Tom Kindlon
Senior Member (Voting Rights)
Ken Friedman sent me this and asked me to highlight it
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A Narrative Synthesis for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome
The conceptualization of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (from here on referred to as ME/CFS) has classically been frustrated by the sheer complexity and breadth of its presentation. First described operationally in the 20th century by the Center for Disease Control & Prevention ME/CFS has been reported in some manner by the medical community since at least the 19th century.1 Throughout the disease’s history it has been described as a potentially infectious process similar to mononucleosis,2 a neuroimmunologic process like multiple sclerosis,1,2 a disorder of centralized pain processing such as fibromyalgia3, and in some instances something in the realm of conversion disorder, maladaptive psychology, and even hysterical delusion1,2,4. This variety of potential models is a consequence of the historically difficult nature of this disease to be studied and represented biologically. Typical rheumatologic and autoimmune laboratory studies often fail to produce a meaningfully abnormal result even in the most symptomatic of patients.4 Until recently neural imaging was not sophisticated enough to find the differences between the brains of those with ME/CFS versus the unaffected population, and even today we still have not isolated a pathogen that can be linked definitively to the development of this cluster of symptoms.2
This lack of understanding often manifests as frustration from both patients and the physicians who treat them. Due to the complexity of this disease process treatment primarily focused on using cognitive behavioral therapy and progressive increase in exertional tolerance for symptomatic relief, coping, and rehabilitation.5 The results of these strategies were inconsistent and, in some cases, even harmful.6 This variability in outcome further contributed to doubt in some medical communities as to whether the pathology even existed at all.1,2,7 This doubt paralleled the evolution of a patient population who often felt frustrated, abandoned, lost, and consequently at risk for developing true psychopathology if they have not done so already.8
However, breakthroughs in the scientific disciplines have gotten us past the once impenetrable wall of normal results and inconclusive studies. Thanks to new research investigating both the disease process and the clinical reality we are beginning to develop a more sophisticated and clinically meaningful understanding of ME/CFS. The purpose of this writing is to discuss several of these recent studies in hopes of facilitating a better understanding of ME/CFS’s pathology, possible epidemiology, and their implications on both clinical practice and further research.
Myalgic Encephalitis/ Chronic Fatigue Syndrome is defined by the CDC as requiring three primary symptoms for diagnosis: 1. greatly lowered ability to do activities that were usual before illness lasting six months or longer; 2. Worsening of ME/CFS symptoms after physical or mental activity that would not have caused a problem before illness. This is known as post-exertional malaise (PEM); 3. Sleep problems.9 There is also a stricter criteria which has been used by many researchers since 2003 referred to as the Canadian Consensus Criteria which defines ME/CFS as a patient meeting the criteria for fatigue, post-exertional malaise, sleep dysfunction, and pain; have two or more neurologic/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine, and immune manifestations persisting for at least six months usually with a distinct onset.10 The combination of these two criteria plus the very similar Oxford criteria is what was used to define the disease for much of the research hereafter.
The first of the major breakthroughs to be discussed is the literature that collectively establishes ME/CFS as a quantifiable and distinct clinical entity. They serve as a foundation of
knowledge from which appropriate therapies and future studies can be developed. Furthermore, without these studies ME/CFS’s existence could still be considered by some to be purely in the realm of psychopathology. Having confirmation of a biological pattern that can explain a constellation of clinical symptoms is the difference between knowing one has a disease that is diagnosable and treatable versus the existential anxiety that comes with wondering if these symptoms are uniquely one’s own, unprecedented, and perhaps—untreatable.
Some of the most compelling literature has centered on describing the phenomenon of post-exertional malaise (PEM). Since PEM is the defining symptom of ME/CFS, a better understanding of it is can lead to a better understanding the overall pathology. For this we will focus on the research of Wang et al, Light et al, and Cook et al which, through different methods of analysis, come to very similar conclusions. Wang’s systematic review of polymorphisms in patients with chronic fatigue showed that patients with ME/CFS had several single nucleotide polymorphisms (SNPs) which, when searched for as a panel, were able to accurately identify ME/CFS patients from the unafflicted population 76% of the time.11 These mutations were noted to be mostly in the genes 5-HTT/TPH2, COMT, and NR3C1; these are the genes for serotonin, catecholamine, and glucocorticoid production respectively. SNPs were also found in genes involved in neurotransmission, circadian rhythm maintenance, and regulation of the hypothalamic-pituitary-adrenal (HPA) axis.11 Thus, the evidence suggests that the genes integral to the processing of stress, arousal, and emotion are uniquely different in those with ME/CFS.11 This provides a possible explanation regarding an organic mechanism. However, genetic code and phenotypic expression are not one and the same. To go further and make this evidence pertinent these findings would need to match what was happening in actuality.
In accordance with Wang et al’s work, Light et al’s research on the epigenetics of ME/CFS showed that in response to acute exertion these patients had dramatic increases in mRNA transcribed from genes such as P2X4, P2X5, TRPV1, α-2A, β-2, COMT, and IL10.12,13,14 These genes collectively produce several of the cellular receptors and neurotransmitters responsible for energy utilization of the nervous system, the signaling of nociception, and the higher order processing of pain. His studies were able to positively correlate the level of mRNA transcription of these genes with the severity of ME/CFS patient symptoms across time.13 This is significant because it is a common report among these patients that PEM symptoms occur in the twenty-four to forty-right hours after fatiguing exertion.1,12,15 By measuring the levels of mRNA transcription during multiple time points within that forty-eight hour window he was able to represent biochemically what patients were presenting clinically. In addition Light et al. also evaluated these genes in healthy subjects and patients with other pathologies where chronic fatigue was prominent and was able to display that they had no such changes in their mRNA transcription.13,14 That is to say the evidence suggests ME/CFS had a distinct and recognizable epigenetic and, consequently, phenotypic presentation. To take this a step further it is also worth noting that the phenotypic expression correlated well with the genotypic variations described by Wang et al.
Given the altered transcription pattern some manifestation in the physiology is expected. Cook et al. was able to demonstrate using fMRI that after performing activities such as acute cardiovascular exercise or cognitively demanding visual and mathematical problems patients with ME/CFS had augmented neural firing in the regions of the brain associated with attention, higher-order information processing, pain perception, and emotional processing.15 Specifically, he was able to display heightened activity of the superior temporal lobes, the inferior-frontal lobes, the hippocampus, and the thalamus. By using this fMRI analysis in conjunction with questionnaires and evaluations of performance during the various study tasks Cook et al then correlated the augmented neural activity he was measuring with the subjective experiences of PEM. When the fMRI scans showed heightened neurologic activity in the aforementioned regions his subjects noted worsened subjective experience of fatigue, increased pain, and—almost paradoxically—worsening performance in the cognitive tasks.15 By way of fMRI Cook’s work was able to demonstrate the “brain fog” often described by ME/CFS patients in the midst of their post-exertional malaise.
This combination of increasing neurologic activity and worsening performance was contrasted against control subjects without ME/CFS. In response to the same stimuli the control subjects showed progressively diminishing levels of neural activation as the tasks were repeated.15 This phenomenon is the mark of adaptation via familiarization to novel stimuli. The current understanding of learning from the neuroscientific perspective suggests that as one becomes more familiar with a task the metabolic resources necessary to accomplish it (that is to say, the amount of cognitive effort) should decrease while the quality of the performance increases.15,16 Given this knowledge and the evidence generated by Cook et al. there is the implication that patients with ME/CFS lack the ability to adapt to stressful stimulation in the most literal sense.15
Due to the use of fMRI as the mode of evaluation Cook et al’s research also noted that these patients had preexisting differences in the inferior-frontal and temporal cortices as well as the hippocampus and thalamus when compared to control subjects. This finding was supported independently by a study in the British Medical Journal of Radiology which specifically showed that the hippocampus of ME/CFS patients had markedly decreased hippocampal volume.17 Jean-Michel Saury expanded greatly on these anatomic findings with his narrative synthesis of the functional neurologic research regarding ME/CFS. In his work he implicates the preexisting decrease in hippocampal volume as a powerful contributor to both generation and propagation ME/CFS’s symptoms of fatigue, pain, and impaired cognition.18
Saury ultimately suggests that the basic pathophysiology of ME/CFS is the dysregulated interaction between the HPA axis and the limbic system.18 The hippocampus houses the physical connection that links the HPA axis to the remaining limbic system. The hippocampus via the CA1 and CA3 areas of the subiculum projects axons directly to the parvoventricular nucleus of the hypothalamus whose role is the management of the body’s metabolic state via the adrenal glands. In response to circulating cortisol these hippocampal projections inhibit the hypothalamus and prevent it from secreting corticotropin-releasing hormone, therefore mitigating the hormonal cascade in response to acute stressors.18 This pathway forms the inhibitory arc of the HPA’s negative feedback loop. Evidence demonstrating this function is further provided by studies which show that lesions to the hippocampus lead to destruction of the negative feedback loop and, subsequently, result in chronic over-activity of the adrenal system, the effects of which are incredibly deleterious.18,19,20
Saury et al. argues that hyperactivation of the HPA axis and limbic system via an atrophied hippocampus correlates well with the neurocognitive impairment, psychological manifestations, and exertional intolerance that define ME/CFS and PEM.9,10,18 Unregulated activation of the HPA axis puts the body in a state of chronic physiologic stress whose symptoms are primarily the result of an overactive sympathetic nervous system and long-term maladaptation of the neuroendocrine structures which produce the HPA axis in the first place.16,18 Regarding the maladaptation, normally stressors activate the amygdala which in turn is modulated by the hippocampus.18 Together they form the neural computer which determines how powerfully the HPA axis becomes activated. This combined amygdala-hippocampal substructure simultaneously projects to higher order structures such as the parietal and frontal cortices generating emotional and mental states congruent with the level of activation of the sympathetic nervous system.16,18,19 In the case of chronic stress, however, the amygdala and sympathetic nervous system are abnormally augmented while the hippocampus becomes inhibited. With sufficient chronicity the amygdala itself will actually hypertrophy (i.e. strengthen its neural connections) while the hippocampus atrophies (i.e. weaken its neural connections) resulting in a preferentially activated stress response system with progressively diminishing capacity to regulate it via the higher order cognitive structures.18,19,20 Aside from its key role in modulating the HPA axis the hippocampus also plays the critical role in the creation and retrieval of episodic and procedural memory necessary for abstract thought.15,16,17 Impairment of the hippocampus, therefore, also correlates with the neurocognitive impairment that ME/CFS patients describe as a “brain fog”.
Parallel to the neuroscience, research regarding cortisol and stress physiology has produced an appropriately congruent, albeit less robust, series of conclusions. Research conducted by Rimes, Papadopoulos, Cleare, and Chalder revealed attenuated diurnal variability of cortisol in patients with ME/CFS as well as decreased cortisol levels throughout the day.22 Though the decrease in total level is modest it is the undulations of cortisol, not necessarily the total amount, which correlates with alertness and arousal.18,20,21,23 It is possible that the chronic fatigue of ME/CFS patients is being represented by this decreased variability. In another study Nijhof et al examined adolescents with ME/CFS and presented evidence suggesting that these teenagers also had mildly depressed levels of cortisol when compared against healthy peers. More importantly, however, this study demonstrated that the return of cortisol to normal levels positively correlated with self-reported recovery of symptoms.24 Lastly, a study by Hall et al regarding subject’s personal perception of ME/CFS presented two profoundly useful insights. Subject’s perceived stress management skill is positively correlated with levels of awakening cortisol, and awakening levels of cortisol is positively correlated with reduced severity of PEM exacerbations.25 The ability to link one’s mindset to one’s symptom severity lends support for continued use of well-designed cognitive behavioral therapy and stress-reducing adjustments to the environment these patients are nested in. 25
Thus, the physiologic literature emergently conceptualizes ME/CFS as the clinical manifestation of a collapsing and maladaptive stress response system.16-25, This model that focuses on autonomics, neural architecture, cortisol, and an altered ability to make use of the body’s metabolic resources complements the genetic and epigenetic literature of Light et al. and Wang et al. discussed previously. The convergence of the neurologic, endocrine, and genetic literature gives strength to this model in that if any of these findings were coincidental it is unlikely that separate methods of analysis would produce the congruent results. This congruence allows one to more confidently affirm that patients with ME/CFS indeed have measurable pathologic changes. Furthermore, one can attest that there are organic changes and searching for a biological solution is not a futile endeavor.
---
A Narrative Synthesis for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome
The conceptualization of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (from here on referred to as ME/CFS) has classically been frustrated by the sheer complexity and breadth of its presentation. First described operationally in the 20th century by the Center for Disease Control & Prevention ME/CFS has been reported in some manner by the medical community since at least the 19th century.1 Throughout the disease’s history it has been described as a potentially infectious process similar to mononucleosis,2 a neuroimmunologic process like multiple sclerosis,1,2 a disorder of centralized pain processing such as fibromyalgia3, and in some instances something in the realm of conversion disorder, maladaptive psychology, and even hysterical delusion1,2,4. This variety of potential models is a consequence of the historically difficult nature of this disease to be studied and represented biologically. Typical rheumatologic and autoimmune laboratory studies often fail to produce a meaningfully abnormal result even in the most symptomatic of patients.4 Until recently neural imaging was not sophisticated enough to find the differences between the brains of those with ME/CFS versus the unaffected population, and even today we still have not isolated a pathogen that can be linked definitively to the development of this cluster of symptoms.2
This lack of understanding often manifests as frustration from both patients and the physicians who treat them. Due to the complexity of this disease process treatment primarily focused on using cognitive behavioral therapy and progressive increase in exertional tolerance for symptomatic relief, coping, and rehabilitation.5 The results of these strategies were inconsistent and, in some cases, even harmful.6 This variability in outcome further contributed to doubt in some medical communities as to whether the pathology even existed at all.1,2,7 This doubt paralleled the evolution of a patient population who often felt frustrated, abandoned, lost, and consequently at risk for developing true psychopathology if they have not done so already.8
However, breakthroughs in the scientific disciplines have gotten us past the once impenetrable wall of normal results and inconclusive studies. Thanks to new research investigating both the disease process and the clinical reality we are beginning to develop a more sophisticated and clinically meaningful understanding of ME/CFS. The purpose of this writing is to discuss several of these recent studies in hopes of facilitating a better understanding of ME/CFS’s pathology, possible epidemiology, and their implications on both clinical practice and further research.
Myalgic Encephalitis/ Chronic Fatigue Syndrome is defined by the CDC as requiring three primary symptoms for diagnosis: 1. greatly lowered ability to do activities that were usual before illness lasting six months or longer; 2. Worsening of ME/CFS symptoms after physical or mental activity that would not have caused a problem before illness. This is known as post-exertional malaise (PEM); 3. Sleep problems.9 There is also a stricter criteria which has been used by many researchers since 2003 referred to as the Canadian Consensus Criteria which defines ME/CFS as a patient meeting the criteria for fatigue, post-exertional malaise, sleep dysfunction, and pain; have two or more neurologic/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine, and immune manifestations persisting for at least six months usually with a distinct onset.10 The combination of these two criteria plus the very similar Oxford criteria is what was used to define the disease for much of the research hereafter.
The first of the major breakthroughs to be discussed is the literature that collectively establishes ME/CFS as a quantifiable and distinct clinical entity. They serve as a foundation of
knowledge from which appropriate therapies and future studies can be developed. Furthermore, without these studies ME/CFS’s existence could still be considered by some to be purely in the realm of psychopathology. Having confirmation of a biological pattern that can explain a constellation of clinical symptoms is the difference between knowing one has a disease that is diagnosable and treatable versus the existential anxiety that comes with wondering if these symptoms are uniquely one’s own, unprecedented, and perhaps—untreatable.
Some of the most compelling literature has centered on describing the phenomenon of post-exertional malaise (PEM). Since PEM is the defining symptom of ME/CFS, a better understanding of it is can lead to a better understanding the overall pathology. For this we will focus on the research of Wang et al, Light et al, and Cook et al which, through different methods of analysis, come to very similar conclusions. Wang’s systematic review of polymorphisms in patients with chronic fatigue showed that patients with ME/CFS had several single nucleotide polymorphisms (SNPs) which, when searched for as a panel, were able to accurately identify ME/CFS patients from the unafflicted population 76% of the time.11 These mutations were noted to be mostly in the genes 5-HTT/TPH2, COMT, and NR3C1; these are the genes for serotonin, catecholamine, and glucocorticoid production respectively. SNPs were also found in genes involved in neurotransmission, circadian rhythm maintenance, and regulation of the hypothalamic-pituitary-adrenal (HPA) axis.11 Thus, the evidence suggests that the genes integral to the processing of stress, arousal, and emotion are uniquely different in those with ME/CFS.11 This provides a possible explanation regarding an organic mechanism. However, genetic code and phenotypic expression are not one and the same. To go further and make this evidence pertinent these findings would need to match what was happening in actuality.
In accordance with Wang et al’s work, Light et al’s research on the epigenetics of ME/CFS showed that in response to acute exertion these patients had dramatic increases in mRNA transcribed from genes such as P2X4, P2X5, TRPV1, α-2A, β-2, COMT, and IL10.12,13,14 These genes collectively produce several of the cellular receptors and neurotransmitters responsible for energy utilization of the nervous system, the signaling of nociception, and the higher order processing of pain. His studies were able to positively correlate the level of mRNA transcription of these genes with the severity of ME/CFS patient symptoms across time.13 This is significant because it is a common report among these patients that PEM symptoms occur in the twenty-four to forty-right hours after fatiguing exertion.1,12,15 By measuring the levels of mRNA transcription during multiple time points within that forty-eight hour window he was able to represent biochemically what patients were presenting clinically. In addition Light et al. also evaluated these genes in healthy subjects and patients with other pathologies where chronic fatigue was prominent and was able to display that they had no such changes in their mRNA transcription.13,14 That is to say the evidence suggests ME/CFS had a distinct and recognizable epigenetic and, consequently, phenotypic presentation. To take this a step further it is also worth noting that the phenotypic expression correlated well with the genotypic variations described by Wang et al.
Given the altered transcription pattern some manifestation in the physiology is expected. Cook et al. was able to demonstrate using fMRI that after performing activities such as acute cardiovascular exercise or cognitively demanding visual and mathematical problems patients with ME/CFS had augmented neural firing in the regions of the brain associated with attention, higher-order information processing, pain perception, and emotional processing.15 Specifically, he was able to display heightened activity of the superior temporal lobes, the inferior-frontal lobes, the hippocampus, and the thalamus. By using this fMRI analysis in conjunction with questionnaires and evaluations of performance during the various study tasks Cook et al then correlated the augmented neural activity he was measuring with the subjective experiences of PEM. When the fMRI scans showed heightened neurologic activity in the aforementioned regions his subjects noted worsened subjective experience of fatigue, increased pain, and—almost paradoxically—worsening performance in the cognitive tasks.15 By way of fMRI Cook’s work was able to demonstrate the “brain fog” often described by ME/CFS patients in the midst of their post-exertional malaise.
This combination of increasing neurologic activity and worsening performance was contrasted against control subjects without ME/CFS. In response to the same stimuli the control subjects showed progressively diminishing levels of neural activation as the tasks were repeated.15 This phenomenon is the mark of adaptation via familiarization to novel stimuli. The current understanding of learning from the neuroscientific perspective suggests that as one becomes more familiar with a task the metabolic resources necessary to accomplish it (that is to say, the amount of cognitive effort) should decrease while the quality of the performance increases.15,16 Given this knowledge and the evidence generated by Cook et al. there is the implication that patients with ME/CFS lack the ability to adapt to stressful stimulation in the most literal sense.15
Due to the use of fMRI as the mode of evaluation Cook et al’s research also noted that these patients had preexisting differences in the inferior-frontal and temporal cortices as well as the hippocampus and thalamus when compared to control subjects. This finding was supported independently by a study in the British Medical Journal of Radiology which specifically showed that the hippocampus of ME/CFS patients had markedly decreased hippocampal volume.17 Jean-Michel Saury expanded greatly on these anatomic findings with his narrative synthesis of the functional neurologic research regarding ME/CFS. In his work he implicates the preexisting decrease in hippocampal volume as a powerful contributor to both generation and propagation ME/CFS’s symptoms of fatigue, pain, and impaired cognition.18
Saury ultimately suggests that the basic pathophysiology of ME/CFS is the dysregulated interaction between the HPA axis and the limbic system.18 The hippocampus houses the physical connection that links the HPA axis to the remaining limbic system. The hippocampus via the CA1 and CA3 areas of the subiculum projects axons directly to the parvoventricular nucleus of the hypothalamus whose role is the management of the body’s metabolic state via the adrenal glands. In response to circulating cortisol these hippocampal projections inhibit the hypothalamus and prevent it from secreting corticotropin-releasing hormone, therefore mitigating the hormonal cascade in response to acute stressors.18 This pathway forms the inhibitory arc of the HPA’s negative feedback loop. Evidence demonstrating this function is further provided by studies which show that lesions to the hippocampus lead to destruction of the negative feedback loop and, subsequently, result in chronic over-activity of the adrenal system, the effects of which are incredibly deleterious.18,19,20
Saury et al. argues that hyperactivation of the HPA axis and limbic system via an atrophied hippocampus correlates well with the neurocognitive impairment, psychological manifestations, and exertional intolerance that define ME/CFS and PEM.9,10,18 Unregulated activation of the HPA axis puts the body in a state of chronic physiologic stress whose symptoms are primarily the result of an overactive sympathetic nervous system and long-term maladaptation of the neuroendocrine structures which produce the HPA axis in the first place.16,18 Regarding the maladaptation, normally stressors activate the amygdala which in turn is modulated by the hippocampus.18 Together they form the neural computer which determines how powerfully the HPA axis becomes activated. This combined amygdala-hippocampal substructure simultaneously projects to higher order structures such as the parietal and frontal cortices generating emotional and mental states congruent with the level of activation of the sympathetic nervous system.16,18,19 In the case of chronic stress, however, the amygdala and sympathetic nervous system are abnormally augmented while the hippocampus becomes inhibited. With sufficient chronicity the amygdala itself will actually hypertrophy (i.e. strengthen its neural connections) while the hippocampus atrophies (i.e. weaken its neural connections) resulting in a preferentially activated stress response system with progressively diminishing capacity to regulate it via the higher order cognitive structures.18,19,20 Aside from its key role in modulating the HPA axis the hippocampus also plays the critical role in the creation and retrieval of episodic and procedural memory necessary for abstract thought.15,16,17 Impairment of the hippocampus, therefore, also correlates with the neurocognitive impairment that ME/CFS patients describe as a “brain fog”.
Parallel to the neuroscience, research regarding cortisol and stress physiology has produced an appropriately congruent, albeit less robust, series of conclusions. Research conducted by Rimes, Papadopoulos, Cleare, and Chalder revealed attenuated diurnal variability of cortisol in patients with ME/CFS as well as decreased cortisol levels throughout the day.22 Though the decrease in total level is modest it is the undulations of cortisol, not necessarily the total amount, which correlates with alertness and arousal.18,20,21,23 It is possible that the chronic fatigue of ME/CFS patients is being represented by this decreased variability. In another study Nijhof et al examined adolescents with ME/CFS and presented evidence suggesting that these teenagers also had mildly depressed levels of cortisol when compared against healthy peers. More importantly, however, this study demonstrated that the return of cortisol to normal levels positively correlated with self-reported recovery of symptoms.24 Lastly, a study by Hall et al regarding subject’s personal perception of ME/CFS presented two profoundly useful insights. Subject’s perceived stress management skill is positively correlated with levels of awakening cortisol, and awakening levels of cortisol is positively correlated with reduced severity of PEM exacerbations.25 The ability to link one’s mindset to one’s symptom severity lends support for continued use of well-designed cognitive behavioral therapy and stress-reducing adjustments to the environment these patients are nested in. 25
Thus, the physiologic literature emergently conceptualizes ME/CFS as the clinical manifestation of a collapsing and maladaptive stress response system.16-25, This model that focuses on autonomics, neural architecture, cortisol, and an altered ability to make use of the body’s metabolic resources complements the genetic and epigenetic literature of Light et al. and Wang et al. discussed previously. The convergence of the neurologic, endocrine, and genetic literature gives strength to this model in that if any of these findings were coincidental it is unlikely that separate methods of analysis would produce the congruent results. This congruence allows one to more confidently affirm that patients with ME/CFS indeed have measurable pathologic changes. Furthermore, one can attest that there are organic changes and searching for a biological solution is not a futile endeavor.
