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Blog

Connection, Compassion and the Genome

Posted on June 8, 2014 at 9:17 AM Comments comments (91)
Steve Cole, Phd one of the pioneer researchers in the new field of psycho-immunology, delivers the Meng Wu Lecture at CCARE Stamford University. Watch it here.

My transcript of Steve Cole's lecture: 

How we interact, how we connect has a tremendous influence on how our genes are expressed.  Traditionally we saw ethics, morality and the world of tangible, molecular biology of cells as very different worlds/domains. We are starting to see the shadow of each domain playing out in the other.
 
Gene expression and social factors

The genome isn’t expressing all its 20.000 genes at the same time. There is a lot of decision about which genes get expressed. The change of the activity of genes within our white blood cell is linked to
protracted, extended situations:
  • Low SES (social-economic status) 
  • Social Loss/ Anticipated bereavement
  • Post-traumatic stress
  • Cancer diagnosis
  • Social threat
  • Loneliness
  • Social instability
  • Chronic stress
  • Low social rank
  • Caregiving for seriously ill
  • Depression
  • Early life low SES
  • Poverty

The stress-response and the genome 

From a study by Irwin and Comle, Nature Reviews, Immunology, 2011
One of the major ways in which these experiences play on the genome is through the fight-flight stress response activated by the sympathetic nervous system, with the release of adrenaline (epinephrine) and noradrenaline (norepinephrine). Noradrenaline is released in the vicinity of a cell. Through its nteraction with receptors (ADRB2) on the surface of the cell the result is a pumped-up activity of genes involved in the expression of pro-inflamatory immune response genes and a stomping down of the activity of other genes (antiviral immune response genes).  

Through exposure to really overwhelming stress a second response kicks in – a defeat/withdrawal response, where your system shuts down, you are overwhelmed and your body hunkers down and just tries to survive. That response is mediated by a second hormonal pathway - the HPA (Hypothalamus - Pituitary - Adrenal). The hypothalamus tells your adrenal glands to produce more cortisol, which has a different impact on gene expression – it lowers the expression of antiviral immune response genes and lowers the expression of pro-inflammatory immune response genes.
 
Different experiences of the same event – either as a challenge that can be overcome or as something profoundly overwhelming is going to have different effects on my genome, it will evoke different kinds of biological response.

Studies by Cole et al. Proc Nat Acad of Sci USA, 2011 and Powell et al. Proc Nat Acad of Sci, USA, 2013
Our bodies are extremely dynamic at a cellular or molecular level. The average protein in the human body has a half-life of eighty days so that every single day we have to replace 1 – 2% of the proteins in our body and that process is open to ‘advice’ from the world outside the body, including the world that psychology creates in my mind. 

Gene expression can also catalyse the production of new cells (monocytes and dendritic cells which don’t live very long). This process is also orchestrated by changes in gene expression that are susceptible to regulation by the nervous system. In people who are confronting uncertain environments, the brain interprets those environments as threatening and activates these fight-and-fight responses. 

Norepinephrine signalling is delivered into the bone marrow in a form of a ‘piece of advice’ to the stem cell which says 'produce more myeloid cells: monocytes, granulocytes, dendritic cells'. As a consequence of that we have more of these cells going out into the body and circulating. For most of our development that made good sense but if there is nothing for those cells to respond to - because there is no physical injury and hence no bacterial infections. These cells are programmed to find trouble and do something about it. Some of the trouble they find might be the early stages of proliferation of cancer or damage to the wall of our blood vessels or minor damage in brain cells, all of which attracts these charged, primed immune cells. As these cells attempt to repair tissue damage but can inadvertently contribute to the sort of disease that nowadays are the true architects of our longevity . We no longer die of infectious disease, we now die of heart disease, cancer and neuro-degenerative diseases.

Cancer 

(Sloan et al. 2010 Cancer Research – done on a mouse injected with cancer cells and then confined to a small space – a stress inducing situation)
When animals have too many of these charged up monocytes in their body during the early stages of tumour-development they get many more cancer cells escaping from the initial tumour site and spreading out (metastasising). This is mediated by those immune cells, which having gone into the tumour to kill the microbes and repair damaged tissue. They liquify tissue so that the cancer cells can grow out, they help grow blood vessels into the tumour thus feeding it and suppress the rest of the immune system’s response to the growing cancer.
 
Psycho-social events alter our biology

We used to think of the brain and the immune system as separate it turns out that what is going on in the world has some association with what goes on in our body at a microbial level. Over millions of years our immune system has learned to listen to the chatter from the brain and if it hears indications that you are feeling substantially threatened it gets ready to deal wit tissue damage, whether tissue damage is happening or not and inadvertently it fertilisers diseases and becomes the architect of a host of problems.
-       Central nervous system: inflammation and neuro-degenerative disease
-       Vasculature: artherosclerosis
-       Lungs: URI, asthma
-       Lymphoid tissue: neoinnervation, HIV/SIV
-       Solid tumor in the breast, ovaries: metastasis
 
That is why so many different types of adversity (isolation, low SES, social threat, bereavement) seem to draw out disease. There are many different ways that humans have learned to feel threatened and stressed.

Attachment and isolation and how the body responds to stress

There are two different ways to run our bodies which correspond to two social genomic programs in immune cells. One operates in a world in which we are attached and safe, connected. In this the big threats that we confront are the diseases that travel from one to another (viruses). A separate modus operandi takes place in the context in which we are separated from our community or feel threatened within our community, which up-regulates these inflammatory genes which produce monocytes, geared to fight bacteria (in anticipation of tissue damage). It doesn’t help us as well because it fertilises chronic diseases.  
 
Hedonic versus eudaimonic happiness

What is the secret to making people feel genuinely safe? (Frederickson et al., PNAS, 2013) How should we live? What is the best way to thrive in human life? What is the nature of true happiness. Hedonic happiness: consuming happy experiences (Epicur). Eudaimonic happiness: satisfaction that derives from a deeper sense of making a contribution to a purpose or a group outside ourselves, a community, a cause, creation, discovery. It turns out that either eudaimonic or hedonic pursuits are correlated to low levels of depression, but when researchers asked the genome, eudaimonic happiness is correlated with healthy immune profiles whereas hedonic happiness is not.  

Physical illness increases the risk of mental illness

Posted on November 12, 2012 at 10:15 AM Comments comments (2)
According to an article in the Times: "Doctors must give equal priority to mental cases"  the new NHS mandate will be to place mental health care at the heart of its new framework. The Centre for Mental Health produced a report (read it here in full), which highlights the prevalance of mental health illness among people with physical health conditions (two to three times higher than in the general non-clinical population, as well as the fact that medical staff are routinely over-looking this aspect of their patients care, or are simply not inclined to see it having a crucial influence over the patient's recovery rates.  

The Centre for Mental Health wants to see more liaison psychiatrists involved in the overall assessment and care management of patients. 

I have selected below a few paragraphs from the report. I have included subtitles and italics to highlight the most striking statements. 

"Physical health and mental health are inextricably linked. Poor physical health is a major risk factor  for poor mental health, and equally, poor mental health is a major risk for poor physical health. 

Despite this pervasive interplay, NHS services for mental and physical health are largely  commissioned, funded and provided in separate compartments. A heavy price is paid for this lack of integration in terms of poorer health outcomes for patients and in greatly increased costs of care to the taxpayer. 

The better management of co-morbid physical and mental health conditions probably offers more scope for contributing to the Quality, Innovation, Productivity and Prevention (QIPP) agenda of better health at lower cost than any other activity in the 
NHS."

Co-morbidity
"A recent review of the evidence on co-morbidities indicates that people with long-term physical health conditions, who together account for around 70% of all expenditure in the NHS, are two to three times more likely than the general population to experience mental health problems such as depression, anxiety or dementia (Naylor et al., 2012). In total, this amounts to some 4.6 million people in England with co-morbid physical and mental health problems.The prevalence of mental and physical health co-morbidities is particularly high among patients in general and acute hospitals. 

One reason for this is that a significant number of patients develop a health problem during their stay in hospital, in addition to those who are admitted with an existing condition. Another is the very high proportion of older people in the inpatient population."

Undetected mental health issues
"Many cases of mental illness among hospital patients go undetected by acute clinical staff. Estimates of detection rates vary between studies but are commonly put at around 50%, and may be even lower for some conditions such as delirium. There are various reasons for this. The presence of physical illness may make the detection of mental health problems more difficult. Hospital staff often have little training or expertise in the identification of mental health conditions. They may understandably focus attention on the primary health condition for which a patient has been admitted. And they may feel that a degree of mental distress is a natural reaction to illness and hospitalisation even though this may conceal more serious problems."

Poor health outcomes
"Co-morbid mental health problems lead to much poorer health outcomes for people with physical health conditions. For example, mortality rates for individuals with co-morbid asthma and depression are twice as high as among people with asthma on its own (Walters et al., 2011). Similarly, people with chronic heart failure are eight times more likely to die within 30 months if they also have depression (Junger et al., 2005). There is also evidence that co-morbid mental health problems can have a greater effect on the functional status and quality of life of people with long-term physical conditions than the severity of their physical illness (Yohannes et al., 2010; de Jonge et al., 2006), and that quality of life for those with co-morbid mental and physical health problems is considerably worse than among people with two or more physical health problems (Moussavi et al., 2007)."

Medically unexplained symptoms
"Medically unexplained symptoms are surprisingly common. For example, they account for about 50% of all first attendances at outpatient departments in general hospitals (Nimnuan et al., 2001), and patients with medically unexplained symptoms may be among the most frequent and intensive users of health services in both primary and secondary care settings. Medically unexplained symptoms are not covered in the cost estimates given in Naylor et al., but a separate study published in 2010 indicates that the overall cost to the NHS of medically unexplained symptoms is nearly £3 billion a year (Bermingham et al., 2010)."

Older patients
"Detection rates for mental health conditions among older patients are typically very low. For example, one study found that delirium was missed in up to two-thirds of cases (Inouye, 1994), while a meta-analysis of studies of depression in older medical patients showed a median detection rate of just 10% (Cole & Bellavance, 1997). And even when problems are identified, the treatment provided by clinical staff in acute hospitals is often sub-optimal, including over-use of psychotropic medication in the management of dementia and delirium (Holmes et al., 2003) and failure to provide anti-depressants for the majority of depressed older patients (Holmes & House, 2000). Psychological interventions are very rarely used."

Functional disorders

Posted on October 10, 2012 at 3:41 PM Comments comments (157)
BBC 4 Inside health programme tackled the topic Functional disorders today - previously known as Medically Unexplained Symtoms (MUS). GP tend to assume that these symptoms have no biological explanation (they do not show up on scans or tests), which leads medics to assume that they are dealing with fictitious symptoms - in other words that the client is making them up. Fatigue, limb lameness or paralysis are just a few examples. These complaints are quite common and represent a staggering 30% of presenting problems are MUS or functional disorders.