14 monkeys with clinical SAIDS were indistinguishable from those of 9 normal juvenile rhesus monkeys, whereas monocytes from 3 monkeys with terminal SAIDS had enhanced phagocytosis and respiratory burst capacity. Chemotaxis, candidacidal/stasis activity, and response to stimulating agents were normal in these terminal cases. Plasma from the SAIDS monkeys was as capable of opsonizing yeasts and of being able to generate chemotactic factors by endotoxin as was control plasma. SAIDS retrovirus (SRV) was detected by co-cultivation of pure monocyte-derived macrophage cultures with Raji cells, an indicator cell line which forms syncytia in the presence of SRV. Four terminal SAIDS cases and one late-stage clinical SAIDS case were virus-positive when the number of macrophages in the cultures ranged from less than 50 to about 500. Terminal SAIDS monocyte-derived macrophages in culture as long as 17 days produced SRV. These data show that in monkeys with SAIDS the major effector functions of monocytes and macrophages involved in host defense are intact (even up until death). Additionally, some of the monocytes are productively infected, and these infected monocytes are viable and adherent in culture.
This is a ground-breaking book. Randolph Nesse, a physician interested in what evolutionary biolo... more This is a ground-breaking book. Randolph Nesse, a physician interested in what evolutionary biology has to offer the medical sciences, has teamed up with George Williams, one of the deans of evolutionary biology, to present a subject with something for everyone. The simplicity of the title, Why We Get Sick, shows that it was written in a highly readable style suitable for a lay audience. The subtitle, The New Science of Darwinian Medicine, points to the excitement and importance of the synthesis of evolutionary thought with medicine. Nesse and Williams seek to give medical science the same tremendous boost that the ecological and behavioral sciences have received from embracing evolutionary biology. Williams’ leadership role in the Darwinian synthesis is based on his 1957 paper on the evolutionary basis for senescence, his 1975 book, Sex and Evolution, and his early insistence on the gene (or the individual) as the unit of selection, rather than the group or species. As editor of The Quarterly Review of Biology, he has been promoting researchers who apply an evolutionary approach to medical problems. There is a fascinating discussion of David Haig’s application of parental-offspring conflict theory to maternal-fetal interactions. This induced me to read Haig’s original paper (Haig D, Quarterly Review of Biology 68: 495-532, 1993), which Williams says will revolutionize the practice of obstetrics in the next century. Haig discusses why both the ovary and placenta secrete many of the same hormones and why the pregnant female is flooded with hormones with opposing actions, thus helping me make sense of reproductive endocrinology. Another evolutionary hypothesis that Nesse and Williams spotlight that is directly applicable to toxicologic pathologists is Margie Profet’s explanation for pregnancy (morning) sickness. While working with Bruce Ames on the toxic arsenals that plants use for their defense, she suspected that pregnancy sickness might help protect the embryo from plant-derived teratogens. In reviewing the literature, she found a number of studies documenting the higher incidence of miscarriages and birth defects in women who are relatively free of pregnancy sickness. The authors of several of these papers expressed surprise with their findings and could offer no explanation. Like Haig, Profet invokes matemal-fetal genetic conflict, with the suggestion that pregnancy sickness is the embryo making the mother sick, through secretion of placental hormones, for its benefit. Almost all of the book has direct relevance for pathologists. I guarantee new insights on a variety of subjects. The book has an outstanding introduction to the latest in evolutionary theory and how it can be used effectively. For pathologists looking to see their field in a new and exciting light, this is the book.
A cell's decision whether to undergo apoptosis (cell suicide) is examined herefrom an adaptationi... more A cell's decision whether to undergo apoptosis (cell suicide) is examined herefrom an adaptationist perspective, rather than a mechanistic one. External and internal inputs to the cell's protein-based information processing network are used in making this decision, with the cell factoring in its replaceability. A system in which each cell takes primary responsibility for deciding its own fate has great adaptive value because it harnesses each cell's self-knowledge rather than waitingfor external cues to be recognized by other cells. Cell self-destruction can be an important selective mechanism, potentially leading to better performance of tissues over time. However, reliance on cells to monitor themselves has aflaw, since cells may incur selfish mutations that impair their apoptotic responsibility. The tight control exerted over somatic cells serves to check selfish genes involved in neoplasia and viral infections. Germ cells appear to be similarly monitored, both by other germ cells and by supportingfollicular or Sertoli cells, thus maintaining the advantages offered by an apoptotic system. The adaptationist approach views the limited replacement of neurons and cardiac myocytes as likely to have net survival value. The linkage of these cells into a network with their neighbors throughout a lifetime allows for a precisely functioning team of cells expected to compensateforgradual declines in individual cellfunctionality. Replacement of apoptotic cells with naive cells might decrease brain functionality and might risk upsetting the conduction of cardiac impulses. The evolutionary viewpoint lends itself to new hypotheses, but only the boldestspeculatorwould havepredicted a system in which cells aregiven primary responsibility for deciding whether to kill themselves when they deem it beneficial to the organism.
Advances in molecular biology have made possible the production of highly purified recombinant hu... more Advances in molecular biology have made possible the production of highly purified recombinant human proteins, and recombinant human growth factors have emerged as potential therapeutic wound healing agents. Becaplermin (recombinant human platelet-derived growth factor-BB [rhPDGF-BB]) quickly emerged as one of the leading candidates for clinical trials. Before the expected therapeutic potential of rhPDGF-BB and other growth factors could be realized, a number of concerns had to be addressed (eg, would growth factors show effects in normal animals, what parameters of wound healing would be affected, and would quality of healed wounds be normal?). In animal models, rhPDGF-BB demonstrated wound healing activity, predominantly by enhancing the formation of granulation tissue, but it was not known whether this effect on granulation tissue would translate into enhanced healing of chronic skin ulcers in humans. The objective of this article is to review how the study of rhPDGF-BB in animal wound healing models has assisted in addressing the potential clinical utility of rhPDGF-BB. Results of animal studies are summarized, and the advantages and limitations of the animal models are discussed.
The benefits of apoptosis in the removal of unnecessary, damaged, or dangerous cells are dependen... more The benefits of apoptosis in the removal of unnecessary, damaged, or dangerous cells are dependent on the altruism resulting from the absence of genetic conflict between genes in cells. However, this altruism can be exploited by self-promoting or ultra-selfish genes.These self-promoting genes can be endogenous, as with neoplasia or germ cell mutations, or exogenous, as with cellular pathogens. The fundamental flaw of apoptosis is that its development and maintenance as a system is constantly opposed by the emergence of self-promoting genes. Since apoptotically impaired cells cannot be relied on to kill themselves, apoptotic input from other cells is required for controlling self-promoting genes. Certain unique features of germ cell development, such as linkage by cytoplasmic bridges and the requirement for granulosa or Sertoli cells, appear to serve this requirement for control of self-promoting genes. G ENETIC CONFLICT CAN OCCUR whenever the survival "interests" of genes differ. Because it leads to competing evolutionary spirals, genetic conflict is an area of major interest to evolutionary biologists. This discussion examines cell suicide/apoptosis, not in the usual strictly mechanistic approach but in the strategic light of genetic conflict, with the aim of exploring perspectives otherwise not readily apparent. The basic unit of selection is at the level of the gene (Dawkins 1976; Williams 1992). The genetic composition observed at any time is a legacy of the differential effects of genes on their own survival and reproduction. Genetic conflict
A medically important paradox is why the body's own cytokines lead to reduced appetite and appare... more A medically important paradox is why the body's own cytokines lead to reduced appetite and apparently inefficient metabolism as part of the acute-phase response. This self-induced nutrient restriction occurs just when the body must maintain a fever and other defensive functions. This paradox is often ignored or considered a metabolic derangement. Others, recognizing it to be a programmed response which must have net beneficial effects, consider the nutrient restriction to be an attempt to deny resources to infectious organisms. However, this explanation fails to address how the pathogen can be harmed more than the host. The hypothesis presented here offers an explanation. Apoptosis, or cell suicide, is becoming recognized as a useful defense against intracellular parasites, and nutrient restriction promotes apoptosis. Thus, nutrient restriction may encourage apoptosis of infected cells. Nutrient restriction can thereby offer protection by simultaneously limiting nutrients to both the host cells and the infectious organisms.
Apoptosis is widely recognized as being a host defense against viral infections, since viruses re... more Apoptosis is widely recognized as being a host defense against viral infections, since viruses require live cells. There has been increasing acceptance of the view that apoptosis is also a defense against other intracellular pathogens and even against pathogens that adhere to host cells. An implication of apoptosis being a host defense is a need to reassess to what extent the cell death at infection sites may constitute a protective host response. A concept stressed here is that infected cells are a hazard to other cells and to the individual, so the benefits of early apoptosis are emphasized. Therefore, promoting the survival of infected cells, even though still functional, may carry risks. A further consideration is the possibility that the apoptotic stimulus of nutrient restriction may be acting in infection-induced anorexia to promote apoptosis of infected cells, thereby serving as a non-specific host defense.
In the evolutionary view of endotoxin presented here, endotoxin is the primary signal animals use... more In the evolutionary view of endotoxin presented here, endotoxin is the primary signal animals use to detect gram negative (Gr-) bacteria. Since endotoxin, or lipopolysaccharide (LPS), is an integral part of the surface of all Gr- bacteria, it was excellent evolutionary 'choice' for the signal. The concept of an 'endotoxin response system' (ERS) is introduced. The ERS protects against Gr- bacteria by employing many of the body's defenses to both detect and react against LPS. The intensity of the response has evolved to maximize protection while minimizing the biological cost and self-damaging effects. The setting of the response, here termed the 'endostat', is programmed by natural selection and fine tuned by feedback mechanisms. Other potentially invasive organisms are detected by different signals, but the effector components of the defenses are similar. This evolutionary view of LPS offers a framework for the seemingly contradictory findings on endotoxin and suggests new avenues of productive research.
Tolmetin sodium's efficacy in preventing primary adhesions was evaluated in two adhesion ... more Tolmetin sodium's efficacy in preventing primary adhesions was evaluated in two adhesion models each in two species: (1) rabbit uterine horn, (2) rat uterine horn, (3) rabbit peritoneal side wall, and (4) rat peritoneal side wall. In each model a single instillation of tolmetin sodium solution into the peritoneal cavity at the time of surgery effectively reduced adhesion formation. This efficacy extended over a wide range of concentrations, volumes, and total dosages, and was similar in rabbits and rats. An aqueous solution of 1 mg/ml tolmetin sodium in 5-15 ml in rabbits and in 3 ml in rats was consistently efficacious in reducing postoperative adhesion formation.
A variety of nonsteroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit postsurgical... more A variety of nonsteroidal anti-inflammatory drugs (NSAIDs) has been found to inhibit postsurgical peritoneal adhesion formation in a number of animal models. A rabbit uterine horn adhesion model was used to directly compare several commonly used NSAIDs of different chemical classes in a single animal study to evaluate their ability to prevent adhesion formation. The effect of thromboxane inhibitors on adhesion prevention was also evaluated. Each of the NSAIDs tested (tolmetin, ibuprofen, aspirin, and indomethacin) showed significant and comparable efficacy. In this same study, imidazole, a thromboxane synthetase inhibitor, also showed significant efficacy. In a second study, ridogrel, an inhibitor of thromboxane synthetase as well as a thromboxane A2 receptor blocker, also showed significant efficacy in reducing peritoneal adhesion severity. These results further support the view that NSAIDs act to prevent adhesions through a common mechanism. In addition, thromboxane A2 inhibitors were also shown to be efficacious in adhesion prevention, suggesting that platelets may play a substantial role in adhesion formation.
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Papers by Edmund LeGrand