Stress Fractures

Social adversity shapes humans’ immune systems—and probably their susceptibility to disease—by altering the expression of large groups of genes.

By | January 1, 2015

© ISTOCKPHOTO.COM/FIREHORSE

In 2005, Steve Cole began to peer inside the cells of lonely people, training his sights on the activity of their genomes. Cole, a psychologist turned molecular biologist at the University of California, Los Angeles, was interested in how psychological stressors such as chronic social isolation could be bad for our health, increasing our susceptibility to certain diseases. Research had already implicated stress hormones, which are produced at higher-than-average levels in people who feel lonely for long stretches. But Cole wanted to know what was going in the genes, and not just one or two. He suspected that the expression of large collections of genes might be disrupted in people who consistently reported feeling isolated. “I had an abiding mistrust of one-gene answers because genes generally work in coordinated networks in cells,” he says.

Cole teamed up with University of Chicago social psychologist John Cacioppo, who had already been tracking 166 healthy middle-aged adults for three years, periodically asking them how socially isolated they felt and gathering all manner of biomedical, psychological, social, and economic data. Cole and Cacioppo took blood samples from 153 of the study subjects and focused on the eight most socially secure people and the six loneliest, who had scored highest on the UCLA Loneliness Scale for the past three years. When Cole ran these 14 subjects’ white blood cells through a microarray analysis, he spotted more than 200 genes that were expressed differently between the two groups. Many of the genes dialed up in lonely individuals were involved in inflammation, while the downregulated genes tended to be associated with antiviral response, antibody production, and restraint of inflammatory responses.1

It was a tiny sample, but the implications of the study, published in 2007, were great: loneliness, it seems, shapes one’s health by controlling the “dimmer switch” for whole networks of immune-related genes. Indeed, this overexpression of proinflammatory genes and suppression of anti-inflammatory and antiviral genes might explain why lonely people are more likely to succumb to a variety of diseases, and why HIV ravages socially isolated people more quickly than their more connected peers. “It was gratifying to see the story [of how loneliness affects health] move beyond the genotype to include the functional aspect of the genome,” says Cacioppo.

Cole and others have since produced evidence for similar gene-expression shifts in people experiencing various types of social stress, from facing the death of a loved one or intentional rejection by close friends to low socioeconomic status and physical abuse during childhood. Across such diverse experiences, Cole spotted the same pattern. “You see the same general increase in inflammatory gene expression and decrease in antiviral gene expression,” he says. “It’s pretty consistent.”

Social stress seems to reach deep into cellular control centers to shape key aspects of the immune system—and, as a result, can impair one’s ability to avoid or fight off disease and psychiatric disorders. Now researchers are trying to pin down the molecular mechanisms by which psychological stress is translated into gene-expression changes, and to develop a more precise understanding of the conditions under which stress-mediated gene regulation affects health.

“The emphasis so far has been on demonstrating that the relationship [between stress and disease] exists,” says Jenny Tung of Duke University who studies gene-behavior interactions in nonhuman primates. “Now it’s about understanding which pathways are important and what kinds of social adversity have the greatest effect in which types of people.”

Worried sick

Forty years ago, few scientists accepted the idea that psychological states could affect physiology and potentially influence disease. Then a string of studies in the 1980s revealed that the nervous and immune systems are in communication, and that their conversations can impact health. In 1984, for example, researchers found that the innate immune system’s virus- and tumor-fighting natural killer cells were less active in medical students during exam time.2 In addition, large epidemiological studies revealed that chronic social stressors correspond with marked disparities in death rates and susceptibility to disease. Among British civil servants, for instance, employment grade—a proxy for socioeconomic status—correlated with big differences in mortality from coronary heart disease, despite universal access to health care.3

More recent studies of British civil servants have demonstrated that chronic work stress increases susceptibility to heart disease, type 2 diabetes, depression, and more. These days it’s widely accepted that stress does influence disease risk. Figuring out the mechanisms underlying this link, however, has been tricky: How do feelings induced by our social environment feed into our physiology and, ultimately, our health?

Researchers have demonstrated that the brain responds to psychological stress in the same way that it reacts to physical threats: by activating the hypothalamic-pituitary-adrenal (HPA) axis and “fight or flight” responses via the sympathetic nervous system (SNS). These two pathways control the release of stress hormones, such as cortisol, which help regulate inflammation. But scientists are also now starting to understand the effects of stress at a deeper level—that of individual genes and networks of genes that work in concert. “There is a sense that something has to be going on at the level of genome regulation,” says Tung. “But insight has come pretty recently in terms of how long we’ve been trying to solve the puzzle.”

Since Cole and Cacioppo’s 2007 study, the evidence for a correlation between social stress and widespread proinflammatory gene expression has been stacking up. In 2011, the two researchers replicated their loneliness results in an expanded study of 93 people, detailing the types of white blood cells, or leukocytes, that exhibited the most pronounced differences in gene expression.4 Meanwhile, collaborating with Northwestern University psychologist Greg Miller, Cole demonstrated similar transcriptional signatures in people caring for family members with brain cancer and people experiencing long-term interpersonal troubles. 5,6

The altered expression of immune-related genes resulting from social adversity can linger much longer than the adversity itself. Cole and Miller have discovered, for instance, that healthy adults who experienced low socioeconomic status during childhood carried the same skewed expression profile, while participants who had grown up in higher-income homes had normal levels of expression.7 The disparities were independent of the subjects’ current socioeconomic status, lifestyle, or perceived stress.

Cole proposes that this pattern of upregulated proinflammatory genes and downregulated anti-inflammatory and antiviral genes represents a conserved transcriptional response to adversity—a phenomenon that likely evolved as an adaptive response to accelerate wound healing and to limit bacterial infection in the face of myriad physical threats. In the modern developed world, however, where people tend to live comfortably indoors, chronic inflammation in response to social stress is unnecessary. Worse, it appears to contribute to a long list of maladies.

There is a sense that something has to be going on at the level of genome regulation. But insight has come pretty recently in terms of how long we’ve been trying to solve the puzzle.—Jenny Tung, Duke University

Greg Gibson, director of the Center for Integrative Genomics at Georgia Tech in Atlanta, says this sort of work is important. While most genomics researchers focus on identifying single genes involved in disease risk, he points out, Cole and others are “trying to understand the bigger picture in terms of how whole suites of genes are coordinately regulated . . . and how all sorts of environmental and behavioral factors are involved.”

Studying humans, though, it’s difficult to establish a direct causal connection. For starters, it’s not possible to experimentally manipulate social stress in people over long time spans. Moreover, human lives are so complex that it’s extremely hard to rule out confounding factors, such as diet and exercise or access to health care, particularly with the relatively small sample sizes used so far.

A handful of animal studies have yielded results that support the idea that stress can influence widespread gene expression. Turning to captive rhesus macaques, for example, Tung—along with her postdoc advisor Yoav Gilad of the University of Chicago and other colleagues—found that when mid-ranking females were randomly assigned to a low rank in a new group, their white blood cells dialed up inflammatory genes. Even more strikingly, gene-expression data alone were sufficient to predict dominance rank with 80 percent accuracy.8 “That gestures toward causality,” says Tung.

Feelings to physiology

STRESS IN THE BODY: See full infographic: JPG | PDF© SCOTT LEIGHTONTo understand how stress is translated into gene-expression changes, Cole and his colleagues performed bioinformatics analyses to identify transcription factors that act on the promoter regions of genes dialed up or down in circulating leukocytes of stressed people, monkeys, and mice. Their results suggested that transcriptional shifts in some genes are the result of increased activity of NF-κB transcription factors, a family of DNA-binding proteins known to increase inflammatory gene expression. Cortisol released via the HPA axis in response to acute stress puts the body on high alert, stimulating increased glucose production. Cortisol also plays a key role in shutting down the stress response by binding to glucocorticoid receptors, which inhibits NF-κB activity and thereby restrains inflammation. Under chronic stress, however, the glucocorticoid receptor is somehow desensitized, resulting in unrestricted proinflammatory gene expression. (See illustration.)

Meanwhile, the SNS responds to perceived threats by releasing the neurotransmitter norepinephrine directly from nerve fibers and the hormone epinephrine via the adrenal gland. Epinephrine and norepinephrine bind beta-adrenergic receptors, leading to the activation of transcription factors such as the cyclic AMP response element-binding protein (CREB), which upregulates genes encoding proinflammatory cytokines. So stress, it seems, serves up a one-two punch, with signals from the HPA axis failing to restrain inflammation, while messages coming though the SNS ramp it up. In addition, epinephrine and norepinephrine binding of beta-adrenergic receptors inhibits interferon response factor (IRF) transcription factors, thereby suppressing genes involved in antiviral responses.

The beta-adrenergic pathway could also account for more lasting changes in immune-cell growth and development. In a 2013 study, Cole, Miller, and others demonstrated that blood taken from mice and humans exposed to chronic stress contained significantly higher levels of immature proinflammatory monocytes than controls.9 Mediated by norepinephrine released from nerve fibers, social stress appears to alter the process of immune-cell production. Last year, another group observed the same phenomenon in mice and in 29 doctors working in an intensive care unit.10

“The sympathetic nervous system advises blood stem cells to lighten up on making big, smart lymphocytes [that fight viruses and restrain inflammation] and instead tells them to invest in first-line defense cells like monocytes” that ramp up inflammation, says Cole. “So social stress doesn’t just change which genes are active in the existing complement of cells, but has the capacity to change the cellular composition.” These proinflammatory cells can hide out in the spleen and reemerge months and possibly even years later in response to subsequent stressors, potentially explaining how experiences of social adversity early in life can shape one’s inflammatory landscape as an adult.

Other possible mediators of stress-induced gene expression changes are epigenetic processes, such as DNA methylation. “Epigenetic modifications are attractive because we know they can respond to the environment, they can effect downstream gene regulation, and they can be stable over time,” says Tung. “There is a good case to look into it.”

This idea stems from an oft-cited 2004 study showing that maternal neglect in young rodents is correlated with increased DNA methylation of the promoter region of the glucocorticoid receptor gene in the hippocampus, suppressing the receptor’s expression.11 With fewer receptors to bind to, cortisol fails to shut down the stress response, which continues to pump out more cortisol. Thus, this epigenetic modification appears to account for higher baseline cortisol levels and greater secretion in response to subsequent stress.

Last year, Seth Pollack, a psychologist at the University of Wisconsin–Madison, and colleagues found that children who suffered neglect or abuse had increased methylation at several sites on the same gene, compared with children who were not maltreated.12 To date, researchers have charted stress-induced epigenetic modifications in several genes of mice, monkeys, and humans. In Tung’s rhesus macaque study, high- and low-status females had different methylation patterns around the very genes whose expression changed in response to the animals’ social demotion. And in 2012, Northwestern’s Miller teamed up with Michael Kobor, who runs an epigenetics lab at the University of British Columbia in Vancouver, and showed a correlation between early-life poverty and DNA methylation across the genome in the white blood cells of adults.13 Some studies even suggest that stress-induced epigenetic modifications can be passed down to offspring, though that idea is controversial. (See “Echoes of trauma” here.)

But researchers casting around for methylation on more than a handful of genes have come up empty, leading Cole to suggest that epigenetics “doesn’t seem to play a significant role in the dynamics we see in leukocytes.” Even where epigenetic marks do appear, he adds, it’s hard to know how much of an effect they have on gene expression. But Kobor thinks it’s possible that methylation at one or two key sites could indirectly affect the expression of multiple genes. “You could imagine, hypothetically speaking, that methylation of the promoter of a gene that makes a key transcriptional regulator would have effects downstream, potentially regulating the expression of groups of genes.”

Relax and reverse?

Although several studies point to the enduring effects of social stress on gene regulation, molecular evidence is also emerging to suggest that those transcriptional changes are reversible. In a handful of small randomized trials, Cole and his collaborators have demonstrated that it’s possible to reverse stress-related gene expression by taking steps to reduce anxiety. In a 2012 study involving 200 women with early-stage breast cancer, Cole and University of Miami psychologist Michael Antoni found that a 10-week stress-management course reversed anxiety-related upregulation of proinflammatory gene expression. Women who attended a one-day educational seminar, on the other hand, retained the gene expression alterations associated with adversity.14

“You do get detectable changes in transcription profiles over time” as a result of stress management, says Cole, who admits he was surprised to find evidence in subsequent trials that meditation could elicit a similar change in proinflammatory gene expression in the cells of chronically lonely people and people caring for relatives with dementia. Again, the sample sizes are small, but Cole is confident. “From any one study I’d be very queasy,” he says, “but we now have several studies finding similar results.” Tung’s macaque study provides further evidence that gene expression can be mediated by taking steps to reduce stress: when monkeys who had been relegated to lower social ranks were later promoted, their immune–gene expression profiles tracked the upturn in social status.8

Given the evidence that stress affects the activity of genes known to be important in disease risk and progression, researchers are already starting to think about implementing formal strategies to mitigate the ill effects of anxiety. “This is an enormous public health issue,” says Georgia Tech’s Gibson. “What can we do to reverse adverse gene expression profiles that result from social stress?”

Stress management is one option; drugs that block the pathways involved in stress-induced expression shifts are another. The University of Chicago’s Cacioppo, for example, is investigating compounds that could hold off the biological effects of loneliness in conjunction with cognitive behavioral therapy. “I think there could be value in pharmacological interventions, but we have to test them,” says Cacioppo.

And although scientists still need to forge a more precise and nuanced understanding of the conditions under which stress-induced changes in gene regulation are important for disease, Cole doesn’t think it’s too early to start thinking about clinical applications. “There is one crowd who won’t believe it at all until you have a full molecular mechanism; we’re working diligently on that,” says Cole. But in the meantime, “I don’t think you have to foreswear all consideration of how this stuff might be bent to good purposes.” 

Daniel Cossins, a former associate editor of The Scientist, is a freelance writer living in London.

Echoes of trauma

SURVIVORS: Young prisoners at Auschwitz upon the concentration camp’s liberation in January 1945UNITED STATES HOLOCAUST MEMORIAL MUSEUM/WIKIMEDIA COMMONSPeople exposed to severe social stress in early life are more likely to suffer behavioral and psychiatric disorders during adulthood than people who grew up stress-free. That much is well established. More contentious is the idea that those effects can be passed down through the generations.

The most extreme examples come from people with posttraumatic stress disorder (PTSD). The children and grandchildren of people who survived the Nazi death camps, for instance, have a greater-than-average risk of suffering symptoms associated with PTSD. Numerous epidemiological studies have shown that the offspring of people who experienced other forms of early-life stress, such as neglect or abuse, are also more likely to develop behavioral and psychiatric problems, despite not having themselves been exposed to childhood stress.

“It’s something that has been observed for many years, but it has not been explained from a mechanistic perspective,” says Isabelle Mansuy, a neurobiologist at the University of Zurich.

The observed next-generation problems could be the result of genetic predisposition, or of having been raised by traumatized parents. In the past few years, however, researchers have begun to produce experimental evidence in support of another explanation: that stress-induced epigenetic alterations in the genome can be inherited.

Children of people who experienced early-life stress are more likely to develop behavioral and psychiatric problems, despite not having been exposed to childhood stress themselves.

In 2010, for example, Mansuy and colleagues showed that male mouse pups that were repeatedly and unpredictably separated from their mothers showed symptoms of depression later in life, and that their offspring displayed the same behavioral traits despite having been reared normally. Examining the genomes of the mice, the researchers found that repeated maternal separation altered DNA methylation in the promoter region of several genes associated with social behavior in the germline of stressed males. They then identified similar methylation profiles in the brains of those males’ offspring, suggesting that the epigenetic effects of stress are transmitted to offspring via sperm.1

Many researchers aren’t buying it, though. Critics insist that the process of epigenetic reprogramming that takes place in sperm and eggs wipes the slate clean of any epigenetic marks. But Mansuy says it’s possible for some marks to survive. “Yes, there is massive reprogramming [in gametes], but no one ever showed that the entire genome is reprogrammed.” Indeed, in 2013, Jamie Hackett and colleagues at the University of Cambridge in the U.K. demonstrated that a small number of methylated genes escape multiple rounds of reprogramming in the primordial germ cells of mice.2 Still, Mansuy says, “we don’t know exactly how [epigenetic inheritance] works, and clearly there is still a lot to be discovered.”

A 2014 study from Mansuy’s lab pointed to the possibility that changes in gene expression induced by exposure to early-life traumatic stress might be mediated by noncoding microRNAs (miRNAs). Newborn male mice exposed to chronic stress showed depressive-like behaviors, and altered levels of miRNAs in the blood; in the hypothalamus and hippocampus, two regions of the brain involved in the stress response; and in sperm, which carry thousands of different RNAs. The offspring of these mice displayed comparable behaviors and had similar changes in the levels of miRNAs in the brain and the blood, despite not having experienced trauma themselves. To nail down a causal connection, Mansuy and colleagues injected all RNAs extracted from the sperm of traumatized males into fertilized eggs from wild-type females. Sure enough, when the resulting pups grew up, they displayed the same depressive behavioral traits as the mice subjected to trauma.3 “It’s the first evidence that traumatic stress can alter noncoding RNAs, and that these RNAs can act as mediators of the expression and transmission of the phenotypes,” says Mansuy.

The researchers don’t know how trauma alters miRNAs in sperm, though Mansuy suspects there may be components in the blood that somehow modulate epigenetic factors in testes or sperm cells that dial up the production of miRNAs in the resulting offspring.

Recent work in humans also hints at the epigenetic inheritance of trauma. In August 2014, a team led by Rachel Yehuda at Mount Sinai School of Medicine in New York City investigated 80 adults with at least one parent who had survived the Holocaust and suffered PTSD. The researchers found that in children with a father who survived the Holocaust and a mother who did not suffer traumatic experiences, the promoter region of a gene that encodes a glucocorticoid receptor—which binds cortisol to control stress response—had higher levels of methylation than controls. If both parents were survivors, their offspring had lower-than-control methylation in this promoter region.4

And in another study published last year, scientists from the University of Geneva and colleagues in Rwanda compared the children of 25 Tutsi women who experienced the 1994 genocide firsthand during pregnancy and 25 Tutsi women who were pregnant during the same period but did not witness the violence. The researchers found that children born to women who had experienced the brutality, just like their moms, had lower cortisol levels than controls, and higher levels of methylation on a gene known to play a role in regulating the stress hormone.5

“This is a relatively new field, and there is a great deal still to learn about germline epigenetic changes,” says John Krystal, a neurobiologist at Yale University and editor of Biological Psychiatry. Ultimately, though, “it may be helpful in guiding the development of pharmacologic or behavioral therapies aimed at . . . preventing relatively small adjustment issues in young people from developing into more serious or long-standing threats to mental and physical health.”

“The clinical relevance won’t be immediate,” says Mansuy, “but [for now] I think it’s important for psychiatrists to take into account that patients may have inherited nongenetic marks that may make them more susceptible to psychiatric problems.”

  1. T.B. Franklin et al., “Epigenetic transmission of the impact of early stress across generations,” Biol Psychiatry, 68:408-15, 2010.
  2. J.A. Hackett et al., “Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine,” Science, 339:448-52, 2012.
  3. K. Gapp et al., “Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice,” Nat Neurosci, 17:667-69, 2014.
  4. R. Yehuda et al., “Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring,” Am J Psychiatry, 171:872-80, 2014.
  5. N. Perroud et al., “The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis,” World J Biol Psychia, 15:334-45, 2014.

References

  1. S.W. Cole et al., “Social regulation of gene expression in human leukocytes,” Genome Biol, 8:R189, 2007.
  2. J.K. Kiecolt-Glaser et al., “Psychosocial modifiers of immunocompetence in medical students,” Psychosom Med, 46:7-14, 1984.
  3. M.G. Marmot et al., “Inequalities in death: specific explanations of a general pattern,” Lancet, 1:1003-06, 1984.
  4. S.W. Cole et al., “Transcript origin analysis identifies antigen-presenting cells as primary targets of socially regulated gene expression in leukocytes,” PNAS, 108:3080-85, 2011.
  5. G.E. Miller et al., “A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-κB signaling,” Biol Psychiatry, 64:266-72, 2008.
  6. G.E. Miller et al., “Chronic interpersonal stress predicts activation of pro- and anti-inflammatory signaling pathways 6 months later,” Psychosom Med, 71:57-62, 2009
  7. G.E Miller et al., “Low early-life social class leaves a biological residue manifested by decreased glucocorticoid and increased proinflammatory signaling,” PNAS, 106:14716-21, 2009.
  8. J. Tung et al., “Social environment is associated with gene regulatory variation in the rhesus macaque immune system,” PNAS, 109:6490-95, 2012.
  9. N.D. Powell et al., “Social stress upregulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis,” PNAS, 110:16574-79, 2013.
  10. T. Heidt et al., “Chronic variable stress activates hematopoietic stem cells,” Nat Med, 20:754-58, 2014.
  11. I.C.G. Weaver et al, “Epigenetic programming by maternal behavior,” Nat Neurosci, 7:847-54, 2004.
  12. S.E. Romens et al., “Associations between early life stress and gene methylation in children,” Child Dev, doi:10/1111/cdev.12270, 2014.
  13. L.L. Lam et al., “Factors underlying variable DNA methylation in a human community cohort,” PNAS, 109:17253-60, 2012.
  14. M.H. Antoni, “Cognitive-behavioral stress management reverses anxiety-related leukocyte transcriptional dynamics,” Biol Psychiatry, 71:366-72, 2012.

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Avatar of: James V. Kohl

James V. Kohl

Posts: 419

January 5, 2015

Nutrient stress and social stress appear to be epigenetically linked to RNA-mediated amino acid substitutions and cell type differentiation via the same interactive neuronal pathways that link gonadotropin releasing hormone to hormone-organized and hormone-activated behaviors in all vertebrates.

The effect of histone deacetylase inhibitors on the behavioral responses to social defeat in Syrian hamsters

See also: Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults

Avatar of: Jcbioteck

Jcbioteck

Posts: 1

January 5, 2015

Great insights into the influence of social experience on behavior. Just imagine if the causal relationships uncovered by these researchers, in their focused investigations, apply to humanity as a whole, it provides us with an opportunity to not only understand why some people suffer more than others, but opens up new areas of inquiry into ways to affect gene methylation patterns and miRNA expression to provide humanity with the greatest opportunity to evolve past our conditioning. For me the question of how do we create social experiences that affect the human genome in ways to produce human beings with the greatest capacity for compassion, creativiety, and collaborative genius.  

Avatar of: EvMedDr

EvMedDr

Posts: 14

January 6, 2015

The effects of physiologic stress, both acute and transgenerational are an important and timely subject, given 'insults' of U.S. Socioeconomics and Climate Change. It is unfortunate that the article did not go into the inter- and transgenerational  epigenetics of stress in more detail. In a recently-published paper from our laboratory (Rehan VK, Liu J, Naeem E, Tian J, Sakurai R, Kwong K, Akbari O, Torday JS.Perinatal nicotine exposure induces asthma in second generation offspring. BMC Med. 2012 Oct 30;10:129.) on the transgeneratonal effects of maternal smoking on childhood asthma, we unequivocally demonstrated an effect on epigenetic marks in the gonads of the offspring that would account for the inheritance of enviromental agents.

Avatar of: EvMedDr

EvMedDr

Posts: 14

Replied to a comment from Jcbioteck made on January 5, 2015

January 6, 2015

Based on my own research into the how and why of evolution, by understanding our biologic history, both short-term ontogeny and long-term phylogeny, at the cellular-molecular level offers an understanding of where we've come from. This is a corollary to Santayana's 'Those who cannot learn from history are doomed to repeat it'. That insight is critically important in maximizing human potential for compassion, creativity and collaborative genius. Evolution is not competition as Darwin portrayed it, that's merely the consequence of what lies beneath and was unknown to him. But we now know better. We just have to utilize information more effectively as knowledge. We tend to think that Information is knowledge, but that's incorrect.

Avatar of: James V. Kohl

James V. Kohl

Posts: 419

Replied to a comment from EvMedDr made on January 6, 2015

January 8, 2015

Re: "We tend to think that Information is knowledge..."


Not if WE know anything about physics, chemistry, and the conserved molecular mechanisms of nutrient-dependent pheromone-controlled ecological adaptations.  See: Life is physics and chemistry and communication

Information is useless to life unless it can be communicated in the context of physics, chemistry, and molecular biology.

 

Avatar of: isra91

isra91

Posts: 1

January 15, 2015

One of the greatest articles I have ever read. It says so many things I have never known how to express or interpret them. 

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