Cytokine

From Wikipedia, the free encyclopedia

Cytokines are a broad and loose category of small proteins (~5–20 kDa) that are important in cell signaling. Their release has an effect on the behavior of cells around them. It can be said that cytokines are involved in autocrine signaling, paracrine signaling and endocrine signaling as immunomodulating agents. Their definite distinction from hormones is still part of ongoing research. Cytokines may include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors but generally not hormones or growth factors (despite some overlap in the terminology). Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell.

They act through receptors, and are especially important in the immune system; cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways.

They are different from hormones, which are also important cell signaling molecules, in that hormones circulate in higher concentrations and tend to be made by specific kinds of cells.
They are important in health and disease, specifically in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction.

The word comes from Greek: cyto, from Greek "κύτος" kytos "cavity, cell" + kines, from Greek "κίνησις" kinēsis "movement".

Discovery of cytokines

Interferon-alpha, an interferon type I, was identified in 1957 as a protein that interfered with viral replication. The activity of interferon-gamma (the sole member of the interferon type II class) was described in 1965; this was the first identified lymphocyte-derived mediator. Macrophage migration inhibitory factor (MIF) was identified simultaneously in 1966 by John David and Barry Bloom.

In 1969 Dudley Dumonde proposed the term "lymphokine" to describe proteins secreted from lymphocytes and later, proteins derived from macrophages and monocytes in culture were called "monokines".

ln 1974, Stanley Cohen published an article describing the production of MIF in virus-infected allantoic membrane and kidney cells, showing its production is not limited to immune cells. This led to his proposal of the term cytokine.

Difference from hormones

Classic hormones circulate in nanomolar (10^-9 M) concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines (such as IL-6) circulate in picomolar (10^-12 M) concentrations that can increase up to 1,000 times during trauma or infection. The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Virtually all nucleated cells, but especially endo/epithelial cells and resident macrophages (many near the interface with the external environment) are potent producers of IL-1, IL-6, and TNF-α. In contrast, classic hormones, such as insulin, are secreted from discrete glands (e.g., the pancreas). The current terminology refers to cytokines as immunomodulating agents.

A contributing factor to the difficulty of distinguishing cytokines from hormones is that some immunomodulating effects of cytokines are systemic rather than local. For instance, to accurately utilize hormone terminology, cytokines may be autocrine or paracrine in nature, and chemotaxis, chemokinesis and endocrine as a pyrogen. Essentially, cytokines are not limited to their immunomodulatory status as molecules.

Nomenclature

Cytokines have been classed as lymphokines, interleukins, and chemokines, based on their presumed function, cell of secretion, or target of action. Because cytokines are characterised by considerable redundancy and pleiotropism, such distinctions, allowing for exceptions, are obsolete.

• The term interleukin was initially used by researchers for those cytokines whose presumed targets are principally leukocytes. It is now used largely for designation of newer cytokine molecules and bears little relation to their presumed function. The vast majority of these are produced by T-helper cells.
• Lymphokines: produced by lymphocytes
• Monokines: produced exclusively by monocytes
• Interferons: involved in antiviral responses
• Colony stimulating factors: support the growth of cells in semisolid media
• Chemokines: mediate chemoattraction (chemotaxis) between cells.

Classification

Structural

Structural homogeneity has been able to partially distinguish between cytokines that do not demonstrate a considerable degree of redundancy so that they can be classified into four types:

• The four-α-helix bundle family: member cytokines have three-dimensional structures with four bundles of α-helices. This family, in turn, is divided into three sub-families:
  1. the IL-2 subfamily
  2. the interferon (IFN) subfamily
  3. the IL-10 subfamily.
  • The first of these three, the IL-2 subfamily, is the largest. It contains several non-immunological cytokines including erythropoietin (EPO) and thrombopoietin (TPO). Furthermore, four-α-helix bundle cytokines can be grouped into long-chain and short-chain cytokines.^{[citation needed]}
• the IL-1 family, which primarily includes IL-1 and IL-18
• the IL-17 family, which has yet to be completely characterized, though member cytokines have a specific effect in promoting proliferation of T-cells that cause cytotoxic effects.
• the cysteine-knot cytokines include members of the Transforming growth factor beta superfamily, including TGF-β1, TGF-β2 and TGF-β3.

Functional

A classification that proves more useful in clinical and experimental practice outside of structural biology divides immunological cytokines into those that enhance cellular immune responses, type 1 (TNFα, IFN-γ, etc.), and type 2 (TGF-β, IL-4, IL-10, IL-13, etc.), which favor antibody responses.
A key focus of interest has been that cytokines in one of these two sub-sets tend to inhibit the effects of those in the other. Dysregulation of this tendency is under intensive study for its possible role in the pathogenesis of autoimmune disorders.

Several inflammatory cytokines are induced by oxidative stress. The fact that cytokines themselves trigger the release of other cytokines and also lead to increased oxidative stress makes them important in chronic inflammation, as well as other immunoresponses, such as fever and acute phase proteins of the liver (IL-1,6,12, IFN-a).

Cytokines also play a role in anti-inflammatory pathways and are a possible therapeutic treatment for pathological pain from inflammation or peripheral nerve injury. There are both pro-inflammatory and anti-inflammatory cytokines that regulate this pathway.

Receptors

In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly because a deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states. In this regard, and also because the redundancy and pleomorphism of cytokines are, in fact, a consequence of their homologous receptors, many authorities think that a classification of cytokine receptors would be more clinically and experimentally useful.

A classification of cytokine receptors based on their three-dimensional structure has, therefore, been attempted. Such a classification, though seemingly cumbersome, provides several unique perspectives for attractive pharmacotherapeutic targets.

• Immunoglobulin (Ig) superfamily, which are ubiquitously present throughout several cells and tissues of the vertebrate body, and share structural homology with immunoglobulins (antibodies), cell adhesion molecules, and even some cytokines. Examples: IL-1 receptor types.
• Hemopoietic Growth Factor (type 1) family, whose members have certain conserved motifs in their extracellular amino-acid domain. The IL-2 receptor belongs to this chain, whose γ-chain (common to several other cytokines) deficiency is directly responsible for the x-linked form of Severe Combined Immunodeficiency (X-SCID).
• Interferon (type 2) family, whose members are receptors for IFN β and γ.
• Tumor necrosis factors (TNF) (type 3) family, whose members share a cysteine-rich common extracellular binding domain, and includes several other non-cytokine ligands like CD40, CD27 and CD30, besides the ligands on which the family is named (TNF).
• Seven transmembrane helix family, the ubiquitous receptor type of the animal kingdom. All G protein-coupled receptors (for hormones and neurotransmitters) belong to this family. Chemokine receptors, two of which act as binding proteins for HIV (CD4 and CCR5), also belong to this family.
• Interleukin-17 receptor (IL-17R) family, which shows little homology with any other cytokine receptor family. Structural motifs conserved between members of this family include: an extracellular fibronectin III-like domain, a transmembrane domain and a cytoplasmic SERIF domain. The known members of this family are as follows: IL-17RA, IL-17RB, IL-17RC, IL17RD and IL-17RE.

Cellular effects

Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signaling then alter cell functions. This may include the upregulation and/or downregulation of several genes and their transcription factors, resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect by feedback inhibition.

The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular abundance, the presence and abundance of the complementary receptor on the cell surface, and downstream signals activated by receptor binding; these last two factors can vary by cell type. Cytokines are characterized by considerable "redundancy", in that many cytokines appear to share similar functions.

It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.

Said et al. showed that inflammatory cytokines cause an IL-10-dependent inhibition of T-cell expansion and function by up-regulating PD-1 levels on monocytes which leads to IL-10 production by monocytes after binding of PD-1 by PD-L.

Adverse reactions to cytokines are characterized by local inflammation and/or ulceration at the injection sites. Occasionally such reactions are seen with more widespread papular eruptions.

Roles of endogenous cytokines in health and disease

Cytokines are often involved in several developmental processes during embryogenesis.

Cytokines are crucial for fighting off infections and in other immune responses. However, they can become dysregulated and pathological in inflammation, trauma, and sepsis.

Adverse effects of cytokines have been linked to many disease states and conditions ranging from schizophrenia, major depression and Alzheimer's disease to cancer. Normal tissue integrity is preserved by feedback interactions between diverse cell types mediated by adhesion molecules and secreted cytokines; disruption of normal feedback mechanisms in cancer threatens tissue integrity. Over-secretion of cytokines can trigger a dangerous syndrome known as a cytokine storm; this may have been the cause of severe adverse events during a clinical trial of TGN1412. Cytokine storms are suspected to be the main cause of death in the 1918 "Spanish Flu" pandemic. Deaths were weighted more heavily towards people with healthy immune systems, due to its ability to produce stronger immune responses, likely increasing cytokine levels. Another important example of cytokine storm is seen in acute pancreatitis. Cytokines are integral and implicated in all angles of the cascade resulting in the systemic inflammatory response syndrome and multi organ failure associated with this intra-abdominal catastrophe.

Medical use as drugs

Some cytokines have been developed into protein therapeutics using recombinant DNA technology. Recombinant cytokines being used as drugs as of 2014 include:

• Bone morphogenetic protein (BMP), used to treat bone-related conditions
• Erythropoietin (EPO), used to treat anemia
• Granulocyte colony-stimulating factor (G-CSF), used to treat neutropenia in cancer patients
• Granulocyte macrophage colony-stimulating factor (GM-CSF), used to treat neutropenia and fungal infections in cancer patients
• Interferon alfa, used to treat hepatitis C and multiple sclerosis
• Interferon beta, used to treat multiple sclerosis
• Interleukin 2 (IL-2), used to treat cancer.
• Interleukin 11 (IL-11), used to treat thrombocytopenia in cancer patients.
• Interferon gamma is used to treat chronic granulomatous disease and osteopetrosis.

Evolutionary approaches to depression

From Wikipedia, the free encyclopedia

 

Evolutionary approaches to depression are attempts by evolutionary psychologists to use the theory of evolution to shed light on the problem of mood disorders. Depression has generally been thought of as dysfunction, but it is much more common than schizophrenia or autism, and its prevalence does not increase with age the way dementia and other organic dysfunction commonly does. Some researchers have surmised that the disorder may have evolutionary roots, in the same way that others suggest evolutionary contributions to schizophrenia, sickle cell anemia and other disorders. Psychology and psychiatry have not generally embraced evolutionary explanations for behaviors, and the proposed explanations for the evolution of depression remain controversial.

Background

Major depression (also called "major depressive disorder", "clinical depression" or often simply "depression") is a leading cause of disability worldwide, and in 2000 was the fourth leading contributor to the global burden of disease (measured in DALYs); it is also an important risk factor for suicide. It is understandable, then, that clinical depression is thought to be a pathology—a major dysfunction of the brain.

In most cases, rates of organ dysfunction increase with age, with low rates in adolescents and young adults, and the highest rates in the elderly. These patterns are consistent with evolutionary theories of aging which posit that selection against dysfunctional traits decreases with age (because there is a decreasing probability of surviving to later ages).

In contrast to these patterns, prevalence of clinical depression is high in all age categories, including otherwise healthy adolescents and young adults. In one study of the US population, for example, the 12 month prevalence for a major depression episode was highest in the youngest age category (15- to 24-year-olds). The high prevalence of depression is also an outlier when compared to the prevalence of major mental retardation, autism, and schizophrenia, all with prevalence rates about one tenth that of depression, or less.

The common occurrence and persistence of a trait like clinical depression with such negative effects early in life is difficult to explain. (Rates of infectious disease are high in young people, of course, but clinical depression is not thought to be caused by an infection.) Evolutionary psychology and its application in evolutionary medicine suggest how behaviour and mental states, including seemingly harmful states such as depression, may have been beneficial adaptations of human ancestors which improved the fitness of individuals or their relatives. It has been argued, for example, that Abraham Lincoln's lifelong depression was a source of insight and strength. Some even suggest that "we aren't designed to have happiness as our natural default" and so a state of depression is the evolutionary norm.

The following hypotheses attempt to identify a benefit of depression that outweighs its obvious costs.
Such hypotheses are not necessarily incompatible with one another and may explain different aspects, causes, and symptoms of depression.

Psychic pain hypothesis

One reason depression is thought to be a pathology is that it causes so much psychic pain and distress. However, physical pain is also very distressful, yet it has an evolved function: to inform the organism that it is suffering damage, to motivate it to withdraw from the source of damage, and to learn to avoid such damage-causing circumstances in the future. Sadness is also distressing, yet is widely believed to be an evolved adaptation. In fact, perhaps the most influential evolutionary view is that most cases of depression are simply particularly intense cases of sadness in response to adversity, such as the loss of a loved one.

According to the psychic pain hypothesis, depression is analogous to physical pain in that it informs the sufferer that current circumstances, such as the loss of a friend, are imposing a threat to biological fitness. It motivates the sufferer to cease activities that led to the costly situation, if possible, and it causes him or her to learn to avoid similar circumstances in the future. Proponents of this view tend to focus on low mood, and regard clinical depression as a dysfunctional extreme of low mood—and not as a unique set of characteristics that are physiologically distanced from regular depressed mood.
Alongside the absence of pleasure, other noticeable changes include psychomotor retardation, disrupted patterns of sleeping and feeding, a loss of sex drive and motivation—which are all also characteristics of the body's reaction to actual physical pain. In depressed people there is an increased activity in the regions of the cortex involved with the perception of pain, such as the anterior cingulate cortex and the left prefrontal cortex. This activity allows the cortex to manifest an abstract negative thought as a true physical stressor to the rest of the brain.

Behavioral shutdown model

The behavioral shutdown model states that if an organism faces more risk or expenditure than reward from activities, the best evolutionary strategy may be to withdraw from them. This model proposes that emotional pain, like physical pain, serves a useful adaptive purpose. Negative emotions like disappointment, sadness, grief, fear, anxiety, anger, and guilt are described as "evolved strategies that allow for the identification and avoidance of specific problems, especially in the social domain." Depression is characteristically associated with anhedonia and lack of energy, and those experiencing it are risk-aversive and perceive more negative and pessimistic outcomes because they are focused on preventing further loss. Although the model views depression as an adaptive response, it does not suggest that it is beneficial by the standards of current society; but it does suggest that many approaches to depression treat symptoms rather than causes, and underlying social problems need to be addressed.

A related phenomenon to the behavioral shutdown model is learned helplessness. In animal subjects, a loss of control or predictability in the subject's experiences results in a condition similar to clinical depression in humans. That is to say, if uncontrollable and unstoppable stressors are repeated for long enough, a rat subject will adopt a learned helplessness, which shares a number of behavioral and psychological features with human depression. The subject will not attempt to cope with problems, even when placed in a stressor-free novel environment. Should their rare attempts at coping prove successful in a new environment, a long lasting cognitive block prevents them from perceiving their action as useful and their coping strategy does not last long. From an evolutionary perspective, learned helplessness also allows a conservation of energy for an extended period of time should people find themselves in a predicament that is outside of their control, such as an illness or a dry season. However, for today's humans whose depression resembles learned helplessness, this phenomenon usually manifests as a loss of motivation and the distortion of one uncontrollable aspect of a person's life being viewed as representative of all aspects of their life – suggesting a mismatch between ultimate cause and modern manifestation.

Analytical rumination hypothesis

This hypothesis suggests that depression is an adaptation that causes the affected individual to concentrate his or her attention and focus on a complex problem in order to analyze and solve it.
One way depression increases the individual's focus on a problem is by inducing rumination. Depression activates the left ventrolateral prefrontal cortex, which increases attention control and maintains problem-related information in an "active, accessible state" referred to as "working memory", or WM. As a result, depressed individuals have been shown to ruminate, reflecting on the reasons for their current problems. Feelings of regret associated with depression also cause individuals to reflect and analyze past events in order to determine why they happened and how they could have been prevented.

Likewise, ruminative tendency itself, some cognitive psychologists argue, increases the likelihood of the onset of depression.

Another way depression increases an individual's ability to concentrate on a problem is by reducing distraction from the problem. For example, anhedonia, which is often associated with depression, decreases an individual's desire to participate in activities that provide short-term rewards, and instead, allows the individual to concentrate on long-term goals. In addition, "psychomotoric changes", such as solitariness, decreased appetite, and insomnia also reduce distractions. For instance, insomnia enables conscious analysis of the problem to be maintained by preventing sleep from disrupting such processes. Likewise, solitariness, lack of physical activity, and lack of appetite all eliminate sources of distraction, such as social interactions, navigation through the environment, and "oral activity", which disrupt stimuli from being processed.

Possibilities of depression as a dysregulated adaptation

Depression, especially in the modern context, may not necessarily be adaptive. The ability to feel pain and experience depression, are adaptive defense mechanisms, but when they are "too easily triggered, too intense, or long lasting", they can become "dysregulated". In such a case, defense mechanisms, too, can become diseases, such as "chronic pain or dehydration from diarrhea". Depression, which may be a similar kind of defense mechanism, may have become dysregulated as well.

Thus, unlike other evolutionary theories this one sees depression as a maladaptive extreme of something that is beneficial in smaller amounts. In particular, one theory focuses on the personality trait neuroticism. Low amounts of neuroticism may increase a person's fitness through various processes, but too much may reduce fitness by, for example, recurring depressions. Thus, evolution will select for an optimal amount and most people will have neuroticism near this amount. However, genetic variation continually occurs, and some people will have high neuroticism which increases the risk of depressions.

Rank theory

Rank theory is the hypothesis that, if an individual is involved in a lengthy fight for dominance in a social group and is clearly losing, then depression causes the individual to back down and accept the submissive role. In doing so, the individual is protected from unnecessary harm. In this way, depression helps maintain a social hierarchy. This theory is a special case of a more general theory derived from the psychic pain hypothesis: that the cognitive response that produces modern-day depression evolved as a mechanism that allows people to assess whether they are in pursuit of an unreachable goal, and if they are, to motivate them to desist.

Social risk hypothesis

This hypothesis is similar to the social rank hypothesis but focuses more on the importance of avoiding exclusion from social groups, rather than direct dominance contests. The fitness benefits of forming cooperative bonds with others have long been recognised—during the Pleistocene period, for instance, social ties were vital for food foraging and finding protection from predators.

As such, depression is seen to represent an adaptive, risk-averse response to the threat of exclusion from social relationships that would have had a critical impact on the survival and reproductive success of our ancestors. Multiple lines of evidence on the mechanisms and phenomenology of depression suggest that mild to moderate (or "normative") depressed states preserve an individual's inclusion in key social contexts via three intersecting features: a cognitive sensitivity to social risks and situations (e.g., "depressive realism"); it inhibits confident and competitive behaviours that are likely to put the individual at further risk of conflict or exclusion (as indicated by symptoms such as low self-esteem and social withdrawal); and it results in signalling behaviours directed toward significant others to elicit more of their support (e.g., the so-called "cry for help"). According to this view, the severe cases of depression captured by clinical diagnoses reflect the maladaptive, dysregulation of this mechanism, which may partly be due to the uncertainty and competitiveness of the modern, globalised world.

Honest signaling theory

Another reason depression is thought to be a pathology is that key symptoms, such as loss of interest in virtually all activities, are extremely costly to the sufferer. Biologists and economists have proposed, however, that signals with inherent costs can credibly signal information when there are conflicts of interest. In the wake of a serious negative life event, such as those that have been implicated in depression (e.g., death, divorce), "cheap" signals of need, such as crying, might not be believed when social partners have conflicts of interest. The symptoms of major depression, such as loss of interest in virtually all activities and suicidality, are inherently costly, but, as costly signaling theory requires, the costs differ for individuals in different states. For individuals who are not genuinely in need, the fitness cost of major depression is very high because it threatens the flow of fitness benefits. For individuals who are in genuine need, however, the fitness cost of major depression is low, because the individual is not generating many fitness benefits. Thus, only an individual in genuine need can afford to suffer major depression. Major depression therefore serves as an honest, or credible, signal of need.

For example, individuals suffering a severe loss such as the death of a spouse are often in need of help and assistance from others. Such individuals who have few conflicts with their social partners are predicted to experience grief—a means, in part, to signal need to others. Such individuals who have many conflicts with their social partners, in contrast, are predicted to experience depression—a means, in part, to credibly signal need to others who might be skeptical that the need is genuine.

Bargaining theory

Depression is not only costly to the sufferer, it also imposes a significant burden on family, friends, and society at large—yet another reason it is thought to be pathological. Yet if sufferers of depression have real but unmet needs, they might have to provide an incentive to others to address those needs.

The bargaining theory of depression is similar to the honest signaling, niche change, and social navigation theories of depression described below. It draws on theories of labor strikes developed by economists to basically add one additional element to honest signaling theory: The fitness of social partners is generally correlated. When a wife suffers depression and reduces her investment in offspring, for example, the husband's fitness is also put at risk. Thus, not only do the symptoms of major depression serve as costly and therefore honest signals of need, they also compel reluctant social partners to respond to that need in order to prevent their own fitness from being reduced.

Social navigation or niche change theory

The social navigation or niche change hypothesis proposes that depression is a social navigation adaptation of last resort, designed especially to help individuals overcome costly, complex contractual constraints on their social niche. The hypothesis combines the analytical rumination and bargaining hypotheses and suggests that depression, operationally defined as a combination of prolonged anhedonia and psychomotor retardation or agitation, provides a focused sober perspective on socially imposed constraints hindering a person's pursuit of major fitness enhancing projects. Simultaneously, publicly displayed symptoms, which reduce the depressive's ability to conduct basic life activities, serve as a social signal of need; the signal's costliness for the depressive certifies its honesty. Finally, for social partners who find it uneconomical to respond helpfully to an honest signal of need, the same depressive symptoms also have the potential to extort relevant concessions and compromises. Depression's extortionary power comes from the fact that it retards the flow of just those goods and services such partners have come to expect from the depressive under status quo socioeconomic arrangements.

Thus depression may be a social adaptation especially useful in motivating a variety of social partners, all at once, to help the depressive initiate major fitness-enhancing changes in their socioeconomic life. There are diverse circumstances under which this may become necessary in human social life, ranging from loss of rank or a key social ally which makes the current social niche uneconomic to having a set of creative new ideas about how to make a livelihood which begs for a new niche. The social navigation hypothesis emphasizes that an individual can become tightly ensnared in an overly restrictive matrix of social exchange contracts, and that this situation sometimes necessitates a radical contractual upheaval that is beyond conventional methods of negotiation. Regarding the treatment of depression, this hypothesis calls into question any assumptions by the clinician that the typical cause of depression is related to maladaptive perverted thinking processes or other purely endogenous sources. The social navigation hypothesis calls instead for analysis of the depressive's talents and dreams, identification of relevant social constraints (especially those with a relatively diffuse non-point source within the social network of the depressive), and practical social problem-solving therapy designed to relax those constraints enough to allow the depressive to move forward with their life under an improved set of social contracts. This theory has been the subject of criticism.

Prevention of infection

It has been hypothesized that depression is an evolutionary adaptation because it helps prevent infection in both the affected individual and his/her kin.

First, the associated symptoms of depression, such as inactivity and lethargy, encourage the affected individual to rest. Energy conserved through such methods is highly crucial, as immune activation against infections is relatively costly; there must be, for instance, a 10% increase in metabolic activity for even a 1℃ change in body temperature. Therefore, depression allows one to conserve and allocate energy to the immune system more efficiently.

Depression further prevents infection by discouraging social interactions and activities that may result in exchange of infections. For example, the loss of interest discourages one from engaging in sexual activity, which, in turn, prevents the exchange of sexually transmitted diseases. Similarly, depressed mothers may interact less with their children, reducing the probability of the mother infecting her kin. Lastly, the lack of appetite associated with depression may also reduce exposure to food-borne parasites.

However, it should also be noted that chronic illness itself may be involved in causing depression. In animal models, the prolonged overreaction of the immune system, in response to the strain of chronic disease, results in an increased production of cytokines (a diverse group of hormonal regulators and signaling molecules). Cytokines interact with neurotransmitter systems—mainly norepinephrine, dopamine, and serotonin, and induce depressive characteristics. The onset of depression may help an individual recover from their illness by allowing them a more reserved, safe and energetically efficient lifestyle. The overproduction of these cytokines, beyond optimal levels due to the repeated demands of dealing with a chronic disease, may result in clinical depression and its accompanying behavioral manifestations that promote extreme energy reservation.

The third ventricle hypothesis

Third ventricle

The third ventricle hypothesis of depression proposes that the behavioural cluster associated with depression (hunched posture, avoidance of eye contact, reduced appetites for food and sex plus social withdrawal and sleep disturbance) serves to reduce an individual's attack-provoking stimuli within the context of a chronically hostile social environment. It further proposes that this response is mediated by the acute release of an unknown (probably cytokine) inflammatory agent into the third ventricular space. In support of this suggestion imaging studies reveal that the third ventricle is enlarged in depressives, which is indicative of damage-induced loss of volume in the structures surrounding it.

Reception

Clinical psychology and psychiatry have historically been relatively isolated from the field of evolutionary psychology. Some psychiatrists raise the concern that evolutionary psychologists seek to explain hidden adaptive advantages without engaging the rigorous empirical testing required to back up such claims. While there is strong research to suggest a genetic link to bipolar disorder and schizophrenia, there is significant debate within clinical psychology about the relative influence and the mediating role of cultural or environmental factors. For example, epidemiological research suggests that different cultural groups may have divergent rates of diagnosis, symptomatology, and expression of mental illnesses. There has also been increasing acknowledgment of culture-bound disorders, which may be viewed as an argument for an environmental versus genetic psychological adaptation. While certain mental disorders may have psychological traits that can be explained as 'adaptive' on an evolutionary scale, these disorders cause afflicted individuals significant emotional and psychological distress and negatively influence the stability of interpersonal relationships and day-to-day adaptive functioning.

Evolutionary medicine

From Wikipedia, the free encyclopedia

 

The bacteria Mycobacterium tuberculosis can evolve to subvert the protection offered by immune defenses

Evolutionary medicine or Darwinian medicine is the application of modern evolutionary theory to understanding health and disease. Modern medical research and practice have focused on the molecular and physiological mechanisms underlying health and disease, while evolutionary medicine focuses on the question of why evolution has shaped these mechanisms in ways that may leave us susceptible to disease. The evolutionary approach has driven important advances in our understanding of cancer, autoimmune disease, and anatomy. Medical schools have been slower to integrate evolutionary approaches because of limitations on what can be added to existing medical curricula.

Core Principles of Evolutionary Medicine

Utilizing the Delphi method, 56 experts from a variety of disciplines, including anthropology, medicine, and biology agreed upon 14 core principles intrinsic to the education and practice of evolutionary medicine. These 14 principles can be further grouped into five general categories: question framing, evolution I and II (with II involving a higher level of complexity), evolutionary trade-offs, reasons for vulnerability, and culture. Additional information regarding these principles may be found in the table below.

Core Principles of Evolutionary Medicine

Topic	Core Principle
Types of explanation (question framing)	Both proximate (mechanistic) and ultimate (evolutionary) explanations are needed to provide a full biological understanding of traits, including those that increase vulnerability to disease.
Evolutionary processes (evolution I)	All evolutionary processes, including natural selection, genetic drift, mutation, migration and non-random mating, are important for understanding traits and disease.
Reproductive success (evolution I)	Natural selection maximizes reproductive success, sometimes at the expense of health and longevity.
Sexual selection (evolution I)	Sexual selection shapes traits that result in different health risks between sexes.
Constraints (evolution I)	Several constraints inhibit the capacity of natural selection to shape traits that are hypothetically optimal for health.
Trade-offs (evolutionary trade-offs)	Evolutionary changes in one trait that improve fitness can be linked to changes in other traits that decrease fitness.
Life History Theory (evolutionary trade-offs)	Life history traits, such as age at first reproduction, reproductive lifespan and rate of senescence, are shaped by evolution, and have implications for health and disease.
Levels of selection (evolution II)	Vulnerabilities to disease can result when selection has opposing effects at different levels (e.g. genetic elements, cells, organisms, kin and other levels).
Phylogeny (evolution II)	Tracing phylogenetic relationships for species, populations, traits or pathogens can provide insights into health and disease.
Coevolution (evolution II)	Coevolution among species can influence health and disease (e.g. evolutionary arms races and mutualistic relationships such as those seen in the microbiome).
Plasticity (evolution II)	Environmental factors can shift developmental trajectories in ways that influence health and the plasticity of these trajectories can be the product of evolved adaptive mechanisms.
Defenses (reasons for vulnerability)	Many signs and symptoms of disease (e.g. fever) are useful defenses, which can be pathological if dysregulated.
Mismatch (reasons for vulnerability)	Disease risks can be altered for organisms living in environments that differ from those in which their ancestors evolved.
Cultural practices (culture)	Cultural practices can influence the evolution of humans and other species (including pathogens), in ways that can affect health and disease (e.g. anti-biotic use, birth practices, diet, etc.).

Human adaptations

Adaptation works within constraints, makes compromises and trade-offs, and occurs in the context of different forms of competition.

Constraints

Adaptations can only occur if they are evolvable. Some adaptations which would prevent ill health are therefore not possible.

• DNA cannot be totally prevented from undergoing somatic replication corruption; this has meant that cancer, which is caused by somatic mutations, has not (so far) been completely eliminated by natural selection.
• Humans cannot biosynthesize vitamin C, and so risk scurvy, vitamin C deficiency disease, if dietary intake of the vitamin is insufficient.
• Retinal neurons and their axon output have evolved to be inside the layer of retinal pigment cells. This creates a constraint on the evolution of the visual system such that the optic nerve is forced to exit the retina through a point called the optic disc. This, in turn, creates a blind spot. More importantly, it makes vision vulnerable to increased pressure within the eye (glaucoma) since this cups and damages the optic nerve at this point, resulting in impaired vision.

Other constraints occur as the byproduct of adaptive innovations.

Trade-offs and conflicts

One constraint upon selection is that different adaptations can conflict, which requires a compromise between them to ensure an optimal cost-benefit tradeoff.

• Running efficiency in women, and birth canal size
• Encephalization, and gut size
• Skin pigmentation protection from UV, and the skin synthesis of vitamin D
• Speech and its use of a descended larynx, and increased risk of choking

Competition effects

Different forms of competition exist and these can shape the processes of genetic change.

• mate choice and disease susceptibility
• genomic conflict between mother and fetus that results in pre-eclampsia

"Diseases of civilization"

Humans evolved to live as simple hunter-gatherers in small tribal bands. Contemporary humans now have a very different environment and way of life. This change makes present humans vulnerable to a number of health problems, termed "diseases of civilization" and "diseases of affluence". Stone-age humans evolved to live off the land, taking advantage of the resources that were readily available to them. Evolution is slow, and the rapid change from stone-age environments and practices to the world of today is problematic because we are still adapted to stone-age circumstances that no longer apply. This misfit has serious implications for our health. "Modern environments may cause many diseases such as deficiency syndromes like scurvy and rickets".

Diet

In contrast to the diet of early hunter-gatherers, the modern Western diet often contains high quantities of fat, salt, and simple carbohydrates, such as refined sugars and flours. These relatively sudden dietary changes create health problems.

• Trans fat health risks
• Dental caries
• High GI foods
• Modern diet based on "common wisdom" regarding diets in the paleolithic era

Life expectancy

Examples of aging-associated diseases are atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension and Alzheimer's disease. The incidence of all of these diseases increases rapidly with aging (increases exponentially with age, in the case of cancer).

Age-Specific SEER Incidence Rates, 2003-2007

Of the roughly 150,000 people who die each day across the globe, about two thirds—100,000 per day—die of age-related causes. In industrialized nations, the proportion is much higher, reaching 90%.

Exercise

Many contemporary humans engage in little physical exercise compared to the physically active lifestyles of ancestral hunter-gatherers. Prolonged periods of inactivity may have only occurred in early humans following illness or injury, so a modern sedentary lifestyle may continuously cue the body to trigger life preserving metabolic and stress-related responses such as inflammation, and this eventually causes chronic diseases.

Cleanliness

Contemporary humans in developed countries are mostly free of parasites, particularly intestinal ones. This is largely due to frequent washing of clothing and the body, and improved sanitation. Although such hygiene can be very important when it comes to maintaining good health, it can be problematic for the proper development of the immune system. The hygiene hypothesis is that humans evolved to be dependent on certain microorganisms that help establish the immune system, and modern hygiene practices can prevent necessary exposure to these microorganisms. "Microorganisms and macroorganisms such as helminths from mud, animals, and feces play a critical role in driving immunoregulation" (Rook, 2012). Essential microorganisms play a crucial role in building and training immune functions that fight off and repel some diseases, and protect against excessive inflammation, which has been implicated in several diseases. For instance, recent studies have found evidence supporting inflammation as a contributing factor in Alzheimer's Disease.

Specific explanations

This is a partial list: all links here go to a section describing or debating its evolutionary origin.

Life stage related

• Adipose tissue in human infants
• Arthritis and other chronic inflammatory diseases
• Ageing
• Alzheimer disease
• Childhood
• Menarche
• Menopause
• Menstruation
• Morning sickness

Other

• Atherosclerosis
• Arthritis and other chronic inflammatory diseases
• Cough
• Cystic fibrosis
• Dental occlusion
• Diabetes Type II
• Diarrhea
• Essential hypertension
• Fever
• Gestational hypertension
• Gout
• Hemochromatosis
• Iron deficiency (paradoxical benefits)
• Obesity
• Phenylketonuria
• Placebos
• Osteoporosis
• Red blood cell polymorphism disorders
• Sickle cell anemia
• Sickness behavior
• Women’s reproductive cancers

Evolutionary psychology

As noted in the table below, adaptationist hypotheses regarding the etiology of psychological disorders are often based on analogies with evolutionary perspectives on medicine and physiological dysfunctions (see in particular, Randy Nesse and George C. Williams' book Why We Get Sick). Evolutionary psychiatrists and psychologists suggest that some mental disorders likely have multiple causes.

Possible Causes of Psychological 'Abnormalities' from an Adaptationist Perspective Summary based on information in Buss (2011), Gaulin & McBurney (2004), Workman & Reader (2004)
Possible cause	Physiological Dysfunction	Psychological Dysfunction
Functioning adaptation (adaptive defense)	Fever / Vomiting (functional responses to infection or ingestion of toxins)	Mild depression or anxiety (functional responses to mild loss or stress)
By-product of an adaptation(s)	Intestinal gas (byproduct of digestion of fiber)	Sexual fetishes (?) (possible byproduct of normal sexual arousal adaptations that have 'imprinted' on unusual objects or situations)
Adaptations with multiple effects	Gene for malaria resistance, in homozygous form, causes sickle cell anemia	Adaptation(s) for high levels of creativity may also predispose schizophrenia or bi-polar disorder (adaptations with both positive and negative effects, perhaps dependent on alternate developmental trajectories)
Malfunctioning adaptation	Allergies (over-reactive immunological responses)	Autism (possible malfunctioning of theory of mind module)
Frequency-dependent morphs	The two sexes / Different blood and immune system types	Personality traits and personality disorders (may represent alternative behavioral strategies dependent on the frequency of the strategy in the population)
Mismatch between ancestral & current environments	Modern diet-related Type 2 Diabetes	More frequent modern interaction with strangers (compared to family and close friends) may predispose greater incidence of depression & anxiety
Tails of normal (bell shaped) curve	Very short or tall height	Tails of the distribution of personality traits (e.g., extremely introverted or extroverted)

See several topic areas, and the associated references, below.

• Agoraphobia
• Anxiety
• Depression
• Drug abuse
• Schizophrenia
• Unhappiness

History

Charles Darwin

Charles Darwin did not discuss the implications of his work for medicine, though biologists quickly appreciated the germ theory of disease and its implications for understanding the evolution of pathogens, as well as an organism’s need to defend against them.

Medicine, in turn, ignored evolution, and instead focused (as done in the hard sciences) upon proximate mechanical causes.

medicine has modelled itself after a mechanical physics, deriving from Galileo, Newton, and Descartes.... As a result of assuming this model, medicine is mechanistic, materialistic, reductionistic, linear-causal, and deterministic (capable of precise predictions) in its concepts. It seeks explanations for diseases, or their symptoms, signs, and cause in single, materialistic— i.e., anatomical or structural (e.g., in genes and their products)— changes within the body, wrought directly (linearly), for example, by infectious, toxic, or traumatic agents.

George C. Williams was the first to apply evolutionary theory to health in the context of senescence. Also in the 1950s, John Bowlby approached the problem of disturbed child development from an evolutionary perspective upon attachment.

An important theoretical development was Nikolaas Tinbergen’s distinction made originally in ethology between evolutionary and proximate mechanisms.

Randolph M. Nesse summarizes its relevance to medicine:

all biological traits need two kinds of explanation, both proximate and evolutionary. The proximate explanation for a disease describes what is wrong in the bodily mechanism of individuals affected by it. An evolutionary explanation is completely different. Instead of explaining why people are different, it explains why we are all the same in ways that leave us vulnerable to disease. Why do we all have wisdom teeth, an appendix, and cells that can divide out of control?

The paper of Paul Ewald in 1980, “Evolutionary Biology and the Treatment of Signs and Symptoms of Infectious Disease”, and that of Williams and Nesse in 1991, “The Dawn of Darwinian Medicine” were key developments. The latter paper “draw a favorable reception”, and led to a book, Why We Get Sick (published as Evolution and healing in the UK). In 2008, an online journal started: Evolution and Medicine Review.

Biomechanics

From Wikipedia, the free encyclopedia

 

Page of one of the first works of Biomechanics (De Motu Animalium of Giovanni Alfonso Borelli) in the 17th century

Biomechanics is the study of the structure and function of the mechanical aspects of biological systems, at any level from whole organisms to organs, cells and cell organelles, using the methods of mechanics.

Etymology

The word "biomechanics" (1899) and the related "biomechanical" (1856) come from the Ancient Greek βίος bios "life" and μηχανική, mēchanikē "mechanics", to refer to the study of the mechanical principles of living organisms, particularly their movement and structure.

Method

Biomechanics is closely related to engineering, because it often uses traditional engineering sciences to analyze biological systems. Some simple applications of Newtonian mechanics and/or materials sciences can supply correct approximations to the mechanics of many biological systems. Applied mechanics, most notably mechanical engineering disciplines such as continuum mechanics, mechanism analysis, structural analysis, kinematics and dynamics play prominent roles in the study of biomechanics.

Usually biological systems are much more complex than man-built systems. Numerical methods are hence applied in almost every biomechanical study. Research is done in an iterative process of hypothesis and verification, including several steps of modeling, computer simulation and experimental measurements.

Subfields

Applied subfields of biomechanics include:

• Soft body dynamics
• Forensic Biomechanics
• Kinesiology (kinetics + physiology)
• Animal locomotion & Gait analysis
• Musculoskeletal & orthopedic biomechanics
• Cardiovascular biomechanics
• Ergonomy
• Human factors engineering & occupational biomechanics
• Implant (medicine), Orthotics & Prosthesis
• Rehabilitation
• Sports biomechanics
• Allometry
• Injury biomechanics
• Biotribology
• Biofluid mechanics
• Comparative biomechanics
• Computational biomechanics

Sports biomechanics

In sports biomechanics, the laws of mechanics are applied to human movement in order to gain a greater understanding of athletic performance and to reduce sport injuries as well. It focuses on the application of the scientific principles of mechanical physics to understand movements of action of human bodies and sports implements such as cricket bat, hockey stick and javelin etc. Elements of mechanical engineering (e.g., strain gauges), electrical engineering (e.g., digital filtering), computer science (e.g., numerical methods), gait analysis (e.g., force platforms), and clinical neurophysiology (e.g., surface EMG) are common methods used in sports biomechanics.

Biomechanics in sports can be stated as the muscular, joint and skeletal actions of the body during the execution of a given task, skill and/or technique. Proper understanding of biomechanics relating to sports skill has the greatest implications on: sport's performance, rehabilitation and injury prevention, along with sport mastery. As noted by Doctor Michael Yessis, one could say that best athlete is the one that executes his or her skill the best.

Continuum biomechanics

The mechanical analysis of biomaterials and biofluids is usually carried forth with the concepts of continuum mechanics. This assumption breaks down when the length scales of interest approach the order of the micro structural details of the material. One of the most remarkable characteristic of biomaterials is their hierarchical structure. In other words, the mechanical characteristics of these materials rely on physical phenomena occurring in multiple levels, from the molecular all the way up to the tissue and organ levels.

Biomaterials are classified in two groups, hard and soft tissues. Mechanical deformation of hard tissues (like wood, shell and bone) may be analysed with the theory of linear elasticity. On the other hand, soft tissues (like skin, tendon, muscle and cartilage) usually undergo large deformations and thus their analysis rely on the finite strain theory and computer simulations. The interest in continuum biomechanics is spurred by the need for realism in the development of medical simulation.

Biofluid mechanics

Red blood cells

Biological fluid mechanics, or biofluid mechanics, is the study of both gas and liquid fluid flows in or around biological organisms. An often studied liquid biofluids problem is that of blood flow in the human cardiovascular system. Under certain mathematical circumstances, blood flow can be modelled by the Navier–Stokes equations. In vivo whole blood is assumed to be an incompressible Newtonian fluid. However, this assumption fails when considering forward flow within arterioles. At the microscopic scale, the effects of individual red blood cells become significant, and whole blood can no longer be modelled as a continuum. When the diameter of the blood vessel is just slightly larger than the diameter of the red blood cell the Fahraeus–Lindquist effect occurs and there is a decrease in wall shear stress. However, as the diameter of the blood vessel decreases further, the red blood cells have to squeeze through the vessel and often can only pass in single file. In this case, the inverse Fahraeus–Lindquist effect occurs and the wall shear stress increases.

An example of a gaseous biofluids problem is that of human respiration. Recently, respiratory systems in insects have been studied for bioinspiration for designing improved microfluidic devices.

Biotribology

The main aspects of Contact mechanics and tribology are related to friction, wear and lubrication. When the two surfaces come in contact during motion i.e. rub against each other, friction, wear and lubrication effects are very important to analyze in order to determine the performance of the material. Biotribology is a study of friction, wear and lubrication of biological systems especially human joints such as hips and knees. For example, femoral and tibial components of knee implant routinely rub against each other during daily activity such as walking or stair climbing. If the performance of tibial component needs to be analyzed, the principles of biotribology are used to determine the wear performance of the implant and lubrication effects of synovial fluid. In addition, the theory of contact mechanics also becomes very important for wear analysis. Additional aspects of biotribology can also include analysis of subsurface damage resulting from two surfaces coming in contact during motion, i.e. rubbing against each other, such as in the evaluation of tissue engineered cartilage.

Comparative biomechanics

Chinstrap penguin leaping over water

Comparative biomechanics is the application of biomechanics to non-human organisms, whether used to gain greater insights into humans (as in physical anthropology) or into the functions, ecology and adaptations of the organisms themselves. Common areas of investigation are Animal locomotion and feeding, as these have strong connections to the organism's fitness and impose high mechanical demands. Animal locomotion, has many manifestations, including running, jumping and flying. Locomotion requires energy to overcome friction, drag, inertia, and gravity, though which factor predominates varies with environment.

Comparative biomechanics overlaps strongly with many other fields, including ecology, neurobiology, developmental biology, ethology, and paleontology, to the extent of commonly publishing papers in the journals of these other fields. Comparative biomechanics is often applied in medicine (with regards to common model organisms such as mice and rats) as well as in biomimetics, which looks to nature for solutions to engineering problems.

Plant biomechanics

The application of biomechanical principles to plants, plant organs and cells has developed into the subfield of plant biomechanics. Application of biomechanics for plants ranges from studying the resilience of crops to environmental stress to development and morphogenesis at cell and tissue scale, overlapping with mechanobiology.

Computational biomechanics

Computational biomechanics is the application of engineering computational tools, such as the Finite element method to study the mechanics of biological systems. Computational models and simulations are used to predict the relationship between parameters that are otherwise challenging to test experimentally, or used to design more relevant experiments reducing the time and costs of experiments. Mechanical modeling using finite element analysis has been used to interpret the experimental observation of plant cell growth to understand how they differentiate, for instance. In medicine, over the past decade, the Finite element method has become an established alternative to in vivo surgical assessment. One of the main advantages of computational biomechanics lies in its ability to determine the endo-anatomical response of an anatomy, without being subject to ethical restrictions. This has led FE modeling to the point of becoming ubiquitous in several fields of Biomechanics while several projects have even adopted an open source philosophy (e.g. BioSpine).

History

Antiquity

Aristotle, a student of Plato can be considered the first bio-mechanic, because of his work with animal anatomy. Aristotle wrote the first book on the motion of animals, De Motu Animalium, or On the Movement of Animals. He not only saw animals' bodies as mechanical systems, but pursued questions such as the physiological difference between imagining performing an action and actually doing it. In another work, On the Parts of Animals, he provided an accurate description of how the ureter uses peristalsis to carry urine from the kidneys to the bladder.

With the rise of the Roman Empire, technology became more popular than philosophy and the next bio-mechanic arose. Galen (129 AD-210 AD), physician to Marcus Aurelius, wrote his famous work, On the Function of the Parts (about the human body). This would be the world’s standard medical book for the next 1,400 years.

Renaissance

The next major biomechanic would not be around until 1452, with the birth of Leonardo da Vinci. Da Vinci was an artist and mechanic and engineer. He contributed to mechanics and military and civil engineering projects. He had a great understanding of science and mechanics and studied anatomy the a mechanics context. He analyzed muscle forces and movements and studied joint functions. These studies could be considered studies in the realm of biomechanics. Leonardo da Vinci studied anatomy in the context of mechanics. He analyzed muscle forces as acting along lines connecting origins and insertions, and studied joint function. Da Vinci tended to mimic some animal features in his machines. For example, he studied the flight of birds to find means by which humans could fly; and because horses were the principal source of mechanical power in that time, he studied their muscular systems to design machines that would better benefit from the forces applied by this animal.

In 1543, Galen’s work, On the Function of the Parts was challenged by Andreas Vesalius at the age of 29. Vesalius published his own work called, On the Structure of the Human Body. In this work, Vesalius corrected many errors made by Galen, which would not be globally accepted for many centuries. With the death of Copernicus came a new desire to understand and learn about the world around people and how it works. On his deathbed, he published his work, On the Revolutions of the Heavenly Spheres. This work not only revolutionized science and physics, but also the development of mechanics and later bio-mechanics.

Galileo Galilee, the father of mechanics and part time biomechanic was born 21 years after the death of Copernicus. Galileo spent many years in medical school and often questioned everything his professors taught. He found that the professors could not prove what they taught so he moved onto mathematics where everything had to be proven. Then, at the age of 25, he went to Pisa and taught mathematics. He was a very good lecturer and students would leave their other instructors to hear him speak, so he was forced to resign. He then became a professor at an even more prestigious school in Padua. His spirit and teachings would lead the world once again in the direction of science. Over his years of science, Galileo made a lot of biomechanical aspects known. For example, he discovered that  "animals' masses increase disproportionately to their size, and their bones must consequently also disproportionately increase in girth, adapting to loadbearing rather than mere size. [The bending strength of a tubular structure such as a bone is increased relative to its weight by making it hollow and increasing its diameter. Marine animals can be larger than terrestrial animals because the water's buoyancy [sic] relieves their tissues of weight."

Galileo Galilei was interested in the strength of bones and suggested that bones are hollow because this affords maximum strength with minimum weight. He noted that animals' bone masses increased disproportionately to their size. Consequently, bones must also increase disproportionately in girth rather than mere size. This is because the bending strength of a tubular structure (such as a bone) is much more efficient relative to its weight. Mason suggests that this insight was one of the first grasps of the principles of biological optimization.

In the 16th century, Descartes suggested a philosophic system whereby all living systems, including the human body (but not the soul), are simply machines ruled by the same mechanical laws, an idea that did much to promote and sustain biomechanical study. Giovanni Alfonso Borelli embraced this idea and studied walking, running, jumping, the flight of birds, the swimming of fish, and even the piston action of the heart within a mechanical framework. He could determine the position of the human center of gravity, calculate and measured inspired and expired air volumes, and showed that inspiration is muscle-driven and expiration is due to tissue elasticity. Borelli was the first to understand that the levers of the musculoskeletal system magnify motion rather than force, so that muscles must produce much larger forces than those resisting the motion. Influenced by the work of Galileo, whom he personally knew, he had an intuitive understanding of static equilibrium in various joints of the human body well before Newton published the laws of motion.

Industrial era

The next major bio-mechanic, Giovanni Alfonso Borelli, was the first to understand that “the levers of the musculature system magnify motion rather than force, so that muscles must produce much larger forces than those resisting the motion”. Using the works of Galileo and building off from them, Borelli figured out the forces required for equilibrium in various joints of the human body. He even discovered the human center of gravity and air volume as well as  muscle elasticity. His work is often considered the most important in the history of bio-mechanics because he made so many new discoveries that opened the way for the future generations to continue his work and studies.
It was many years after Borelli before the field of bio-mechanics made any major leaps. After that time, more and more scientists took to learning about the human body and its functions. There are not many notable scientists from the 19th or 20th century in bio-mechanics because the field is far too vast now to attribute one thing to one person. However, the field is continuing to grow every year and continues to make advances in discovering more about the human body. Because the field became so popular, many institutions and labs have opened over the last century and people continue doing research. With the Creation of the American Society of Bio-mechanics in 1977, the field continues to grow and make many new discoveries.

In the 19th century Étienne-Jules Marey used cinematography to scientifically investigate locomotion. He opened the field of modern 'motion analysis' by being the first to correlate ground reaction forces with movement. In Germany, the brothers Ernst Heinrich Weber and Wilhelm Eduard Weber hypothesized a great deal about human gait, but it was Christian Wilhelm Braune who significantly advanced the science using recent advances in engineering mechanics. During the same period, the engineering mechanics of materials began to flourish in France and Germany under the demands of the industrial revolution. This led to the rebirth of bone biomechanics when the railroad engineer Karl Culmann and the anatomist Hermann von Meyer compared the stress patterns in a human femur with those in a similarly shaped crane. Inspired by this finding Julius Wolff proposed the famous Wolff's law of bone remodeling.

Applications

The study of biomechanics ranges from the inner workings of a cell to the movement and development of limbs, to the mechanical properties of soft tissue, and bones. Some simple examples of biomechanics research include the investigation of the forces that act on limbs, the aerodynamics of bird and insect flight, the hydrodynamics of swimming in fish, and locomotion in general across all forms of life, from individual cells to whole organisms. With growing understanding of the physiological behavior of living tissues, researchers are able to advance the field of tissue engineering, as well as develop improved treatments for a wide array of pathologies.

Biomechanics is also applied to studying human musculoskeletal systems. Such research utilizes force platforms to study human ground reaction forces and infrared videography to capture the trajectories of markers attached to the human body to study human 3D motion. Research also applies electromyography to study muscle activation, investigating muscle responses to external forces and perturbations.

Biomechanics is widely used in orthopedic industry to design orthopedic implants for human joints, dental parts, external fixations and other medical purposes. Biotribology is a very important part of it. It is a study of the performance and function of biomaterials used for orthopedic implants. It plays a vital role to improve the design and produce successful biomaterials for medical and clinical purposes. One such example is in tissue engineered cartilage.