I’d just like to draw everyone’s attention to a very nicely written essay on evolution and cancer by Joshua Schiffman, in Mel Greaves’ Darwin Cancer Blog. It is titled “Lessons from cancer risk in animals” and results from collaborative research with Carlo Maley. Schiffman draws from comparative work throughout the animal kingdom and takes inspiration from research on dogs, which are extremely inbred and have breed-dependent high rates of cancer; and elephants, which have multiple (up to 40) copies of the “guardian of the genome” gene TP53, that might explain Peto’s paradox which pondered why large animals – like elephants – with consequent large reservoirs of actively dividing stem cells, nevertheless enjoyed great cancer-free longevity. Schiffman directly compares these examples with the phenomenon of Li-Fraumeni Syndrome in humans – an inherited defect of one of the TP53 genes which leads to a 100% lifetime risk of cancer or multiple cancers. Photo credit for the “jumbo” picture goes to Joshua.
Last Friday, the Evolutionary Psychiatry Special Interest Group held a half-day meeting at the Royal College of Psychiatrists in London and heard two talks of interest to anyone in evolutionary medicine.
First up was Carmine Pariante, professor of biological psychiatry at Kings College, London, with a talk entitled “Depression and Inflammation: A Life-Saving Response Gone Awry.” Much of the substance of what he had to say will come as no surprise to EvMedders, but it was interesting to hear a slightly different perspective from (for me) a new quarter. For instance, it is now well understood that you cannot separate the brain from the body and that, consequently, the body is an important part of the pathogenesis of mental health disorders. It’s well represented by that well-known interactive triangle of the brain; hormones, particularly those involved in the hypothalamic-pituitary-adrenal (HPA) axis of the stress response; the immune system and inflammation. There’s now piles of evidence for the influence of the immune system on behavior – you only have to remember the depression that probably attended your last serious bout of ‘flu. Also, sickness behaviour, first elucidated by Benjamin Hart, applies equally to animals and humans, whereby, in the throes of illness – infection or poisoning – the immune system spews out inflammatory cytokines which act on the brain to produce symptoms of lethargy and social withdrawal which conserve body heat to fight off infection and discourage the individual from sallying forth where they may be insulted anew by infectious microorganisms or poison in the environment. For Pariante, stress is oblivious to the modern cultural contexts that can induce it. Blind to the threat of unemployment, a relationship going sour etc. etc. it harks back to the spectacle of the roaring lion in front of our ancestors – or even ancestor species – and identifies only alarm and avoidance. What has his own research made of pathology generated by stress/depression and inflammation?
He found, some years ago, that plasma interleukin 6 (IL-6) – which is an inflammatory cytokine – is elevated in depressed patients versus controls. But plasma cortisol is also elevated. This puzzled him. Why does this state exist where both are raised in the blood at the same time? After all, cortisol is antagonistic to inflammation, which is why it is given to patients for a wide range of inflammatory diseases – like arthritis. In Pariante’s words, the water feeds the fire rather than being antagonistic to it. It is because in depression immune cells develop glucocorticoid resistance. In his research inflammatory cytokines were up-regulated: IL-1ß by up to 48% and TNF-å by up to 52%, whereas the glucocorticoid receptor was down-regulated. The FKBP-5 gene, whose protein binds to the glucocorticoid receptor and inactivates it, was found to be up-regulated by 27%.
With colleagues, Pariante looked at the occurrence of depression in patients with coronary heart disease. They already have a high baseline inflammatory state. They found that superimposing depression on CHD doubled the concentration of IL-6, C-reactive protein (CRP), and VEGF. Why are some CHD patients depressed and others not? Part of the answer, he says, lies in genetics. They have regularly found 4 polymorphisms of genes that are involved in the production of the inflammatory cytokines, like IL-6 and TNF-å. The assumption is that they exist to make the immune system more reactive and so lasting inflammation and depression may be the price some of us pay for hair-trigger and over-reactive immunity.
Pariente has also collaborated with Avshalom Caspi, a lead scientist on the longitudinal Dunedin child study in New Zealand. Childhood adversity produced a lasting scar in these children which resulted in long-term elevation of inflammatory cytokines. They noted that in individuals who were depressed but had not been maltreated as children there was some elevation in inflammation; in those that had been earlier maltreated but were not depressed at the time of measurement, inflammation was slightly more elevated; and in those who had been previously maltreated and were currently depressed the elevation in inflammation was substantially greater still. So, exposure to stress primes the immune system to be overreactive, which, later on, can lead to depression. And CRP (a main indicator of inflammation) is therefore predictive of future depression.
They have also looked at children born of mothers who were clinically depressed during pregnancy and followed them up for 25 years. They were running much higher inflammatory states than individuals born of non-depressed mothers. Their default CRP levels were set at a much higher level. This all suggests the depressed mother is transferring to her fetus important (and negative) information about the environment, along with the metabolic settings that go along with it.
In further work, Pariante and others have shown that macrophage migration inhibitory factor (MIF) and IL-1ß predict the treatment response to conventional types of anti-depressive medication. At high levels of MIF and IL-1 there is zero chance of response. He thinks this insight could lead to a more personalized medicine in psychiatry – non-responders might benefit from being treated concurrently with anti-depressants and anti-inflammatories – and this idea, he says, is being tested at the moment.
I would have liked to have seen some discussion of the putative role of efficient immune system regulation in this relationship between depression and inflammation. Graham Rook, for instance, believes that a thriving gut microbiota (or lack of it) is the crucially under-investigated variable in these longitudinal studies of abuse, inflammation and subsequent depression and inflammatory disease. And Tom McDade conducted a study in the Philippines which showed that children subjected to great stress through separation from their mothers in early life did not go on to suffer from chronic depression if they had been born in rural areas at the time of year when they would have been most likely to have imported a healthy gut microbiota from their environment.
Susanne Shultz is a former post-grad of Robin Dunbar’s, who is now at the University of Manchester. Her talk was titled “The evolution of sociality and social cognition”. She has continued working on social intelligence, particularly on deriving a deeper understanding of what Dunbar’s number (the maximum number of social relationships any individual can support – in humans it’s 150) actually means. When it comes to social intelligence, Schultz reminds us, humans are in a league of their own. Ed Wilson’s 4 pinnacles of sociality run from slime molds to eusocial insects to non-human mammals and then to the extraordinary ultra-sociality of humans.
Does the evolution of brain size inevitably lead to greater social intelligence? The social brain hypothesis says that brain neocortex size tracks social group size but this is only specific to primates – it doesn’t hold for other species groups like ungulates and carnivores. Shultz believes the most important factor is not social group size per se, but social cohesiveness. The limitation of Dunbar’s group size correlation is that it doesn’t tell you anything about cognition and no one actually agrees on what it is that is so challenging about sociality. Andy Whiten’s and Dick Byrne’s beguiling Machiavellian hypothesis to explain the complexity of living in social groups held sway for many years but, she says, we have to look beyond social manipulation to ask why intensely social animals like primates manage to maintain social groups in the first place – how do they hold them together? How do they cognitively manage competition? A lot of it has to do with down-regulating dyadic aggression.
Shultz reminded us of Robert Sapolsky’s research on baboons. The social stress felt by non-dominant individuals equated with a rise in blood pressure, heart problems, immune dysregulation, lower fertility, and depression. But baboon societies are famously demonic and better socially integrated species have lower levels for all Sapolsky’s stress indicators. What seems more important than non-dominance is uncertainty. Barbary macaques, for instance, unlike the more demonic baboons, have low rates of stress except in individuals who are mid-ranking. If you are at the top of the pile – or the bottom – you know where you are, but in the middle confusion reigns. Glucocorticoids were lowest in dominant and subordinate individuals and highest in the middle. This was popularized in the press recently as “the stress of the middle managers!”and relates well to Michael Marmot’s famous Whitehall study of British civil servants which showed that top civil servants enjoyed better health indicators which predicted longevity whereas lower-ranking civil servants had higher levels of ill-health. The key element is uncertainty!
Animals with bigger brains had more neocortex and more prosocial behavior. This had less to do with their propensity for Machiavellian calculation but rather their ability to organise and cooperate in coherent social action. In large non-kin groups, she says, the first thing you see is collective action – usually for defense – followed by policing of anti-social behavior, and then coalitions. This is consistent with Mike Tomasello’s Vygotskian idea of interdependence leading to ultra-sociality.
Monogamy leads to slow maturation, altricial young, and expanding brain size. If you look at the 2D:4D finger length ratio across the primates you see that it is higher in monogamous societies – a more feminized pattern, whereas the ratio is lower, or androgenized, in more demonic societies like baboons and other Old World monkeys where the tang of testosterone hangs in the air like the reek of gasoline at a car racing track and dominant males sequester the most females. Comparison between Neanderthal and Homo sapiens hands suggests a trend toward decreased androgenization over time. Perhaps Steve Pinker was right in “The Better Angels of Our Nature” – there has been a steady trend to lower levels of androgenization. It has been shown, for example, that men with smaller testes make better dads.
There is a special issue of Nature Outlook on IBD flagged up today which is Open Access. Several of the articles could be of some interest to evolutionary medics who are interested in the gut microbiota and commensal helminths and their role in modulating the human immune system. Articles of special interest are one on the possibility of microbiota engineering via faecal transplants for curing IBD, and an interview with helminth therapy pioneer Joel Weinstock on his latest interpretation of the mechanisms by which helminths exert control over the immune system.
It is now widely understood that cancers evade treatment by evolving drug resistance – in much the same way as microbes acquire resistance to antibiotics. This is why patients can relapse even after courses of modern targeted cancer therapies. Encountering this with drug cocktails sometimes fails because the evolution of resistance to one drug sometimes results in a more widespread resistance to a range of drugs – a phenomenon called cross-resistance. However, sometimes the opposite happens and cancer cells, having developed resistance to the first-line drug therapy, develop collateral sensitivity to another drug to which they had previously not been sensitive. These patterns of resistance and sensitivity are very dynamic during cancer treatment and evolution – they are always changing over time – and a collaborative team from the Cleveland Clinic, the Moffitt Cancer Center in Florida, and the University of Oxford have been investigating how they can better understand collateral sensitivity and use it in the novel treatment of cancer. A paper in Nature Scientific Reports by Dhawan et al documents their approach.
The team researched a type of lung cancer called ALK (anaplastic lymphoma kinase)-positive non small cell lung cancer (NSCLC) which is frequently driven by the oncogenic fusion of the ALK and the EML4 genes and which disproportionately affects younger, generally non- or light smoking, patients. As Dhawan et al explain, trials have led to the ALK inhibitor crizotinib to be the first-line standard of care for metastatic tumours driven by this oncogene. Unfortunately, after widespread use began, they say, reports of resistance to ALK inhibition quickly emerged, and it has since become apparent that within one year of starting such therapy, resistance almost inevitably emerges. Typically, oncologists will switch treatment to one of several second-line drugs, but they are oblivious to the unfolding dynamic patterns of cross-resistance and collateral sensitivity that might govern the extent to which these treatment changes prove successful. When a patient is taken off first-line drug treatment there is usually a “drug holiday” before any subsequent treatment with another drug – and it turns out that this drug holiday is also important for the evolution of collateral sensitivity.
For instance, the researchers first induced the evolution of multiple resistance to the major ALK inhibitors crizotinib, alectinib, lorlatinib, and ceritinib in NSCLC cell lines. They then assayed the four resistant cell lines for five drug holiday periods: 1 day, 3 days, 7 days, 14 days, and 21 days. Highly dynamic patterns of cross-resistance and collateral sensitivity emerged that changed particularly quickly. One example they give is the collateral sensitivity to lorlatinib in ceritinib resistant cells, which appeared on the first day of holiday, then disappeared on day 3, re-appeared on day 7, disappeared again on day 14, and finally re-appeared on day 21. These experimental results, they say, indicate that lorlatinib might be a poor choice for first-line therapy, as the cross-resistance it generates is substantial and stable through drug holidays, but it may be a better choice in the second-line, as many resistant lines are sensitized towards it after a drug holiday. This “metronomic” switch too and from collateral sensitivity, once understood, they say, could be used to time metronomic drug therapy. And understanding shifting patterns of resistance and sensitivity can lead to more efficient regimes of drug cycling.
This detailed growing understanding of the dynamics of cancer cell reaction to drug treatment regimes joins a growing school of potential cancer therapies guided by an understanding of cancer evolution, such as the approach by Bob Gatenby and colleagues at the Moffitt, which suggests that the careful titration of low dose cancer therapy – so-called adaptive therapy, can be used to contain a stable and manageable burden of stable tumor rather than provoke resistance via therapeutic onslaught.
This post credits “Targeted Oncology” with the copyright for the featured image it uses.
Back in 2014, Joe Alcock, Athena Aktipis and Carlo Maley co-authored a paper in Bioessays, titled “Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms.” In it they argued that gut microbes are under selective pressure to manipulate the eating behaviour of their host in order to increase their fitness – even if, sometimes, this comes at the expense of the host. Our microbiota can achieve this manipulation over our eating behaviour, they said, by generating cravings for foods that they specialize on or foods that suppress their competitors, or by inducing mental symptoms of depression and dissatisfaction in their hosts until we reward them – and ourselves – by consuming the food they hanker for. The authors put forward an obvious idea – although rather far-fetched given the present state of detailed knowledge of these effects – that appropriate manipulation of the microbiome could result in novel treatments to curb dietary excesses and control the obesity pandemic.
A recent paper in PLoS Biology provides empirical support for this idea through research on the eating behaviour of Drosophila. The paper, by Ribeiro et al, is titled “Commensal bacteria and essential amino acids control for choice behaviour and reproduction.” The interaction of microbiota with ingested nutrients, Ribeiro reminds us, has emerged as a major determinant of health and disease, including obesity. And commensal bacteria have also been proposed to affect a wide array of brain functions ranging from bulk food intake to anxiety, neurodevelopmental disorders, and social behavior. More recently, they say, the importance of commensal bacteria in controlling growth and in protecting children from malnutrition indicates that the microbiome could also play a pivotal role in protein homeostasis. (more…)