Psychosocial Stress, Inflammation, and Adhesion Molecules

I have been re-reading a book by Joseph LeDoux (NYU), Synaptic Self: How Our Brains Become Who We Are (2002), in which he argues that synapses in the brain are the foundation of personality, the basis of our sense of self:

My notion of personality is pretty simple: it‟s that your “self,” the essence of who you are, reflects patterns of interconnectivity between neurons in your brain. Connections between neurons, known as synapses, are the main channels of information flow and storage in the brain. Most of what the brain does is accomplished by synaptic transmission between neurons, and by calling upon the information encoded by past transmission across synapses. (p. 3-4)

This is relevant to some of the work I have been doing for Dr. Cress at the University of Arizona Cancer Center. Dr. Cress has been working for many years on the function of integrins in cancer metastasis, specifically in prostate cancer.

Here is how integrins are defined at Wikipedia, which is as precise as any you will find.

Integrins are transmembrane receptors that are the bridges for cell-cell and cell-extracellular matrix (ECM) interactions. When triggered, integrins in turn trigger chemical pathways to the interior (signal transduction), such as the chemical composition and mechanical status of the ECM, which results in a response (activation of transcription) such as regulation of the cell cycle, cell shape, and/or motility; or new receptors being added to the cell membrane. This allows rapid and flexible responses to events at the cell surface, for example to signal platelets to initiate an interaction with coagulation factors.

There are several types of integrins, and a cell may have several types on its surface. Integrins are found in all metazoa.^[3]

Integrins work alongside other receptors such as cadherins, the immunoglobulin superfamily cell adhesion molecules, selectins and syndecans to mediate cell–cell and cell–matrix interaction. Ligands for integrins include fibronectin, vitronectin, collagen, and laminin.

Integrins are heterdimic adhesion receptors, meaning they have two different parts, the α (alpha) and β (beta) subunits. There are at least 18 α and eight β subunits are known in humans and other vertebrates (Takada, Ye, & Simon, 2007).

Dr. Cress has been work with the A6B4 integrin (alpha 6 beta 4) and its role in metastatic prostate cancer. A6 is one of three laminin-binding molecules in humans (the others are A3 and A7), although other researchers suggest there are five laminin-binding integrins, A1, A2, A3, A6, A7 (Alberts, Johnson, & Lewis; 2007; Molecular Biology of the Cell. 5th edition). This graphic explains the functions of the different integrins and their combinations.

Integrins are also expressed in the brain, especially in synapses and in the lamination of axons, which allows information to more quickly and efficiently through the brain (and through neural cells throughout the body). Schwann cells in peripheral nerves interact with axons and extracellular matrix (ECM) as part of their work in ensheathing and myelinating axons and they express B4 (beta 4 integrin) [Feltri, et al, 1994], and specifically A6B4. 

In digging around for additional information on synapses and brain function, I found a related article by LeDoux - this is the abstract (crucial section is in bold):

STRUCTURAL PLASTICITY AND MEMORY
Raphael Lamprecht and Joseph LeDoux

Much evidence indicates that, after learning, memories are created by alterations in glutamate-dependent excitatory synaptic transmission. These modifications are then actively stabilized, over hours or days, by structural changes at postsynaptic sites on dendritic spines. The mechanisms of this structural plasticity are poorly understood, but recent findings are beginning to provide clues. The changes in synaptic transmission are initiated by elevations in intracellular calcium and consequent activation of second messenger signalling pathways in the postsynaptic neuron. These pathways involve intracellular kinases and GTPases, downstream from glutamate receptors, that regulate and coordinate both cytoskeletal and adhesion remodelling, leading to new synaptic connections. Rapid changes in cytoskeletal and adhesion molecules after learning contribute to short-term plasticity and memory, whereas later changes, which depend on de novo protein synthesis as well as the early modifications, seem to be required for the persistence of long-term memory.

Source: Nature Reviews Neuroscience; January 2004; 5(1):45-54. doi:10.1038/nrn1301 

Rho GTPaseas mediate extracellular stimulation-induced actin cytoskeleton rearrangements. Stimulation of the postsynaptic neuron leads to actin-dependent morphological changes mediated by Rho GTPases105–108. 1) Activation of adhesion molecules, such as integrin or cadherin, which have been shown to be involved in synaptic plasticity, regulates Rho GTPase inactivation by RhoGAPs. 2) Calcium influx through membrane channels can induce activation of tyrosine kinases (TKs), such as the cell adhesion kinase-β/proline-rich tyrosine kinase 2 (CAKβ/Pyk2), that in turn activate Src. The later modulates p190 RhoGAP activity and thereby controls Rho GTPase inactivation. 3) On the other hand, Rho GTPase activators, RhoGEFs, are also regulated by extracellular stimulation. Ephrin A activates, through the receptor tyrosine kinase EphA, a Rho GEF called ephexin. EphA has been implicated in memory formation133. 4) Rho GTPase controls actin polymerization through downstream effectors such as Rho-associated kinase (ROCK). ROCK activates LIM-domain-containing protein kinase (LIMK), which in turn inhibits the actin depolymerizing factor cofilin. This event can contribute to actin polymerization. ROCK, LIMK and cofilin have been shown to be involved in synaptic plasticity. 5) Cdc42 and Rac, other members of the Rho GTPase family, induce actin polymerization by regulating downstream effectors. GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; N-WASP, neuronal Wiskott-Aldrich syndrome; SCAR, suppressor of cAR.

The text above is the caption for the image. Here is another quote from near the end of the paper, which is minimal and could be the topic of an entire paper:

Adhesion molecules and synaptic plasticity 

The formation of new synaptic contacts is a dynamic process that involves ongoing morphological alterations and modulation of adhesion between the pre- and postsynaptic neurons [115,116]. These processes require coordinated activity between molecules that regulate cytoskeletal rearrangements and morphology, and those that control adhesion between the pre- and postsynaptic membranes.Adhesion molecules, mostly integrins, cadherins, neurexin and the immunoglobulin superfamily, are membrane-bound molecules that have hetero- or homophilic interactions with proteins in the extracellular matrix and synaptic membranes to control the adhesion between the pre- and postsynaptic membranes. Adhesion molecules, which also have an intracellular component, can initiate signalling pathways that couple the dynamics of extracellular connectivity with intracellular events that control morphology. For example, cadherin regulates dendritic spine morphogenesis and function. Blockade of cadherin function leads to elongation of the spine, bifurcation of its head structure and alterations in the distribution of postsynaptic proteins [117]. Moreover, neuronal activity induces the movement of β-catenin (which mediates the interaction of cadherin with the actin cytoskeleton) from dendritic shafts into spines to become associated with cadherin and to influence synaptic size and strength [118]. Adhesion molecules such as cadherin also associate with molecules that regulate cytoskeletal rearrangements, such as proteins that control the Rho GTPase pathway [119].

Adhesion molecules could therefore contribute to the morphological alteration and stabilization of connectivity between neurons, a process that is hypothesized to underlie memory consolidation. Consistent with this hypothesis is the role of adhesion molecules in the formation and stabilization of LTP and LTM. Integrin-mediated adhesion helps to stabilize early-phase LTP (E-LTP) into late-phase LTP (L-LTP). For example, inhibition of integrin with a peptide that contains the integrin recognition sequence 10 min before, immediately after and 10 min after LTP induction caused a gradual decay of synaptic strength over 40 min [120]. The peptide had no effect when applied 25 min after LTP initiation, indicating that integrin has a role in stabilization of synaptic connectivity. Furthermore, N-cadherin is synthesized and internalized to new assembled synapses during the induction of L-LTP, and blocking N-cadherin adhesion prevents the induction of L-LTP but not E-LTP [121]. This event depends on glutamate receptor activity. In chicks, memory is impaired 24 h after a visual categorization task when antibodies against the cell adhesion molecule L1 are injected before, 5.5 h or 15–18 h after training (but not later) [122]. In addition, intraventricular injection of antibodies against neural cell adhesion molecule (NCAM) in rats 6–8 h after passive avoidance training, but not later, impaired retention of the avoidance response [123]. These observations indicate that adhesion molecules are essential for memory consolidation during a period of hours after acquisition.

The level and distribution of adhesion molecules is also correlated with synaptic plasticity and learning. In Aplysia, repeated application of 5-hydroxytryptamine (serotonin; 5-HT), which leads to long-term facilitation of the sensory–motor connection, induces the internalization of the adhesion molecule apCAM (Aplysia cell adhesion molecule) [43]. This could destabilize the interaction between sensory neurons, permitting the growth of new sensory axons.ApCAM could be redistributed to the area where new synapses are formed. In rats, N-cadherin is induced in the piriform cortex and hypothalamus 2 h after fear conditioning [124]. N-cadherin was not induced in control animals that were presented with the conditioned stimulus and unconditioned stimulus in a non-associative manner.

On the whole, these observations indicate that adhesion molecules have a central role in mediating neuronal connectivity and morphogenesis, and in the progressive stabilization of synaptic connectivity that leads to memory consolidation. (LeDoux, 2004, pages 50-51)

I did some more digging and found that A3, A5, A8, and B1 (McGeachie, Cingolani, & Godaare, 2011) are all expressed in synaptic formation and function and in the growth and activity of dendrites. If the alpha versions of the integrins are not functioning properly, learning and memory are inhibited, but there are differences for each of the alpha integrins and for the beta integrin:

Interestingly, behavioural tests revealed specific deficits in hippocampal-dependent working memory, while spatial memory was unaffected. Although ITGβ1 is likely to be the major subunit for ITGα3, ITGα5 and ITGα8 in the hippocampus (Hynes, 2002), ITGα3/+;ITGα5/+;ITGα8/+ mice showed behavioural deficits (see above) that are different from those of ITGβ1 conditional knockout mice. Such divergent results may reflect the differences arising from global reduction in ITGα3, ITGα5 and ITGα8 versus a more specific ablation of ITGβ1 mainly in CA1 pyramidal neurons.

[In the quote above, ITGα3, and so on, is used to represent integrin (ITG) alpha 3.] 

Inflammation from Psychosocial Stress

We know that psychosocial stress causes inflammation. University of Arizona researcher/professor Charles Raison (2006) found that depressed patients have higher levels of proinflammatory cytokines, acute phase proteins, chemokines, and cellular adhesion molecules (an important finding for my thesis). It has also been shown that therapeutic administration of the cytokine interferon-α (a cancer treatment drug that inhibits tumor cell growth) leads to depression in up to 50% of patients (Bonaccorso, et al, 2002).

Stress appears to down-regulate immunity through at least three mechanisms:

(A) Stress hormones are influenced by negative events and negative emotions: catecholamines (adrenaline and noradrenaline), adrenocorticotropic hormone (ACTH), cortisol, growth hormone, and prolactin, as examples

(B) Immune modulation by these hormones proceeds through two pathways: 

1. Directly, through binding of the hormone to its cognate receptor at the surface of a cell 
2. Indirectly — for example, by inducing dysregulation of the production of cytokines, such as interferon-γ (IFN-γ), interleukin-1 (IL-1),IL-2,IL-6 and tumour-necrosis factor (TNF)

Cytokines such as IFN-γ have many functions and affect different target cells. Therefore, there are secondary effects of many stress hormones on the immune response

(C) Communication between the CNS and the immune system is bidirectional - examples: 

1. IL-1 influences the production of corticotropin-releasing hormone (CRH) by the hypothalamus. In turn, CRH can affect the HPA axis and thereby trigger increases in stress hormone levels, which results in dysregulation of immune function 
2. Lymphocytes can synthesize hormones such as ACTH, prolactin and growth hormone

Glaser, R., & Kiecolt-Glaser, J. K. (2005). Stress-induced immune dysfunction: implications for health. Nature Reviews Immunology, 5(3), 243-251.

Here is the abstract (edited for relevance) from an excellent review article: Psychosocial stress and inflammation in cancer by Powell, Tarr, and Sheridan (2013) that provides some useful information about how stress (i.e., trauma) can compromise the immune system. [Bold area is my emphasis.]

Stress-induced immune dysregulation results in significant health consequences for immune related disorders including viral infections, chronic autoimmune disease, and tumor growth and metastasis.  Both human and animal studies have shown the sympathetic and neuroendocrine responses to psychosocial stress significantly impacts cancer, in part, through regulation of inflammatory mediators. Psychosocial stressors stimulate neuroendocrine, sympathetic, and immune responses that result in the activation of the hypothalamic–pituitary–adrenal (HPA)-axis, sympathetic nervous system (SNS), and the subsequent regulation of inflammatory responses by immune cells. Social disruption (SDR) stress, a murine model of psychosocial stress and repeated social defeat, provides a novel and powerful tool to probe the mechanisms leading to stress-induced alterations in inflammation, tumor growth, progression, and metastasis.

The following is from the first section of the same paper and it provides an overview of the chemical pathways involved in stress-induced inflammation.

[S]tudies using a mouse model of repeated social defeat, termed social disruption (SDR) stress, have shown that stress alone can trigger the generation, egress, and trafficking of immature, inflammatory myeloid derived-cells that are glucocorticoid (GC) insensitive (Curry et al., 2010, Engler et al., 2004a and Engler et al., 2005). In addition, these GC insensitive cells produce high levels of IL-6 and other inflammatory cytokines and chemokines (Powell et al., 2009, Stark et al., 2002 and Wohleb et al., 2011). As a consequence, these stress-induced changes at the cellular level translate to significant immune (enhanced inflammatory responses and immunity to microbial, viral, and allergen challenge) and behavioral (prolonged anxiety-like behavior) changes (Bailey et al., 2007, Bailey et al., 2009b, Bailey et al., 2009a, Dong-Newsom et al., 2010, Kinsey et al., 2007, Mays et al., 2010, Mays et al., 2012, Powell et al., 2011 and Wohleb et al., 2011). Indicative of the important role of the SNS in stress-induced immune alteration, these changes are reversed by the blockade of sympathetic signaling prior to stressor exposure (Wohleb et al., 2011).

The stress response in vertebrates stems from internal or external stimuli that trigger the “fight or flight” and "defeat/withdrawal" responses expressed in sympathetic nervous system (SNS) and the hypothalamic–pituitary–adrenal (HPA)-axis activation. Years of research has shown that specific central nervous system (CNS) pathways function as translators of social stimuli into peripheral biological signals that regulate inflammatory responses.

For instance, stress activates neuroendocrine and autonomic pathways like the HPA axis, and the SNS resulting in the release of GC, catecholamines, and pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α. The release of these sympathetic, neuroendocrine, and immune factors has a profound influence on immunity, behavior, and physiology in both humans and rodents and triggers peripheral biological responses that, in turn, signal back to the CNS to complete a bi-directional communication circuit. This is evident in models of repeated social defeat, like SDR, that enhance immune responses to microbial, viral, and allergic challenges and promote and prolong anxiety-like behavior in rodents (Kinsey et al., 2007, Bailey et al., 2009a, Bailey et al., 2009b and Mays et al., 2010). Social disruption stress-induced prolonged anxiety-like behavior coincides with a unique pattern of c-Fos activation in brain regions associated with fear and threat appraisal. For example, repeated social defeat, termed social disruption (SDR) causes increased c-Fos activation in the prefrontal cortex, amygdala, hippocampus, paraventricular nucleus, bed nucleus of the stria terminalis and the lateral septum (Wohleb et al., 2011). [Powell, Tarr, and Sheridan, 2013, p. 3]

When the HPA and SNS circuitry are activated, the release of neurotransmitters and stress hormones generates compensatory physiologic changes that impact behavior and the function of the immune system. In humans, chronic or repeated exposure to stress appears to lead to increases in the expression of inflammatory biomarkers, worsened disease states, and affective/emotional disorders (Glaser and Kiecolt-Glaser, 2005; Gouin et al., 2012).

In several studies, stressed individuals exhibit reduced anti-inflammatory glucocorticoid regulation and increased inflammatory nuclear factor (NF)-κB signaling (Miller et al., 2008). In these situations, psychosocial stress represents a challenge to homeostasis that manifests as physiological alterations in the body (Glaser and Kiecolt-Glaser, 2005).

This may be something to look at in terms of how trauma impacts the brain and body, a microbiological model of traumatic stress, inflammation, and the alteration of adhesion molecules, all of which leads to impaired learning and impaired memory.

As of now, there are no known interventions at the cellular level for altering integrin function. However, the are many ways to control and eliminate inflammation. Among the most well-researched (I could provide citations for these, but it's late, so I might add them later):

1) Curcumin/turmeric
2) Resveratrol
3) Exercise
4) Stress-reduction techniques, such as meditation
5) Avoiding smoking, drinking, and processed foods

We have some control over how our bodies manage and adapt to stress. We are not merely victims of our biology.

William P. Hanage - Microbiome Science Needs a Healthy Dose of Skepticism

I am a huge fan of the new research being done on the microbiome, the small universe of bacteria (intestinal flora) living with us. I have seen convincing evidence of the role played by the microbiome in mental illness (depression, especially), obesity, and compromised immunity (our intestines are, in many ways, the home of the immune system). Because we do not yet fully understand this incredibly diverse ecosystem, many of the studies are correlational, unable to show concrete cause and effect.

But I also agree with this editorial from Nature - we need to resist the urge to jump to conclusions and make assertions based solely on correlation. We know so little about this system that the methods we are currently using seem almost child-like. For example,

Much work relies on analysis of 16S rRNA, an ancient gene that tolerates little variation and so is reliably found across the bacterial kingdom. But this allows only a coarse sorting. For example, microbiomes associated with obesity have been distinguished by different ratios of bacterial phyla, which encompass a staggering range of diversity. If this criterion were used to characterize animal communities, an aviary of 100 birds and 25 snails would be considered identical to an aquarium with 8 fish and 2 squid, because each has four times as many vertebrates as molluscs. Even within a single species, strains often differ greatly in the genes they contain.

Sorting and ratios can tell us very little about the genetic and epigenetic mechanisms at work. It may be decades before we can identify with any certainty what is going on in our guts.

Full Citation:
Hanage, WP. (2014, Aug 21). Microbiology: Microbiome science needs a healthy dose of scepticism. Nature; 512:247–248. doi:10.1038/512247a

Microbiology: Microbiome science needs a healthy dose of skepticism

To guard against hype, those interpreting research on the body's microscopic communities should ask five questions, says William P. Hanage.

William P. Hanage
20 August 2014


Eye of Science/SPL - A scanning electron micrograph of bacteria in human faeces, in which 50% of species originate from the gut.
Explorations of how the microscopic communities that inhabit the human body might contribute to health or disease have moved from obscure to ubiquitous. Over the past five years, studies have linked our microbial settlers to conditions as diverse as autism, cancer and diabetes.

This excitement has infected the public imagination. 'We Are Our Bacteria', proclaimed one headline in The New York Times. Some scientists have asserted that antibiotics are causing a great 'extinction' of the microbiome, with dire consequences for human health [1]. Companies offer personalized analysis of the microbial content of faecal samples, promising consumers enlightening information. Separate analyses from the same person can, however, vary considerably, even from the same stool sample. Faecal transplants have been proposed — some more sensible than others — for conditions ranging from diabetes to Alzheimer's disease. With how-to instructions proliferating online, desperate patients must be warned not to attempt these risky procedures on themselves.

Microbiomics risks being drowned in a tsunami of its own hype. Jonathan Eisen, a microbiologist and blogger at the University of California, Davis, bestows awards for “overselling the microbiome”; he finds no shortage of worthy candidates.

Previous 'omics' fields have faltered after murky work slowed progress [2]. Technological advances that allowed researchers to catalogue proteins, metabolites, genetic variants and gene activity led to a spate of associations between molecular states and health conditions. But painstaking further work dampened early excitement. Most initial connections were found to be spurious or, at best, more complicated than originally believed.

The history of science is replete with examples of exciting new fields that promised a gold rush of medicines and health insights but required scepticism and years of slogging to deliver even partially. As such, the criteria for robust microbiome science are instructive for all researchers. As excitement over the microbiome has filtered beyond academic circles, the potential mischief wrought by misunderstanding encompasses journalists, funding bodies and the public.

Crucial questions
Here are five questions that anyone conducting or evaluating this research should ask to keep from getting carried away by hype.

Can experiments detect differences that matter? Profiling a microbiome could produce a catalogue at the level of phyla, species or genes. Much work relies on analysis of 16S rRNA, an ancient gene that tolerates little variation and so is reliably found across the bacterial kingdom. But this allows only a coarse sorting. For example, microbiomes associated with obesity have been distinguished by different ratios of bacterial phyla, which encompass a staggering range of diversity. If this criterion were used to characterize animal communities, an aviary of 100 birds and 25 snails would be considered identical to an aquarium with 8 fish and 2 squid, because each has four times as many vertebrates as molluscs. Even within a single species, strains often differ greatly in the genes they contain.

Modern technology now allows for finer distinctions: we can study more genes in a sample, an ability that may enable us to decipher 'metabolic networks' revealing the biochemical reactions that a microbiome can perform. This kind of analysis could identify gene combinations, potentially from multiple species across a microbial community, that affect health for good or ill. However, pinning an outcome to any particular entity is likely to be hard unless the networks are already well characterized.

To take a simple example from a single bacterial species, we could show that vaccination eliminated 30% of known pneumococcal strains in a human population — but only because we knew in advance to focus on the genes targeted by the vaccine [3]. Our ability to identify functional differences in closely related genes is rarely sophisticated enough to pull out important genes or networks if we do not know what to look for in the first place. Moreover, genomes are littered with clues both true and false, such as 'hypothetical proteins' and genes that are understood poorly or not at all, but could make for important differences in what metabolic networks do.

We need to be able to identify functional differences in closely related genes from sequence alone. Until then, we must remember that apparent similarities might cloak important differences.

Does the study show causation or just correlation? A separate question is raised when distinct microbiomes can be identified and associated with diseases or other conditions. Then we are left with the chestnut of causes and correlates. Sometimes, a particular microbiome found in association with disease will be merely a bystander [4].

A 2012 article comparing the gut microbiomes of old people living in care homes with those of old people living in the community found distinct microbiomes that correlated with multiple scores of frailty [5]. After accounting for some potentially confounding factors, the authors proposed a causal relationship: diet altered the microbiome, which in turn altered health. This explanation fits the data, but the reverse causality — the potential for poor health to alter the gut microbiome — was not explored. Frailer people probably have less active immune systems and differences in digestion (such as the time required for food to pass through the stomach and intestines) — factors that could change the microbiome. This work is not the only example of this sort of confusion.

What is the mechanism? All scientists are taught the catechism that correlation is not causation, but correlation almost always implies some sort of causal relationship. We just don't know what it is. We must determine it with careful experiments.

In the past three or four years, studies have advanced from characterizing a broad community of mainly unculturable microbes to identifying functional elements, individual taxa or particular properties. We can now design experiments to precisely define actions of components of the microbiome [6], for example by reconstituting communities but leaving out specific taxa, or by precisely measuring the biochemical activity of an experimental microbiome in an 'organ on a chip' [7]. A return to a reductionist approach is essential if we are to pinpoint both whether the microbiome affects human health, and exactly how it does so.

How much do experiments reflect reality? Even if the microbiome can have an experimental effect, it may not be an important cause of the symptoms seen in ill people.

Much work has addressed the role that gut flora have in obesity, and several studies have found associations between the gut microbiome and weight gain [8]. To assess whether this association was cause or consequence, researchers collected gut-microbiome samples from human twins (one obese, one not) and introduced the microbiota to mice. Mice previously colonized with an 'obese' microbiome lost weight when supplied with a 'lean microbiome', but only if also fed a normal or low-fat diet. Diet alone had little effect [9]. Although this elegantly controlled experiment suggests great potential for the microbiome and related therapies to affect health, it also shows the microbiome's limits: the effect was dependent on other factors, in this case diet.

Microbiome studies often rely on germ-free mice. These animals allow researchers to readily introduce an experimental microbiota. But they do not represent the animals' natural state and are typically unhealthy owing to the lack of a microbiome. So results may not predict responses in animals with flourishing microbiomes. Mice and their microbiomes are also adapted to a rather different niche from humans, so results may not be generalizable.

Could anything else explain the results? There are good reasons to think that bacteria influence us in a host of ways. But there are many other — possibly more important — influences, such as diet in the earlier example. Whenever a study links a microbiome to a disease, wise critics should ask whether other contributors to disease are considered, compared and reported.

The hype surrounding microbiome research is dangerous, for individuals who might make ill-informed decisions, and for the scientific enterprise, which needs to develop better experimental methods to generate hypotheses and evaluate conclusions. Funding agencies must not let their priorities be distorted by the buzz around the field, but look dispassionately at the data. Press officers must stop exaggerating results, and journalists must stop swallowing them whole. In pre-scientific times when something happened that people did not understand, they blamed it on spirits. We must resist the urge to transform our microbial passengers into modern-day phantoms.

References

1. Blaser, M. J. Missing Microbes: How the Overuse of Antibiotics is Fueling our Modern Plagues (Henry Holt and Co., 2014).
2. Wilkins, M. R. et al. Proteomics 6, 4–8 (2006). Article  PubMed
3. Croucher, N. J. et al. Nature Genet. 45, 656–663 (2013).  Article   PubMed
4. Shanahan, F. Nutr. Rev. 70 (suppl. 1), S31–S37 (2012).  Article  PubMed
5. Claesson, M. J. et al. Nature 488, 178–184 (2012). Article  PubMed
6. Goodman, A. L. et al. Proc. Natl Acad. Sci. USA 108, 6252–6257 (2011). Article  PubMed
7. Huh, D. et al. Nature Protocols 8, 2135–2157 (2013). Article
8. Ley, R. E. Curr. Opin. Gastroenterol. 26, 5–11 (2010).  Article   PubMed
9. Ridaura, V. K. et al. Science 341, 1241214 (2013).  Article  PubMed

Related stories and links

• Microbiome therapy gains market traction 13 May 2014
• Policy: How to regulate faecal transplants 19 February 2014
• Microbiome sequencing offers hope for diagnostics 23 March 2012
• Gut microbial 'enterotypes' become less clear-cut 21 March 2012

Author information
William P. Hanage is associate professor of epidemiology at the Harvard School of Public Health in Boston, Massachusetts, USA.

Corresponding author: Correspondence to William P. Hanage

 

New research has identified small non-coding RNAs (a kind of microRNA) has a possible mediator in the intergenerational transmission of trauma. Here is how those sncRNAs do their work:

Mansuy and her team have succeeded in identifying a key component of these processes: short RNA molecules. These RNAs are synthetized from genetic information (DNA) by enzymes that read specific sections of the DNA (genes) and use them as template to produce corresponding RNAs. Other enzymes then trim these RNAs into mature forms. Cells naturally contain a large number of different short RNA molecules called microRNAs. They have regulatory functions, such as controlling how many copies of a particular protein are made.

The researchers found that traumatic stress alters the amount of several microRNAs in the blood, brain, and sperm. Some microRNAs were over-produced, others were lower than in the corresponding tissues or cells of control animals. These alterations resulted in misregulation of cellular processes normally controlled by these microRNAs.

After exposure to traumatic experiences, the mice lost their natural aversion to open spaces and bright light and had depressive-like behaviors. These behavioral symptoms were also transferred to the next generation via sperm, even though the offspring were not exposed to any traumatic stress themselves, and then to a third generation as well.

Interestingly, as has been reported in other headlines, the trauma is passed down through the father's sperm, not the mother's egg (as far we know right now). 

Scientists unmask a piece in the puzzle of how the inheritance of traumas is mediated

April 13, 2014



The consequences of traumatic experiences can be passed on from one generation to the next. Credit: Isabelle Mansuy / UZH / ETH Zurich
The phenomenon has long been known in psychology: traumatic experiences can induce behavioural disorders that are passed down from one generation to the next. It is only recently that scientists have begun to understand the physiological processes underlying hereditary trauma. "There are diseases such as bipolar disorder, that run in families but can't be traced back to a particular gene", explains Isabelle Mansuy, professor at ETH Zurich and the University of Zurich. With her research group at the Brain Research Institute of the University of Zurich, she has been studying the molecular processes involved in non-genetic inheritance of behavioural symptoms induced by traumatic experiences in early life.

Mansuy and her team have succeeded in identifying a key component of these processes: short RNA molecules. These RNAs are synthetized from genetic information (DNA) by enzymes that read specific sections of the DNA (genes) and use them as template to produce corresponding RNAs. Other enzymes then trim these RNAs into mature forms. Cells naturally contain a large number of different short RNA molecules called microRNAs. They have regulatory functions, such as controlling how many copies of a particular protein are made.

Small RNAs with a huge impact

The researchers studied the number and kind of microRNAs expressed by adult mice exposed to traumatic conditions in early life and compared them with non-traumatized mice. They discovered that traumatic stress alters the amount of several microRNAs in the blood, brain and sperm – while some microRNAs were produced in excess, others were lower than in the corresponding tissues or cells of control animals. These alterations resulted in misregulation of cellular processes normally controlled by these microRNAs.

After traumatic experiences, the mice behaved markedly differently: they partly lost their natural aversion to open spaces and bright light and had depressive-like behaviours. These behavioural symptoms were also transferred to the next generation via sperm, even though the offspring were not exposed to any traumatic stress themselves.

Even passed on to the third generation

The metabolism of the offspring of stressed mice was also impaired: their insulin and blood-sugar levels were lower than in the offspring of non-traumatized parents. "We were able to demonstrate for the first time that traumatic experiences affect metabolism in the long-term and that these changes are hereditary", says Mansuy. The effects on metabolism and behaviour even persisted in the third generation.

"With the imbalance in microRNAs in sperm, we have discovered a key factor through which trauma can be passed on", explains Mansuy. However, certain questions remain open, such as how the dysregulation in short RNAs comes about. "Most likely, it is part of a chain of events that begins with the body producing too much stress hormones."

Importantly, acquired traits other than those induced by trauma could also be inherited through similar mechanisms, the researcher suspects. "The environment leaves traces on the brain, on organs and also on gametes. Through gametes, these traces can be passed to the next generation."

Mansuy and her team are currently studying the role of short RNAs in trauma inheritance in humans. As they were also able to demonstrate the microRNAs imbalance in the blood of traumatized mice and their offspring, the scientists hope that their results may be useful to develop a blood test for diagnostics.

Explore further: DNA modifications measured in blood signal related changes in the brain

More information: Gapp K, Jawaid A, Sarkies P, Bohacek J, Pelczar P, Prados J, Farinelli L, Miska E, Mansuy IM. (2014, Apr 13). Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nature Neuroscience, DOI: 10.1038/nn.3695

Journal reference: Nature Neuroscience  
Provided by ETH Zurich

* * * * *

Here is the abstract from Nature Neuroscience, the full article is behind a pay-wall.

Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice

Katharina Gapp, Ali Jawaid, Peter Sarkies, Johannes Bohacek, Pawel Pelczar, Julien Prados, Laurent Farinelli, Eric Miska & Isabelle M Mansuy

Small non-coding RNAs (sncRNAs) are potential vectors at the interface between genes and environment. We found that traumatic stress in early life altered mouse microRNA (miRNA) expression, and behavioral and metabolic responses in the progeny. Injection of sperm RNAs from traumatized males into fertilized wild-type oocytes reproduced the behavioral and metabolic alterations in the resulting offspring.

David Dobbs - The Social Life of Genes (on Epigenetics)

This article came out in Pacific Standard back in September of last year, and I likely posted it then. But it turned up in tabs again recently and it still feels like an excellent and important article.

The Social Life of Genes

By David Dobbs • September 03, 2013

Your DNA is not a blueprint. Day by day, week by week, your genes are in a conversation with your surroundings. Your neighbors, your family, your feelings of loneliness: They don’t just get under your skin, they get into the control rooms of your cells. Inside the new social science of genetics.

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A few years ago, Gene Robinson, of Urbana, Illinois, asked some associates in southern Mexico to help him kidnap some 1,000 newborns. For their victims they chose bees. Half were European honeybees, Apis mellifera ligustica, the sweet-tempered kind most beekeepers raise. The other half were ligustica’s genetically close cousins, Apis mellifera scutellata, the African strain better known as killer bees. Though the two subspecies are nearly indistinguishable, the latter defend territory far more aggressively. Kick a European honeybee hive and perhaps a hundred bees will attack you. Kick a killer bee hive and you may suffer a thousand stings or more. Two thousand will kill you.

Working carefully, Robinson’s conspirators—researchers at Mexico’s National Center for Research in Animal Physiology, in the high resort town of Ixtapan de la Sal—jiggled loose the lids from two African hives and two European hives, pulled free a few honeycomb racks, plucked off about 250 of the youngest bees from each hive, and painted marks on the bees’ tiny backs. Then they switched each set of newborns into the hive of the other subspecies.

Robinson, back in his office at the University of Illinois at Urbana-Champaign’s Department of Entomology, did not fret about the bees’ safety. He knew that if you move bees to a new colony in their first day, the colony accepts them as its own. Nevertheless, Robinson did expect the bees would be changed by their adoptive homes: He expected the killer bees to take on the European bees’ moderate ways and the European bees to assume the killer bees’ more violent temperament. Robinson had discovered this in prior experiments. But he hadn’t yet figured out how it happened.

He suspected the answer lay in the bees’ genes. He didn’t expect the bees’ actual DNA to change: Random mutations aside, genes generally don’t change during an organism’s lifetime. Rather, he suspected the bees’ genes would behave differently in their new homes—wildly differently.

This notion was both reasonable and radical. Scientists have known for decades that genes can vary their level of activity, as if controlled by dimmer switches. Most cells in your body contain every one of your 22,000 or so genes. But in any given cell at any given time, only a tiny percentage of those genes is active, sending out chemical messages that affect the activity of the cell. This variable gene activity, called gene expression, is how your body does most of its work.

Sometimes these turns of the dimmer switch correspond to basic biological events, as when you develop tissues in the womb, enter puberty, or stop growing. At other times gene activity cranks up or spins down in response to changes in your environment. Thus certain genes switch on to fight infection or heal your wounds—or, running amok, give you cancer or burn your brain with fever. Changes in gene expression can make you thin, fat, or strikingly different from your supposedly identical twin. When it comes down to it, really, genes don’t make you who you are. Gene expression does. And gene expression varies depending on the life you live.

Every biologist accepts this. That was the safe, reasonable part of Robinson’s notion. Where he went out on a limb was in questioning the conventional wisdom that environment usually causes fairly limited changes in gene expression. It might sharply alter the activity of some genes, as happens in cancer or digestion. But in all but a few special cases, the thinking went, environment generally brightens or dims the activity of only a few genes at a time.

Robinson, however, suspected that environment could spin the dials on “big sectors of genes, right across the genome”—and that an individual’s social environment might exert a particularly powerful effect. Who you hung out with and how they behaved, in short, could dramatically affect which of your genes spoke up and which stayed quiet—and thus change who you were.

Robinson was already seeing this in his bees. The winter before, he had asked a new post-doc, Cédric Alaux, to look at the gene-expression patterns of honeybees that had been repeatedly exposed to a pheromone that signals alarm. (Any honeybee that detects a threat emits this pheromone. It happens to smell like bananas. Thus “it’s not a good idea,” says Alaux, “to eat a banana next to a bee hive.”)

To a bee, the pheromone makes a social statement: Friends, you are in danger. Robinson had long known that bees react to this cry by undergoing behavioral and neural changes: Their brains fire up and they literally fly into action. He also knew that repeated alarms make African bees more and more hostile. When Alaux looked at the gene-expression profiles of the bees exposed again and again to alarm pheromone, he and Robinson saw why: With repeated alarms, hundreds of genes—genes that previous studies had associated with aggression—grew progressively busier. The rise in gene expression neatly matched the rise in the aggressiveness of the bees’ response to threats.

Robinson had not expected that. “The pheromone just lit up the gene expression, and it kept leaving it higher.” The reason soon became apparent: Some of the genes affected were transcription factors—genes that regulate other genes. This created a cascading gene-expression response, with scores of genes responding.

This finding inspired Robinson’s kidnapping-and-cross-fostering study. Would moving baby bees to wildly different social environments reshape the curves of their gene-expression responses? Down in Ixtapan, Robinson’s collaborators suited up every five to 10 days, opened the hives, found about a dozen foster bees in each one, and sucked them up with a special vacuum. The vacuum shot them into a chamber chilled with liquid nitrogen. The intense cold instantly froze the bees’ every cell, preserving the state of their gene activity at that moment. At the end of six weeks, when the researchers had collected about 250 bees representing every stage of bee life, the team packed up the frozen bees and shipped them to Illinois.

There, Robinson’s staff removed the bees’ sesame-seed-size brains, ground them up, and ran them through a DNA microarray machine. This identified which genes were busy in a bee’s brain at the moment it met the bee-vac. When Robinson sorted his data by group—European bees raised in African hives, for instance, or African bees raised normally among their African kin—he could see how each group’s genes reacted to their lives.

Robinson organized the data for each group onto a grid of red and green color-coded squares: Each square represented a different gene, and its color represented the group’s average rate of gene expression. Red squares represented genes that were especially active in most of the bees in that group; the brighter the red, the more bees in which that gene had been busy. Green squares represented genes that were silent or underactive in most of the group. The printout of each group’s results looked like a sort of cubist Christmas card.

When he got the cards, says Robinson, “the results were stunning.” For the bees that had been kidnapped, life in a new home had indeed altered the activity of “whole sectors” of genes. When their gene expression data was viewed on the cards alongside the data for groups of bees raised among their own kin, a mere glance showed the dramatic change. Hundreds of genes had flipped colors. The move between hives didn’t just make the bees act differently. It made their genes work differently, and on a broad scale.

What’s more, the cards for the adopted bees of both species came to ever more resemble, as they moved through life, the cards of the bees they moved in with. With every passing day their genes acted more like those of their new hive mates (and less like those of their genetic siblings back home). Many of the genes that switched on or off are known to affect behavior; several are associated with aggression. The bees also acted differently. Their dispositions changed to match that of their hive mates. It seemed the genome, without changing its code, could transform an animal into something very like a different subspecies.

These bees didn’t just act like different bees. They’d pretty much become different bees. To Robinson, this spoke of a genome far more fluid—far more socially fluid—than previously conceived. 

Gene Robinson, an entomologist at the University of Illinois, found that when European honeybees are raised among more aggressive African killer bees, they not only start to become as belligerent as their new hive mates—they come to genetically resemble them. (PHOTO: COURTESY OF GENE ROBINSON)

ROBINSON SOON REALIZED HE was not alone in seeing this. At conferences and in the literature, he kept bumping into other researchers who saw gene networks responding fast and wide to social life. David Clayton, a neurobiologist also on the University of Illinois campus, found that if a male zebra finch heard another male zebra finch singing nearby, a particular gene in the bird’s forebrain would “re up—and it would do so differently depending on whether the other finch was strange and threatening, or familiar and safe.

Others found this same gene, dubbed ZENK ramping up in other species. In each case, the change in ZENK’s activity corresponded to some change in behavior: a bird might relax in response to a song, or become vigilant and tense. Duke researchers, for instance, found that when female zebra finches listened to male zebra finches’ songs, the females’ ZENK gene triggered massive gene-expression changes in their forebrains—a socially sensitive brain area in birds as well as humans. The changes differed depending on whether the song was a mating call or a territorial claim. And perhaps most remarkably, all of these changes happened incredibly fast—within a half hour, sometimes within just five minutes.

ZENK, it appeared, was a so-called “immediate early gene,” a type of regulatory gene that can cause whole networks of other genes to change activity. These sorts of regulatory gene-expression response had already been identified in physiological systems such as digestion and immunity. Now they also seemed to drive quick responses to social conditions.

One of the most startling early demonstrations of such a response occurred in 2005 in the lab of Stanford biologist Russell Fernald. For years, Fernald had studied the African cichlid Astatotilapia burtoni, a freshwater fish about two inches long and dull pewter in color. By 2005 he had shown that among burtoni, the top male in any small population lives like some fishy pharaoh, getting far more food, territory, and sex than even the No. 2 male. This No. 1 male cichlid also sports a bigger and brighter body. And there is always only one No. 1.

I wonder, Fernald thought, what would happen if we just removed him?

So one day Fernald turned out the lights over one of his cichlid tanks, scooped out big flashy No. 1, and then, 12 hours later, flipped the lights back on. When the No. 2 cichlid saw that he was now No. 1, he responded quickly. He underwent massive surges in gene expression that immediately blinged up his pewter coloring with lurid red and blue streaks and, in a matter of hours, caused him to grow some 20 percent. It was as if Jason Schwartzman, coming to work one day to learn the big office stud had quit, morphed into Arnold Schwarzenegger by close of business.

These studies, says Greg Wray, an evolutionary biologist at Duke who has focused on gene expression for over a decade, caused quite a stir. “You suddenly realize birds are hearing a song and having massive, widespread changes in gene expression in just 15 minutes? Something big is going on.”

This big something, this startlingly quick gene-expression response to the social world, is a phenomenon we are just beginning to understand. The recent explosion of interest in “epigenetics”—a term literally meaning “around the gene,” and referring to anything that changes a gene’s effect without changing the actual DNA sequence—has tended to focus on the long game of gene-environment interactions: how famine among expectant mothers in the Netherlands during World War II, for instance, affected gene expression and behavior in their children; or how mother rats, by licking and grooming their pups more or less assiduously, can alter the wrappings around their offspring’s DNA in ways that influence how anxious the pups will be for the rest of their lives. The idea that experience can echo in our genes across generations is certainly a powerful one. But to focus only on these narrow, long-reaching effects is to miss much of the action where epigenetic influence and gene activity is concerned. This fresh work by Robinson, Fernald, Clayton, and others—encompassing studies of multiple organisms, from bees and birds to monkeys and humans—suggests something more exciting: that our social lives can change our gene expression with a rapidity, breadth, and depth previously overlooked.

Why would we have evolved this way? The most probable answer is that an organism that responds quickly to fast-changing social environments will more likely survive them. That organism won’t have to wait around, as it were, for better genes to evolve on the species level. Immunologists discovered something similar 25 years ago: Adapting to new pathogens the old-fashioned way—waiting for natural selection to favor genes that create resistance to specific pathogens—would happen too slowly to counter the rapidly changing pathogen environment. Instead, the immune system uses networks of genes that can respond quickly and flexibly to new threats.

We appear to respond in the same way to our social environment. Faced with an unpredictable, complex, ever-changing population to whom we must respond successfully, our genes behave accordingly—as if a fast, fluid response is a matter of life or death.

ABOUT THE TIME ROBINSON was seeing fast gene expression changes in bees, in the early 2000s, he and many of his colleagues were taking notice of an up-and-coming UCLA researcher named Steve Cole.

Cole, a Californian then in his early 40s, had trained in psychology at the University of California-Santa Barbara and Stanford; then in social psychology, epidemiology, virology, cancer, and genetics at UCLA. Even as an undergrad, Cole had “this astute, fine-grained approach,” says Susan Andersen, a professor of psychology now at NYU who was one of his teachers at UC Santa Barbara in the late 1980s. “He thinks about things in very precise detail.”

In his post-doctoral work at UCLA, Cole focused on the genetics of immunology and cancer because those fields had pioneered hard-nosed gene-expression research. After that, he became one of the earliest researchers to bring the study of whole-genome gene-expression to social psychology. The gene’s ongoing, real-time response to incoming information, he realized, is where life works many of its changes on us. The idea is both reductive and expansive. We are but cells. At each cell’s center, a tight tangle of DNA writes and hands out the cell’s marching orders. Between that center and the world stand only a series of membranes.

“Porous membranes,” notes Cole.

“We think of our bodies as stable biological structures that live in the world but are fundamentally separate from it. That we are unitary organisms in the world but passing through it. But what we’re learning from the molecular processes that actually keep our bodies running is that we’re far more fluid than we realize, and the world passes through us.”

Cole told me this over dinner. We had met on the UCLA campus and walked south a few blocks, through bright April sun, to an almost empty sushi restaurant. Now, waving his chopsticks over a platter of urchin, squid, and amberjack, he said, “Every day, as our cells die off, we have to replace one to two percent of our molecular being. We’re constantly building and re-engineering new cells. And that regeneration is driven by the contingent nature of gene expression.

“This is what a cell is about. A cell,” he said, clasping some amberjack, “is a machine for turning experience into biology.”

When Cole started his social psychology research in the early 1990s, the microarray technology that spots changes in gene expression was still in its expensive infancy, and saw use primarily in immunology and cancer. So he began by using the tools of epidemiology—essentially the study of how people live their lives. Some of his early papers looked at how social experience affected men with HIV. In a 1996 study of 80 gay men, all of whom had been HIV-positive but healthy nine years earlier, Cole and his colleagues found that closeted men succumbed to the virus much more readily.

He then found that HIV-positive men who were lonely also got sicker sooner, regardless of whether they were closeted. Then he showed that closeted men without HIV got cancer and various infectious diseases at higher rates than openly gay men did. At about the same time, psychologists at Carnegie Mellon finished a well-controlled study showing that people with richer social ties got fewer common colds.

Something about feeling stressed or alone was gumming up the immune system—sometimes fatally.

“You’re besieged by a virus that’s going to kill you,” says Cole, “but the fact that you’re socially stressed and isolated seems to shut down your viral defenses. What’s going on there?”

He was determined to find out. But the research methods on hand at the time could take him only so far: “Epidemiology won’t exactly lie to you. But it’s hard to get it to tell you the whole story.” For a while he tried to figure things out at the bench, with pipettes and slides and assays. “I’d take norepinephrine [a key stress hormone] and squirt it on some infected T-cells and watch the virus grow faster. The norepinephrine was knocking down the antiviral response. That’s great. Virologists love that. But it’s not satisfying as a complete answer, because it doesn’t fully explain what’s happening in the real world.

“You can make almost anything happen in a test tube. I needed something else. I had set up all this theory. I needed a place to test it.”

His next step was to turn to rhesus monkeys, a lab species that allows controlled study. In 2007, he joined John Capitanio, a primatologist at the University of California-Davis, in looking at how social stress affected rhesus monkeys with SIV, or simian immunodeficiency virus, the monkey version of HIV. Capitanio had found that monkeys with SIV fell ill and died faster if they were stressed out by constantly being moved into new groups among strangers—a simian parallel to Cole’s 1996 study on lonely gay men.

Capitanio had run a rough immune analysis that showed the stressed monkeys mounted weak antiviral responses. Cole offered to look deeper. First he tore apart the lymph nodes—“ground central for infection”—and found that in the socially stressed monkeys, the virus bloomed around the sympathetic nerve trunks, which carry stress signals into the lymph node.

“This was a hint,” says Cole: The virus was running amok precisely where the immune response should have been strongest. The stress signals in the nerve trunks, it seemed, were getting either muted en route or ignored on arrival. As Cole looked closer, he found it was the latter: The monkeys’ bodies were generating the appropriate stress signals, but the immune system didn’t seem to be responding to them properly. Why not? He couldn’t find out with the tools he had. He was still looking at cells. He needed to look inside them.

Finally Cole got his chance. At UCLA, where he had been made a professor in 2001, he had been working hard to master gene-expression analysis across an entire genome. Microarray machines—the kind Gene Robinson was using on his bees—were getting cheaper. Cole got access to one and put it to work.

Thus commenced what we might call the lonely people studies.

First, in collaboration with University of Chicago social psychologist John Cacioppo, Cole mined a questionnaire about social connections that Cacioppo had given to 153 healthy Chicagoans in their 50s and 60s. Cacioppo and Cole identified the eight most socially secure people and the six loneliest and drew blood samples from them. (The socially insecure half-dozen were lonely indeed; they reported having felt distant from others for the previous four years.) Then Cole extracted genetic material from the blood’s leukocytes (a key immune-system player) and looked at what their DNA was up to.

He found a broad, weird, strongly patterned gene-expression response that would become mighty familiar over the next few years. Of roughly 22,000 genes in the human genome, the lonely and not-lonely groups showed sharply different gene-expression responses in 209. That meant that about one percent of the genome—a considerable portion—was responding differently depending on whether a person felt alone or connected. Printouts of the subjects’ gene-expression patterns looked much like Robinson’s red-and-green readouts of the changes in his cross-fostered bees: Whole sectors of genes looked markedly different in the lonely and the socially secure. And many of these genes played roles in inflammatory immune responses.

Now Cole was getting somewhere.

Normally, a healthy immune system works by deploying what amounts to a leashed attack dog. It detects a pathogen, then sends inflammatory and other responses to destroy the invader while also activating an anti-inflammatory response—the leash—to keep the inflammation in check. The lonely Chicagoans’ immune systems, however, suggested an attack dog off leash—even though they weren’t sick. Some 78 genes that normally work together to drive inflammation were busier than usual, as if these healthy people were fighting infection. Meanwhile, 131 genes that usually cooperate to control inflammation were underactive. The underactive genes also included key antiviral genes.

This opened a whole new avenue of insight. If social stress reliably created this gene-expression profile, it might explain a lot about why, for instance, the lonely HIV carriers in Cole’s earlier studies fell so much faster to the disease.

But this was a study of just 14 people. Cole needed more.

Over the next several years, he got them. He found similarly unbalanced gene-expression or immune-response profiles in groups including poor children, depressed people with cancer, and people caring for spouses dying of cancer. He topped his efforts off with a study in which social stress levels in young women predicted changes in their gene activity six months later. Cole and his collaborators on that study, psychologists Gregory Miller and Nicolas Rohleder of the University of British Columbia, interviewed 103 healthy Vancouver-area women aged 15 to 19 about their social lives, drew blood, and ran gene-expression profiles, and after half a year drew blood and ran profiles again. Some of the women reported at the time of the initial interview that they were having trouble with their love lives, their families, or their friends. Over the next six months, these socially troubled subjects took on the sort of imbalanced gene-expression profile Cole found in his other isolation studies: busy attack dogs and broken leashes. Except here, in a prospective study, he saw the attack dog breaking free of its restraints: Social stress changed these young women’s gene-expression patterns before his eyes. 

Gene-expression microarray printouts (this one comes from a study of autistic versus non-autistic people) depict snapshots of activity across a genome. Red squares represent genes that are more active, green squares represent genes that are less active. (PHOTO: PUBLIC DOMAIN)

IN EARLY 2009, COLE sat down to make sense of all this in a review paper that he would publish later that year in Current Directions in Psychological Science. Two years later we sat in his spare, rather small office at UCLA and discussed what he’d found. Cole, trimly built but close to six feet tall, speaks in a reedy voice that is slightly higher than his frame might lead you to expect. Sometimes, when he’s grabbing for a new thought or trying to emphasize a point, it jumps a register. He is often asked to give talks about his work, and it’s easy to see why: Relaxed but animated, he speaks in such an organized manner that you can almost see the paragraphs form in the air between you. He spends much of his time on the road. Thus the half-unpacked office, he said, gesturing around him. His lab, down the hall, “is essentially one really good lab manager”—Jesusa M. Arevalo, whom he frequently lists on his papers—“and a bunch of robots,” the machines that run the assays.

“We typically think of stress as being a risk factor for disease,” said Cole. “And it is, somewhat. But if you actually measure stress, using our best available instruments, it can’t hold a candle to social isolation. Social isolation is the best-established, most robust social or psychological risk factor for disease out there. Nothing can compete.”

This helps explain, for instance, why many people who work in high-stress but rewarding jobs don’t seem to suffer ill effects, while others, particularly those isolated and in poverty, wind up accruing lists of stress-related diagnoses—obesity, Type 2 diabetes, hypertension, atherosclerosis, heart failure, stroke.

Despite these well-known effects, Cole said he was amazed when he started finding that social connectivity wrought such powerful effects on gene expression.

“Or not that we found it,” he corrected, “but that we’re seeing it with such consistency. Science is noisy. I would’ve bet my eyeteeth that we’d get a lot of noisy results that are inconsistent from one realm to another. And at the level of individual genes that’s kind of true—there is some noise there.” But the kinds of genes that get dialed up or down in response to social experience, he said, and the gene networks and gene-expression cascades that they set off, “are surprisingly consistent—from monkeys to people, from five-year-old kids to adults, from Vancouver teenagers to 60-year-olds living in Chicago.”

COLE’S WORK CARRIES ALL kinds of implications—some weighty and practical, some heady and philosophical. It may, for instance, help explain the health problems that so often haunt the poor. Poverty savages the body. Hundreds of studies over the past few decades have tied low income to higher rates of asthma, flu, heart attacks, cancer, and everything in between. Poverty itself starts to look like a disease. Yet an empty wallet can’t make you sick. And we all know people who escape poverty’s dangers. So what is it about a life of poverty that makes us ill?

Cole asked essentially this question in a 2008 study he conducted with Miller and Edith Chen, another social psychologist then at the University of British Columbia. The paper appeared in an odd forum: Thorax, a journal about medical problems in the chest. The researchers gathered and ran gene-expression profiles on 31 kids, ranging from nine to 18 years old, who had asthma; 16 were poor, 15 well-off. As Cole expected, the group of well-off kids showed a healthy immune response, with elevated activity among genes that control pulmonary inflammation. The poorer kids showed busier inflammatory genes, sluggishness in the gene networks that control inflammation, and—in their health histories—more asthma attacks and other health problems. Poverty seemed to be mucking up their immune systems.

Cole, Chen, and Miller, however, suspected something else was at work—something that often came with poverty but was not the same thing. So along with drawing the kids’ blood and gathering their socioeconomic information, they showed them films of ambiguous or awkward social situations, then asked them how threatening they found them.

The poorer kids perceived more threat; the well-off perceived less. This difference in what psychologists call “cognitive framing” surprised no one. Many prior studies had shown that poverty and poor neighborhoods, understandably, tend to make people more sensitive to threats in ambiguous social situations. Chen in particular had spent years studying this sort of effect.

But in this study, Chen, Cole, and Miller wanted to see if they could tease apart the effect of cognitive framing from the effects of income disparity. It turned out they could, because some of the kids in each income group broke type. A few of the poor kids saw very little menace in the ambiguous situations, and a few well-off kids saw a lot. When the researchers separated those perceptions from the socioeconomic scores and laid them over the gene-expression scores, they found that it was really the kids’ framing, not their income levels, that accounted for most of the difference in gene expression. To put it another way: When the researchers controlled for variations in threat perception, poverty’s influence almost vanished. The main thing driving screwy immune responses appeared to be not poverty, but whether the child saw the social world as scary.

But where did that come from? Did the kids see the world as frightening because they had been taught to, or because they felt alone in facing it? The study design couldn’t answer that. But Cole believes isolation plays a key role. This notion gets startling support from a 2004 study of 57 school-age children who were so badly abused that state social workers had removed them from their homes. The study, often just called “the Kaufman study,” after its author, Yale psychiatrist Joan Kaufman, challenges a number of assumptions about what shapes responses to trauma or stress.

The Kaufman study at first looks like a classic investigation into the so-called depression risk gene—the serotonin transporter gene, or SERT—which comes in both long and short forms. Any single gene’s impact on mood or behavior is limited, of course, and these single-gene, or “candidate gene,” studies must be viewed with that in mind. Yet many studies have found that SERT’s short form seems to render many people (and rhesus monkeys) more sensitive to environment; according to those studies, people who carry the short SERT are more likely to become depressed or anxious if faced with stress or trauma.

Kaufman looked first to see whether the kids’ mental health tracked their SERT variants. It did: The kids with the short variant suffered twice as many mental-health problems as those with the long variant. The double whammy of abuse plus short SERT seemed to be too much.

Then Kaufman laid both the kids’ depression scores and their SERT variants across the kids’ levels of “social support.” In this case, Kaufman narrowly defined social support as contact at least monthly with a trusted adult figure outside the home. Extraordinarily, for the kids who had it, this single, modest, closely defined social connection erased about 80 percent of the combined risk of the short SERT variant and the abuse. It came close to inoculating kids against both an established genetic vulnerability and horrid abuse.

Or, to phrase it as Cole might, the lack of a reliable connection harmed the kids almost as much as abuse did. Their isolation wielded enough power to raise the question of what’s really most toxic in such situations. Most of the psychiatric literature essentially views bad experiences—extreme stress, abuse, violence—as toxins, and “risk genes” as quasi-immunological weaknesses that let the toxins poison us. And abuse is clearly toxic. Yet if social connection can almost completely protect us against the well-known effects of severe abuse, isn’t the isolation almost as toxic as the beatings and neglect?

The Kaufman study also challenges much conventional Western thinking about the state of the individual. To use the language of the study, we sometimes conceive of “social support” as a sort of add-on, something extra that might somehow fortify us. Yet this view assumes that humanity’s default state is solitude. It’s not. Our default state is connection. We are social creatures, and have been for eons. As Cole’s colleague John Cacioppo puts it in his book Loneliness, Hobbes had it wrong when he wrote that human life without civilization was “solitary, poor, nasty, brutish, and short.” It may be poor, nasty, brutish, and short. But seldom has it been solitary.

TOWARD THE END OF the dinner I shared with Cole, after the waiter took away the empty platters and we sat talking over green tea, I asked him if there was anything I should have asked but had not. He’d been talking most of three hours. Some people run dry. Cole does not. He spoke about how we are permeable fluid beings instead of stable unitary isolates; about recursive reconstruction of the self; about an engagement with the world that constantly creates a new you, only you don’t know it, because you’re not the person you would have been otherwise—you’re a one-person experiment that has lost its control.

He wanted to add one more thing: He didn’t see any of this as deterministic.

We were obviously moving away from what he could prove at this point, perhaps from what is testable. We were in fact skirting the rabbit hole that is the free-will debate. Yet he wanted to make it clear he does not see us as slaves to either environment or genes.

“You can’t change your genes. But if we’re even half right about all this, you can change the way your genes behave—which is almost the same thing. By adjusting your environment you can adjust your gene activity. That’s what we’re doing as we move through life. We’re constantly trying to hunt down that sweet spot between too much challenge and too little.

“That’s a really important part of this: To an extent that immunologists and psychologists rarely appreciate, we are architects of our own experience. Your subjective experience carries more power than your objective situation. If you feel like you’re alone even when you’re in a room filled with the people closest to you, you’re going to have problems. If you feel like you’re well supported even though there’s nobody else in sight; if you carry relationships in your head; if you come at the world with a sense that people care about you, that you’re valuable, that you’re okay; then your body is going to act as if you’re okay—even if you’re wrong about all that.”

Cole was channeling John Milton: “The mind is its own place, and in itself can make a heaven of hell, a hell of heaven.”

Of course I did not realize that at the moment. My reaction was more prosaic.

“So environment and experience aren’t the same,” I offered.

“Exactly. Two people may share the same environment but not the same experience. The experience is what you make of the environment. It appears you and I are both enjoying ourselves here, for instance, and I think we are. But if one of us didn’t like being one-on-one at a table for three hours, that person could get quite stressed out. We might have much different experiences. And you can shape all this by how you frame things. You can shape both your environment and yourself by how you act. It’s really an opportunity.”

Cole often puts it differently at the end of his talks about this line of work. “Your experiences today will influence the molecular composition of your body for the next two to three months,” he tells his audience, “or, perhaps, for the rest of your life. Plan your day accordingly.”