Sunday, November 3, 2019

Candida and autism




Shamanic ritual (Wikipedia - Idries Shah). There is a correlation between autism and antibodies for Candida albicans. Does a pathogenic strain of this yeast promote the development of autism? Cui bono?


In my previous posts I've argued that certain pathogens have acquired the capacity to manipulate human behavior. Humans are an interesting target for several reasons:

1. The human mind oversees an extensive range of complex behaviors

2. Humans are long-lived, thus providing a useful vehicle for spreading to other potential hosts.

3. Humans have particularly long generation times and are thus less able to develop resistance to short-generation pathogens, which can more easily “outmanoeuvre” the evolution of human resistance.

Among animal hosts in general, behavior can be manipulated by many pathogens, including fungi. Fungi seem to be better able than viruses and bacteria at producing and coordinating the array of chemicals needed for the targeted neural tissue. One of them may be Candida, a genus of yeasts that most often live in the gut but can be found elsewhere in the body. In particular, there seems to be a connection between their presence and the development of autism spectrum disorders (ASD):

We aimed to determine if children with ASD exhibit elevations in antibodies that target C. albicans, indicating current or previous overgrowth of this fungal species. [...] Plasma anti-C. albicans antibody positivity was found in 36.5% (19/52) of children with ASD. Anti-C. albicans antibodies in typically developing controls was (14.3%; 4/28). Overall, ASD children had a higher rate of high-positive values compared to typically developed children with an unadjusted odds ratio of 3.45 (95% confidence interval, 1.0409 to 11.4650; p = 0.041, two-tailed). (Hughes and Ashwood 2018)

The above study takes the line that Candida albicans is a "passive commensal" that "under certain conditions [...] is capable of transitioning to its pathogenic and invasive fungal form" (Hughes and Ashwood 2018). In reality, C. albicans encompasses a variety of strains, some of which live more as a commensal and others more as a pathogen: 

Here, intra-species analyses of C. albicans isolates revealed extensive variation between strains, both at the genotypic and phenotypic level. Substantial genomic differences were observed between the set of 21 clinical strains and included single nucleotide polymorphisms, inversions, copy number changes, LOH events, and whole or partial chromosomal aneuploidies.

[...] The phenotypic plasticity of this species has long been recognized, and our studies reveal the genetic differences underlying phenotypic differences are due to a variety of mechanisms, of which LOH and aneuploidy are major contributors. Furthermore, we uncover a genetic polymorphism responsible for altered phenotypic behavior, including a change in the balance between commensalism and pathogenesis. (Hirakawa et al. 2015)

Some strains of C. albicans have evolved the capacity to adhere to neural tissue:

An ex vivo adhesion assay was used to examine adhesion of Candida albicans yeast cells to brain tissue of the primate Macaca mulata. Tissues from frontal lobes and striatum (caudate, putamen, and portions of the globus pallidus) were used in the assay. Yeast cells adhered to gray matter at about six times the level of adhesion to white matter. The fungus was able to bind to different cell types within the cortex, basal ganglia, and white matter. Binding to neurons, small neurons or glia, endothelial cells, and neuropil was observed. (Denaro et al. 1995)

What's in it for the pathogen?

This is the weakest link in the argument for behavioral manipulation. How does autism benefit the pathogen? Does it help Candida spread to another host? If not, where is the benefit? People have speculated about the evolutionary advantage of autism, but only from the standpoint of the affected person. Perhaps a low dose makes one more inventive and creative (Pickard et al. 2011). Perhaps it gives rise to the "autonomous imagination" of shamans:

[…] “autonomous imagination” [is] a framework for cross-cultural interpretations of inner experience such as dreams, waking visions, trance, spirit possession and mediumship, and shamanistic and meditative states.

[…] Autonomous imagination is characterized by: a) being more freely and richly inventive than ordinary thought; b) emerging into conscious awareness in the form of vivid hallucinatory imagery which is experienced as an external reality; c) possessing a more extensive access to memory; d) exhibiting a special sensitivity to external cues and direction which enables communication to and from deeper levels of the mind, while bypassing conscious awareness, and; e) possessing a capacity to influence somatic and intrapsychic processes usually beyond conscious control (Stephen and Suryani 2000)

Shamans, through their prestige and reproductive success, may have favored a predisposition to autism in the gene pool. This hypothesis assumes that autism is mainly due to a genetic predisposition, i.e., that autism is highly heritable. In fact, heritability is "moderate": 37% for autism and 38% for autism spectrum disorder (Hallmayer et al. 2011). As with male homosexuality, it looks like something in the environment is interacting with a genetic predisposition.

If we take the pathogen's standpoint, we must ask how an autistic person might become an interesting means to spread from one host to another. One possibility is the shaman's role as a community healer. Certain healing practices involve intimate contact. In particular, a shaman's phlegm may be thought to contain the essence of his power. 

A shaman also has a magical phlegm called yachay, lodged in his stomach, which gives him the ability to blow away evil and to such out the sorcery objects (virote) that cause certain forms of illness. (Gow 1996, p. 93)

By targeting people who are likely to fill the position of community healer, a pathogen could greatly increase its opportunities for transmission. 


Parting thought

This example suggests that the evolution of behavioral manipulation can involve more than a pathogen and a host. It may also require a genetic predisposition and a cultural context that create opportunities for behavioral manipulation.


References

Denaro, F.J., J.L. Lopez-Ribot, and W.L. Chaffin. (1995). Adhesion of Candida albicans to brain tissue of Macaca mulata in an ex vivo assay. Infection and Immunity 63(9): 3438-3441.
https://iai.asm.org/content/iai/63/9/3438.full.pdf

Gow, P. (1996). River People: Shamanism and History in Western Amazonia. In Thomas, N., and C. Humphrey (eds). Shamanism, History, and the State (pp. 90-113). Ann Arbor: The University of Michigan Press. 
https://books.google.ca/books?hl=fr&lr=&id=3_inrj3puRQC&oi=fnd&pg=PA90&dq=%22River+People:+Shamanism+and+History+in+Western+Amazonia%22&ots=r2_OIZbV5M&sig=aH8LVaJwqbmFUn3FpuARh3N3UF8#v=onepage&q=%22River%20People%3A%20Shamanism%20and%20History%20in%20Western%20Amazonia%22&f=false

Hallmayer, J., S. Cleveland, A. Torres, et al. (2011). Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism. Archives of General Psychiatry 68(11): 1095-1102.
http://www.feat.org/Portals/0/Document%20Library/Medical%20Research%20Abstracts/GeneticHeritability_2011_07_04.pdf 

Hirakawa, M.P., D.A. Martinez, S. Sakthikurmar, M.Z. Anderson, A. Berlin, S. Gujja; et al. (2015). Genetic and phenotypic intra-species variation in Candida albicans. Genome Research 25: 413-425.
https://europepmc.org/articles/pmc4352881

Hughes, H.K., and P. Ashwood. (2018). Anti-Candida albicans IgG antibodies in children with autism spectrum disorders. Psychiatry 26 November
https://www.frontiersin.org/articles/10.3389/fpsyt.2018.00627/full

Pickard, C., B. Pickard, and C. Bonsall. (2011). Autistic spectrum disorder in prehistory. Cambridge Archaeological Journal 21(3): 357-364.
https://www.research.ed.ac.uk/portal/files/539348/2011_CAJ_Pickard_etal.pdf

Stephen, M. and L.K. Suryani. (2000). Shamanism, psychosis and autonomous imagination. Culture, Medicine and Psychiatry 24: 5-40.
https://link.springer.com/article/10.1023/A:1005528028869

Sunday, October 27, 2019

Behavioral manipulation: population differences in virulence





Helicobacter pylori (Wikicommons – NIH). Some human populations have become resistant to this bacterium; others have not. Could the same be true for pathogens that manipulate human behavior?



Humans are behavioral creatures par excellence. Our brains oversee a large repertoire of behaviors, each of which is vulnerable to manipulation. We can be manipulated by psychological means, like the parasite who lives off the altruism of others.  There's also ideological manipulation. 

And then there's hardwired manipulation—an organism enters your mind and rewires some of its circuitry. That kind of manipulation is poorly known. We know a lot about short-term infections that make you sick. We know much less about long-term infections where the pathogen hangs around in your body without triggering an immune response. There’s no fever, no rash, no abscess. Yet it may be doing something to the most important organ of your body, perhaps to increase its chances of spreading to another host. Not surprisingly, the adverse effects become worse when you're no longer of much help. It no longer has anything to lose from trashing its host.

So if a pathogen is screwing with your mind, the symptoms will be especially severe in two cases: 

- You’re approaching the end of your life. The pathogen has less incentive to keep you healthy. You’re also less active socially and sexually, and thus less useful as a vehicle for transmission to other hosts.

- The pathogen is spreading out of its original host population and into new hosts that have not had time to develop resistance to its worse effects

This post is about the second case. You pay a cost when a pathogen monkeys around with your mental circuitry. Over time, there will be selection for humans who better resist such manipulation. Eventually, an equilibrium is reached: the pathogen still screws around with your mind, but the negative consequences are kept to a minimum. In most cases. And until it spreads to people who have no resistance.

The latter situation has been covered by a recent review article:


[...] the effects of susceptibility and virulence alleles in the respective gene pools of humans and pathogens are often contingent upon each other. The evolution of virulence is a dynamic process, easily perturbed by extrinsic variables over space and time, and therefore unlikely to follow the same trajectory in every population. [...] Whether the result is a steady-state equilibrium due to a perpetual "arms race" or a commensal detente, the same genes and pathways are unlikely to be involved in every population. As a consequence, when humans and pathogens migrate to new environments or admix, the ensuing disruption of co-evolutionary equilibria and loss of complementarity between host and pathogen genotypes may yield unpredictable and potentially deleterious biomedical consequences. (Kodaman et al. 2014)

The authors cite the example of Helicobacter pylori, a bacterium that lives in the stomach lining. It is a risk factor for gastric cancer, but the level of risk varies according to the population it infects:

Studies of human or H. pylori genetics in isolation have generally failed to explain why populations with similar rates of H. pylori infection exhibit strikingly different susceptibilities to gastric cancer. For example, in many African and South Asian countries, the low incidences of gastric cancer in the presence of almost universal rates of H. pylori infection remain a source of much speculation, and have been referred to collectively as the "African enigma" and the "Asian enigma" [...] In Latin America, where H. pylori strains native to Amerindian populations have been largely displaced by European strains [...], the predominantly Amerindian populations living at high altitudes suffer disproportionately from gastric cancer relative to other populations with similar infection rates [...]. These and other points of evidence raise the possibility that the pathogenicity of a given H. pylori strain may vary with human genomic variation, and that some individuals may be better adapted to their infecting strains than others. (Kodaman et al. 2014)


Manipulating sexual behavior

Pathogens thus differ in their virulence from one human population to another. The same should be true for those pathogens that manipulate human behavior to improve their chances of spreading from one human to another. For them, our most interesting behavior is sex, and the most interesting human populations are "leaky" polygynous ones with high rates of infidelity. In that kind of context they can spread rapidly from one household to another.

Polygyny rates are highest among the tropical farming peoples of sub-Saharan Africa (Dalton and Leung 2011; Pebley and Mbugua 1989). Traditionally, 20 to 40% of all marriages are polygynous, and most women live in polygynous households. Not surprisingly, many men, particularly young men, are single. Their opportunities for sex are limited to rape, affairs with the wives of other men, or abduction of women during times of war:

Typically, the more men are polygynous in a given society, the greater the age difference between husbands and wives. [...] The temporary celibacy of young men in polygynous societies is rarely absolute, however. While it often postpones the establishment of a stable pair-bond and the procreation of children, it often does not preclude dalliance with unmarried girls, adultery with younger wives of older men, or the rape or seduction of women conquered in warfare. Thus, what sometimes looks like temporary celibacy is, in fact, temporary promiscuity. (van den Berghe 1979, pp. 50-51)

Cuckold envy: a case of behavioral manipulation?

This is the environment in which a sexually transmitted pathogen can leapfrog from one polygynous household to another. The main obstacle is male jealousy and male "guarding behavior." The pathogen can increase its chances of transmission by disabling mate guarding or, better yet, reversing it. This kind of host manipulation has been shown in a non-human species: male isopods no longer guard their mates when they get infected by a certain parasite (Mormann, 2010).

In a human context, a pathogen may reverse male jealousy and make its host want to be cuckolded, as a means to gain access to more hosts (Frost 2013). Many sexual fetishes are mentioned in ancient writings: pedophilia, cunnilingus, fellatio, and bestiality, but not cuckold envy. The oldest mentions go back to seventeenth-century England (Kuchar, 2011, pp. 18-19).

Perhaps a sexually transmitted pathogen came to England from West Africa during the early days of the slave trade. Such a pathogen would have evolved in a context where most women were in polygynous marriages and where cuckoldry was the main route for invading one set of wives after another. Meanwhile, the human hosts may have evolved some kind of resistance, perhaps through “overwiring.” Or perhaps a certain level of cuckoldry became socially accepted. No such resistance, however, had evolved in England or elsewhere in the Western world.

As time goes on, we will discover that many STDs have evolved a capacity for behavioral manipulation, specifically by making the host either more promiscuous or less jealous.


References

Dalton, J.T., and T.C. Leung. (2011). Why is Polygyny More Prevalent in Western Africa?
An African Slave Trade Perspective,
http://www.wfu.edu/~daltonjt/PolygynySlaveTrade.pdf

Frost, P. (2013). First, sexual transmissibility and then …? Evo and Proud, January 5
http://evoandproud.blogspot.com/2013/01/first-sexual-transmissibility-and-then.html 

Kodaman, N., R.S. Sobota, R. Mera, B.G. Schneider, and S.M. Williams. (2014). Disrupted human-pathogen co-evolution: a model for disease. Frontiers in Genetics 25 August
https://www.frontiersin.org/articles/10.3389/fgene.2014.00290/full

Kuchar, G. (2001). Rhetoric, Anxiety, and the Pleasures of Cuckoldry in the Drama of Ben Jonson and Thomas Middleton. Journal of Narrative Theory 31(1): 1-30.

Mormann, K. (2010). Factors influencing parasite-related suppression of mating behavior in the isopod Caecidotea intermedius, Theses and Dissertations, paper 48
http://via.library.depaul.edu/etd/48  

Pebley, A. R., and W. Mbugua. (1989). Polygyny and Fertility in Sub-Saharan Africa. In R. J. Lesthaeghe (ed.), Reproduction and Social Organization in Sub-Saharan Africa, Berkeley: University of California Press, pp. 338-364.

van den Berghe, P.L. (1979). Human Family Systems. An Evolutionary View. New York: Elsevier.

Friday, October 18, 2019

I was really something



I was really something (2016), by Judith Carlin. A fungus may live in your brain for years while meddling only as much as necessary with your neurons. Beyond a certain age it gets less benefit and has less incentive to keep you mentally healthy. One result may be Alzheimer's.



Behavior manipulation has been perfected by many organisms: viruses, bacteria, worms, and insects. Fungi, however, seem to be the champions:

Fungi probably represent a special case study in this general field because of several unique factors peculiar to this Kingdom. The first and most prominent is the range and complexity of behavioral manipulation by fungi of arthropods. [...] It is difficult and perhaps futile to rank manipulation across different kingdoms of life and argue that fungal manipulation is more complex than that observed when the manipulator is in the Kingdom Animalia (eg, trematodes). However, what is clear is that the diversity of strategies is greater than that observed in other groups. In addition, it is evident that behavioral manipulation has arisen multiple times independently. (Hughes et al. 2016)

You've probably heard about "zombie ants." A fungus invades an ant's brain and makes it leave its nest, climb up a plant, and fix itself in place with its mandibles. The fungus then kills the ant, and a fruiting body sprouts from behind the ant's head and showers spores onto the forest floor below.

There are other examples. A fungus invades the body of a flying insect and causes a hole to form on the side of the abdomen. It then releases spores through that hole while its host is flying. The infected body gradually falls apart, except for its nervous system and its wings. Is the insect still alive? Not really. The bits and pieces that remain have become extensions of the fungus (Hughes et al. 2016).

Other fungi imitate the smell or visual appearance of a sexually receptive female to lure male insects, who then become infected (Hughes et al. 2016).

In the above cases, the fungus mutilates and kills its host in ways that are not only ghastly but also easy to observe and study. But what about the more subtle cases where the host's behavior is simply altered? Those are the ones we know much less about. Our knowledge is biased toward the most obvious cases of infection. As Greg Cochran observed:

The most conspicuous transmission chains occur when disease manifestations are externally apparent in a high proportion of infected individuals, when they occur soon after the onset of infection, and when contact between infected and susceptible individuals is easy to observe. Under these circumstances chains of transmission are apparent through everyday experience. (Cochran et al. 2000)

Even when we can detect the presence of a pathogen, the causal link with certain effects is far from obvious because the effects are either subtle or long-term:

Pathogens are often classified as relatively harmless or even commensal without sufficient long-term study to warrant such a classification. The historical record illustrates the consequences of this error. Epstein-Barr viruses and human papillomaviruses were once thought of as relatively harmless on the basis of their linkage to relatively benign diseases that occur soon after infection (infectious mononucleosis and warts respectively). But each virus can cause lethal cancers. Bacteroides was once thought to be a harmless commensal, but recent evidence indicates that it may be linked to ulcerative colitis. (Cochran et al. 2000)

Many slowly developing diseases are probably of pathogenic origin. This seems especially the case with various forms of senile dementia. The pathogen targets your brain and gains some benefit while you’re still socially and sexually active. At that stage, it’s living in a commensal relationship with you and confines its neuronal meddling to the minimum necessary. Beyond a certain age, however, it gets less benefit from you and has less incentive to keep you mentally healthy. One result may be Alzheimer's:

The possibility that Alzheimer's disease (AD) has a microbial aetiology has been proposed by several researchers. Here, we provide evidence that tissue from the central nervous system (CNS) of AD patients contain fungal cells and hyphae. Fungal material can be detected both intra- and extracellularly using specific antibodies against several fungi. Different brain regions including external frontal cortex, cerebellar hemisphere, entorhinal cortex/hippocampus and choroid plexus contain fungal material, which is absent in brain tissue from control individuals. Analysis of brain sections from ten additional AD patients reveals that all are infected with fungi. Fungal infection is also observed in blood vessels, which may explain the vascular pathology frequently detected in AD patients. Sequencing of fungal DNA extracted from frozen CNS samples identifies several fungal species. Collectively, our findings provide compelling evidence for the existence of fungal infection in the CNS from AD patients, but not in control individuals. (Pisa et al. 2015)

Alzheimer's is a late onset disease. What is the fungus doing to your brain during the long time when you’re not mentally impaired? 

Another example may be multiple sclerosis:

Many biomarkers of MS are consistent with fungal infections, such as IL-17, chitotriosidase, and antibodies against fungi. Dimethyl fumarate (DMF), first used as an industrial fungicide, was recently repurposed to reduce MS symptoms. Its mechanisms of action in MS have not been firmly established. The low risk of MS during childhood and its moderate association with herpes simplex virus type 2 suggest genital exposure to microbes (including fungi) should be investigated as a possible trigger. (Benito-Leon and Laurence 2017)


References

Benito-Leon, J. and M. Laurence. (2017). The Role of Fungi in the Etiology of Multiple Sclerosis. Frontiers in Neurology 16 October
https://www.frontiersin.org/articles/10.3389/fneur.2017.00535/full

Cochran, G.M., Ewald, P.W., and Cochran, K.D. (2000). Infectious causation of disease: an evolutionary perspective. Perspectives in Biology and Medicine 43: 406-448.
https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.182.5521&rep=rep1&type=pdf  

Hughes, D.P., J.P.M. Araujo, R.G. Loreto, L. Quevillon, C. de Bekker, and H.C. Evans. (2016). Chapter Eleven - From So Simple a Beginning: The Evolution of Behavioral Manipulation by Fungi. Advances in Genetics 94: 437-469.
https://www.sciencedirect.com/science/article/abs/pii/S0065266016300049

Pisa, D., R. Alonso, A. Rabano, and I. Rodal. (2015). Different Brain Regions are Infected with Fungi in Alzheimer's Disease. Scientific Reports 5(15015)
https://www.nature.com/articles/srep15015 

Thursday, October 10, 2019

Is this the Gay Germ? Part II



Courtyard with Lunatics, Francisco Goya (1746-1828). Why is HIV much more likely to cause cognitive impairment in the body of a gay man than in the body of an intravenous drug user? Has an unknown pathogen been caught in the dragnet of AIDS studies?



My last post focused on certain discrepancies in data on AIDS victims: as antiretroviral therapy becomes more widespread, there has been a decline in opportunistic infections, but the decline hasn't been the same for all pathogens. In particular, some brain infections have shown modest declines or no change at all. 

Has an unknown pathogen been caught in the dragnet of AIDS studies? This pathogen would coexist with HIV only because it, too, is associated with the gay lifestyle. It would not be a "cofactor" that makes the HIV infection worse. In fact, it probably precedes the HIV infection by many years. This unknown pathogen may target certain sites in the brain of its host early in life in order to change his sexual orientation and thereby increase its chances of transmission to another host. It thereafter remains in the background until its host has reached an age when he ceases to be useful. The pathogen is then no longer penalized if it causes damage to surrounding neural tissues. Various neurocognitive disorders could therefore develop in its host from late middle age onward.


AIDS in gay men and intravenous drug users

This post will focus on discrepancies in data from two other papers. The first one is a study of AIDS victims in the Italian city of Bologna. Some of them contracted AIDS via homosexual/bisexual behavior, and some via intravenous drug use. One finding strikes me as unusual: "Compared with injecting drug users, homosexual/bisexual and heterosexual participants had ORs of 9.6 (95% CI, 2.2-42.7) and 6.3 (95% CI, 2.2-18.3), respectively, for cognitive impairment" (De Ronchi et al. 2002).

In other words, when the researchers looked at AIDS victims, they found that cognitive impairment was ten times more strongly associated with homosexuality/bisexuality than with intravenous drug use. That finding is curious because the ratio of ten to one doesn't correspond at all to the ratio of homosexuals/bisexuals to intravenous drug users among Italian AIDS cases. In fact, intravenous drug users made up about 60% of those cases in 1997 (Wikipedia 2019). The Bologna study took place between 1994 and 1997.

Why is HIV much more likely to cause cognitive impairment in the body of a gay man than in the body of an intravenous drug user? Do druggies take better care of their mental health? The evidence actually suggests the reverse: HIV-associated dementia seems to progress more rapidly in intravenous drug users (Bouwman et al. 1998). The latter finding also points to a qualitative difference between the two groups: dementia seems to develop more slowly in gay men.


HAND and HAART

The second paper is a review of studies on HAND [HIV-associated neurocognitive disorders]. It notes that HAND can develop even in individuals on HAART [Highly active antiretroviral therapy] with no detectable traces of HIV:

Furthermore, 21% [of individuals in the CHARTER study] developed HAND despite effective HAART (although the precise number who were aviremic is unclear). Similarly, in a cohort of individuals with AIDS, 21% of aviremic individuals (who also had undetectable CSF HIV RNA) progressed to HAD [HIV-associated dementia]. A third prospective study also identified HAND in 8-34% (depending on the time point of the assessment) of aviremic patients without comorbidities and with a nadir CD4 cell count less than 200 cells/µl (McArthur and Brew 2010)

The authors suggest that HIV can produce irreversible neural damage that becomes noticeable only much later in life. Well, perhaps. Nonetheless, it seems to me more parsimonious to postulate a second pathogen.


Parting thoughts

Clearly, HIV does cause cognitive impairment. The Bologna study showed a strong association between HAND and low white cell counts. But it looks like a certain proportion of HANDs are due to a cause that exists independently of HIV infection.

Please note: I'm not arguing that HIV is interacting with an unknown pathogen to cause cognitive impairment. I am arguing that these two pathogens impair cognition independently of each other and in different ways. They share only one thing in common: they have a much higher incidence among gay men than in the general population.

Finally, I'm not arguing that this unknown pathogen is the only cause of male homosexuality. There are likely multiple causes. In a nutshell, male homosexuality seems to be due to a genetic predisposition interacting with something in the environment. The genetic predisposition is a smaller-than-average neuronal population that promotes a heterosexual orientation. Normally, natural selection keeps it from falling below the threshold needed to sustain attraction to women. Certain environmental agents, however, can cause this neuronal population to fall below the threshold: fraternal birth order effects, stressful events during pregnancy, exposure to environmental estrogens during childhood, and, yes, a pathogen.

I don't know whether my views on the "gay germ theory" are consistent with Greg Cochran's. I hope he will deign to provide his comments.


References

Bouwman, F., R. Skolasky, D. Hes, O. Selnes, J. Glass, T. Nance-Sproson, W. Royal, G. Dal Pan,  and J. McArthur. (1998). Variable progression of HIV-associated dementia. Neurology 50(6): 1814-1820.
https://insights.ovid.com/article/00006114-199806000-00048 

Cochran, G.M., Ewald, P.W., and Cochran, K.D. (2000). Infectious causation of disease: an evolutionary perspective. Perspectives in Biology and Medicine 43: 406-448.
https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.182.5521&rep=rep1&type=pdf 

De Ronchi, D., I. Faranca, D. Berardi, et al. (2002). Risk Factors for Cognitive Impairment in HIV-1-Infected Persons with Different Risk Behaviors. Archives of Neurology 59(5): 812-818.
https://jamanetwork.com/journals/jamaneurology/article-abstract/781960

McArthur, J.C., and B.J. Brew. (2010). HIV-associated neurocognitive disorders: is there a hidden epidemic? AIDS 24(9): 1367-1370
https://journals.lww.com/aidsonline/Fulltext/2010/06010/Circulating_proviral_HIV_DNA_and_HIV_associated.17.aspx?Ppt=Article|aidsonline:2010:06010:00017|| 

Wikipedia (2019). HIV/AIDS Public Health Campaigns in Italy
https://en.wikipedia.org/wiki/HIV/AIDS_Public_Health_Campaigns_in_Italy


Wednesday, October 2, 2019

Is this the Gay Germ?



Poster for 1997 World AIDS Day (Wikicommons - Neil Curtis, Christian Michelides). Antiretroviral therapy has reduced infections in AIDS victims, but the decline hasn't been the same for all pathogens. Some infections have shown modest declines or no change at all. Could they be due to the "gay germ"?



Male homosexuality has low to moderate heritability (30 to 45%). A recent study in the UK Biobank and 23andMe has identified a number of genetic variants associated with same-sex sexual behavior. Together, they account for 8 to 25% of variation in male and female same-sex behavior (Ganna et al. 2019). There is thus a genetic predisposition, but it's weak and may simply reflect a smaller population of neurons for heterosexual orientation.

So this genetic predisposition seems to be interacting with something in the environment. But what?

There may be different environmental factors. One possibility would be a pathogen that alters its host's sexual orientation in order to enhance its chances of spreading to other hosts. This is Greg Cochran's "gay germ" theory (Cochran et al. 2000).

With the introduction of antiretroviral therapy for AIDS, we may have a chance to identify candidates for the "gay germ." Over time this therapy should reduce the incidence of infections in AIDS victims. Indeed it has, but the decline has been uneven.  A retrospective study of AIDS autopsies in Vienna between 1984 and 1999 found a lower rate of decline for infections due to fungi and most bacteria than for infections due to protozoa, viruses, and mycobacteria:

Extracerebral protozoal (Pneumocystis carinii, toxoplasmosis), Mycobacterium avium complex, viral [e.g., cytomegalovirus (CMV)], multiple opportunistic organ and CNS infections, and Kaposi sarcoma significantly decreased over time. There was less decrease in fungal infections, while bacterial organ and CNS infections (except for mycobacteriosis), lymphomas, HIV-associated CNS lesions (around 30%), non HIV-associated changes (vascular, metabolic, etc.) and negative CNS findings (10-11%) remained unchanged. (Jellinger et al. 2000)

These findings are in line with those of a retrospective study of AIDS autopsies in San Diego between 1982 and 1998:

Pneumocystis carinii pneumonia and Mycobacterium avium complex decreased, whereas bacterial infections increased and the frequency of fungal infection remained unchanged over time. (Eliezer et al. 2000)

After the lungs, such pathogens most often target the brain:

This study suggests that despite the beneficial effects of antiretroviral and anti-opportunistic infection therapy, involvement of the brain by HIV continues to be a frequent autopsy finding. (Eliezer et al. 2000).


Similar to a recent autopsy study from San Diego, these data suggest that despite the beneficial effects of modern antiretroviral combination therapy, involvement of the brain in AIDS subjects continues to be a frequent autopsy finding. (Jellinger et al. 2000)

Subjects with brain alterations at an early stage otherwise seemed almost normal:

Of the cases with early brain alterations, systemic opportunistic infections were present in only 5.9% of the cases, neoplasms in 0.5%, and neoplasms and opportunistic infections in 1.7%. (Eliezer et al. 2000)


A few caveats

The change in incidence over time partly reflects differences between fast-developing infections and slow-developing ones. By definition, people succumb more quickly to the former than to the latter. When antiretroviral therapy was still unavailable those infections were the ones that generally killed people with AIDS. Better control of aggressive infections may have also created a better environment for the growth of less aggressive infections.


But ...

It is harder to explain why the brain should remain a major pathogenic target. It is especially hard to explain why subjects with brain alterations at an early stage otherwise seemed almost normal.

Eggers et al. (2017) pointed out another apparent contradiction: HIV-associated neurocognitive disorders (HAND) are continuing to develop in people whose HIV infection is under control.

Despite the brain infection taking place in the days after primary infection, the development of HAND takes years. As an explanation for this ostensible contradiction, it has been suggested that initially, the brain infection is relatively well controlled, while later, there is a quantitative and qualitative breakdown of immune control in the CNS (Eggers et al. 2017)

Some authors have suggested co-infection by the Hepatitis C virus, but Eggers et al. (2017) ruled this out:

While some authors implicated HCV co-infection in the pathogenesis of HAND, a recent large and well-controlled study found no evidence for worse cognitive function in HCV co-infected patients, at least in the absence of liver dysfunction. (Eggers et al. 2017)


Pathogen "X"

Could we be looking at an unknown pathogen that exists independently of HIV? Over the years some have suggested that HIV is not the only pathogen involved in AIDS. In this case, pathogen "X" may cause adverse effects that get blamed on HIV, but its relationship with HIV is incidental, the only common denominator being the gay lifestyle.

I would propose the following scenario. Pathogen "X" enters its host early in life, just in time to alter that person's psychosexual development. From then on it remains in the background and reaps whatever benefit it gets from its behavior manipulation. Past the age of 40 the host becomes less useful, and the pathogen begins to cause more adverse effects, including neurocognitive disorders that are wrongly attributed to HIV.

Pathogen "X" is most likely a fungus. If we go back to the two retrospective studies, the fungal infections were the ones that seemed the least influenced by the introduction of antiretroviral therapy.


References

Cochran, G.M., Ewald, P.W., and Cochran, K.D. (2000). Infectious causation of disease: an evolutionary perspective. Perspectives in Biology and Medicine 43: 406-448.
https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.182.5521&rep=rep1&type=pdf 

Eggers, C., G. Arendt, K. Hahn, K., I.W. Husstedt, M. Mashke, et al. (2017). HIV-1-associated neurocognitive disorder: epidemiology, pathogenesis, diagnosis, and treatment. Journal of Neurology 264: 1715-1727
https://link.springer.com/article/10.1007/s00415-017-8503-2

Eliezer, M., R.M. DeTeresa, M.E. Mallory, and L.A. Hansen. (2000). Changes in pathological findings at autopsy in AIDS cases for the last 15 years. AIDS 14(1): 69-74.
https://journals.lww.com/aidsonline/Fulltext/2000/01070/HIV_associated_brain_pathology_in_the_United.8.aspx

Ganna, A., K.J.H. Verweij, M.C. Nivard, R. Maier, R. Weddow, et al. (2019). Large-scale GWAS reveals insights into the genetic architecture of same-sex sexual behavior. Science 365(6456)
https://science.sciencemag.org/content/365/6456/eaat7693 

Jellinger, K.A., U. Setinek, M. Drlicek, G. Böhm, A. Steurer, and F. Lintner. (2000). Neuropathology and general autopsy findings in AIDS during the last 15 years. Acta Neuropathologica 100(2): 213-220.
https://www.ncbi.nlm.nih.gov/pubmed/10963370

Wednesday, September 25, 2019

Differences in the genetic architecture of cognition?



Tableau III, Piet Mondrian (1872-1944). The polygenic score can provide a measure of innate cognitive ability in various human populations. However, it is less valid for African Americans, apparently because of differences in the genetic architecture of cognition.



When IQ is measured in European Americans and African Americans, the two groups differ on average by about 15 points. Is the difference genetic? Or is it due to different environments?

After years of debate, we are coming close to an answer. The weight of evidence is shifting, especially because of two unrelated developments: 

- We can now easily measure ethnic ancestry by means of genetic data. Previously, we had to rely on self-report or indirect measures like skin color.

- We can now measure the genetic component of cognitive ability: the polygenic score. This score is a summation of alleles associated with high educational attainment. Initially a crude measure, it is getting better and better as we identify more and more of these alleles.

Both research tools were used in a recent study. Lasker et al. (2019) applied them to the Philadelphia Neurodevelopmental Cohort, a sample of 9421 individuals from the Philadelphia area who received medical care from the Children's Hospital of Philadelphia network. They ranged in age from 8 to 21 with a mean of 14.2. They were 51.7% female, 55.8% European American, 32.9% African American, and 11.4% other. All of them were genotyped and given a series of cognitive tests.

This dataset had advantages over those of previous studies:

- All participants came from the same geographic area. 

- Heritabilities of cognitive ability were already estimated by another research team, specifically 0.61 for the African American participants and 0.72 for the European American participants.

- Skin, hair, and eye color could be estimated from the genetic data to control for the effects of "colorism" (discrimination favoring lighter-skinned over darker-skinned African Americans)

- Polygenic scores could be calculated from the genetic data

The main disadvantage was the participants’ young age. Before adulthood the brain is plastic and still developing, so the heritability of cognitive ability is lower. 


IQ results

IQ scores were 100 for European Americans, 98 for self-described biracial Americans, and 85 for African Americans. The three groups were respectively 99% European, 80% European, and 19% European.

African Americans only

European admixture significantly correlated with IQ among the African American participants. The correlation remained significant after controlling for either skin color or socioeconomic status. Interestingly, skin and hair color didn't significantly correlate with IQ independently of European admixture, but eye color did. Brown eyes correlated positively with IQ. No explanation was offered by the authors. Did they get the same finding with European Americans?

Biracial Americans only - smarter than expected

As with African Americans, skin color didn't seem to influence intelligence independently of European admixture. On the other hand, "biracial status had a significant effect independently of European ancestry." In other words, racially mixed individuals who identified equally as African American and European American, and not just as African American, tended to be more intelligent than what their degree of European admixture would predict. 

The term "biracial" as a badge of identity is recent and seems to be most popular among middle-class people: 


Interestingly, many of the respondents here who identify as biracial are middle class, educated in private schools, and raised in predominantly white neighborhoods with mostly white social networks (Rockquemore and Brunsma 2008, p. xxii)


It may be, then, that self-identified "biracial" people have parents who are, on average, of higher quality than other people of the same racial background.

African Americans, Biracial Americans, and European Americans combined

When all three groups were combined, the most important factor was European admixture. Next came socioeconomic status, which correlated with cognitive ability independently of European admixture. Finally, self-identification as a European American had an effect over and above that of European admixture. The last factor suggests that European American culture has a positive influence on cognitive ability.


Polygenic score results

The polygenic scores ran into a problem that others have noted: the genetic architecture of cognition seems to be different in African Americans. This is a problem because researchers have used only Europeans or European Americans to identify genetic variants that are associated with high educational attainment. Those variants did correlate with cognitive ability in the African American sample, but to a much lower degree than in the European American sample. Their validity as a measure of cognitive ability was only 20% of what it was in the European American sample.

The authors used a subset of the same variants to create a polygenic score that would be less sensitive to linkage disequilibrium decay and thus more valid across different human populations. This polygenic score had good validity in both the African- and European-American samples (r = 0.112 and r = 0.227 respectively).

The authors then tried to create an even better polygenic score by excluding variants that are rare in African Americans. There was no effect on the results for either African Americans or European Americans. But what about the reverse? Perhaps cognitive ability is improved by some variants that are rare in European Americans but common in African Americans.


Conclusion

This is an excellent study, on a par with the Minnesota Transracial Adoption Study (Frost 2019). The main problem is the participants’ young age. Had adults been used, there would have been less noise in the data, and the results would have been better.

Another problem is the apparently different genetic architecture of cognition in people of sub-Saharan African origin. Piffer (2019) has noted that polygenic scores underestimate African American IQ. He disagrees, however, with the "different genetic architecture" hypothesis, pointing out that no divergence exists between mean population IQ and the polygenic scores he has calculated for various sub-Saharan African groups (Esan, Gambians, Luhya, Mende, Yoruba). None of them, however, are Igbo, and the Igbo are really the one group that stands out from other West Africans on measures of intellectual and educational attainment (Frost 2015a, 2015b). They also contributed to the gene pool of African Americans: "Many of the enslaved Igbo people in the United States were concentrated in Virginia's lower Tidewater region and at some points in the 18th century they constituted over 30% of the enslaved black population" (Wikipedia 2019).

While the polygenic score is a good measure of raw cognitive ability in most humans, we need to develop a modified version for people whose ancestry comes primarily from sub-Saharan Africa.


References

Frost, P. (2015a). The Jews of West Africa? Evo and Proud, July 4
http://evoandproud.blogspot.ca/2015/07/the-jews-of-west-africa.html 

Frost, P. (2015b). No, blacks aren't all alike. Who said they were? Evo and Proud. October 10.
http://evoandproud.blogspot.com/2015/10/no-blacks-arent-all-alike-who-said-they.html 

Frost, P. (2019). IQ of biracial children and adults. Evo and Proud. March 10.
http://evoandproud.blogspot.com/2019/03/iq-of-biracial-children-and-adults.html

Lasker, J., B.J. Pesta, J.G.R. Fuerst, and E.O.W. Kirkegaard. (2019). Global ancestry and cognitive ability. Psych 1(1)
https://www.mdpi.com/2624-8611/1/1/34 

Piffer, D. (2019). Evidence for Recent Polygenic Selection on Educational Attainment and Intelligence Inferred from Gwas Hits: A Replication of Previous Findings Using Recent Data. Psych 1(1): 55-75
https://www.mdpi.com/2624-8611/1/1/5  

Rockquemore, K.A. and D.L. Brunsma. (2008). Beyond Black. Biracial Identity in America. Lanham: Rowman & Littlefield Publishers.
https://books.google.ca/books?id=Nf0eAAAAQBAJ&printsec=frontcover&hl=fr&source=gbs_ge_summary_r&cad=0#v=onepage&q&f=false

Wikipedia. (2019). Igbo Americans
https://en.wikipedia.org/wiki/Igbo_Americans

Wednesday, September 18, 2019

Have we been selected for long-term thinking?


GDP per capita as a function of future orientation (Preis et al. 2012)



To what degree do we value the short term over the long term? The answer varies not only from individual to individual but also from society to society. Hunter-gatherers, for instance, value the short term. Perishable food cannot be stored for future use and, in any case, is not normally obtained in large enough amounts to make storage worthwhile. If a hunter gets more meat than his family can consume, he'll give it away to others in the local band.

There are exceptions, especially at northern latitudes. Meat can be stored in caches during winter and in cold lake waters during summer. With limited opportunities for food gathering, women specialize in technologies that need more cognitive input and longer-term thinking, like garment making, needlework, weaving, leatherworking, pottery, and use of kilns. Finally, men hunt over longer distances and therefore plan over the longer term. Northern hunting peoples thus broke free of the short-term mental straitjacket imposed by hunting and gathering. In time, their descendants would spread south and rise to the challenges of social complexity (Frost 2019).

Those northern hunting peoples were better able to exploit the opportunities created by farming, but the transition from one lifestyle to the other was still far from easy. Farming requires not only longer-term thinking but also less monotony avoidance and higher thresholds for expression of personal violence. In recent times, hunter-gatherers usually refused offers to be settled on farms. They saw farming as akin to slavery.

The change in mindset didn't end with the transition to farming. There were different types of farming, and some required longer-term investment than others. Those types generated stronger selection for future orientation.


Language as a mirror of cultural evolution

Galor et al. (2018) argue that language is a mirror of cultural evolution. It can show a society’s degree of commitment to a long-term mindset, as well as other psychological traits.


The periphrastic future tense

The authors studied the relationship between future orientation and forms of the future tense that express intention and obligation, rather than simply prediction:

Languages differ in the structure of their future tense. In particular, linguists distinguish between languages that are characterized by an inflectional versus periphrastic future tense [...]. Inflectional future tense is associated with verbs that display morphological variation (i.e., a change in the verb form that is associated with the future tense). In contrast, periphrastic future tense is characterized by roundabout or discursive phrases, such as `will', `shall', `want to', `going to' in the English language [...] (Galor et al. 2018, p. 6)

[U]nlike the inflectional future tense, the periphrastic future tense is formed by terms that express a desire, an intention, an obligation, a commitment as well as a movement towards a goal. In particular, in the English language, "shall has developed from a main verb meaning 'to owe', will from a main verb meaning 'to want', and the source of be going to is still transparent" [...]. Moreover, "intention and prediction are most commonly expressed by the periphrastic future, while the synthetic one is more common in generic statements, concessives, and suppositions" [...]. Inflectional futures "also appear systematically (often obligatorily) in sentences which express clear predictions about the future (which are independent of human intentions and planning), whereas less grammaticalized constructions [i.e., periphrastic] often tend to be predominantly used in talk of plans and intentions - a fact which is explainable from the diachronic sources of future tenses" [...] (Galor et al. 2018, p. 6)

Galor et al. (2018, p. 16) used pre-1500 AD data to estimate the return on agricultural investment ("crop return") in the homeland of a language’s speakers. They found a positive correlation between this return on investment and the existence of a periphrastic future tense. They concluded that "a one standard deviation increase in crop return in the language's contemporary homeland is associated with a 6 percentage points increase in the probability that the language is characterized by a periphrastic future tense."

Using the World Values Survey, the authors also found a positive correlation between the existence of a periphrastic future tense and future orientation. The correlation held true both for the people of the world as a whole and for Old World peoples who speak languages originating in the Old World (Galor et al. 2018, p. 23).

Interestingly, the return on agricultural investment did not correlate with other linguistic characteristics, like the existence of the past tense or the perfect tense, the existence of possessive classifications, the existence of coding for evidentiality, the number of consonants, and the number of colors (Galor et al. 2018, pp. 18-19).


Grammatical gender

The authors also looked into the relationship between grammatical gender and the sexual division of labor in a language's homeland:

Further, consider ancient civilizations that had been characterized by a sexual division of labor and consequently by the existence of gender bias. Linguistic traits that had fortified the existing gender biases have plausibly emerged and persisted in these societies over time. In particular, geographical characteristics that had been associated with the adoption of agricultural technology that had contributed to a gender gap in productivity, and thus to the emergence of distinct gender roles in society (e.g., the suitability of land for the usage of the plow […]), may have fostered the emergence and the prevalence of sex-based grammatical gender in the course of human history. (Galor et al. 2018, p. 2)

Galor et al (2018, p. 24) found a negative correlation between grammatical gender and “plow negative” crops (i.e., crops not requiring use of the plow and, hence, requiring less male participation). A one standard deviation increase in the potential caloric yield of plow negative crops was associated with a 13 percentage point decrease in the probability that the language has grammatical gender.  The correlation was reversed in the case of all crops, the caloric yield now being associated with a 17 percentage point increase in the probability that the language has grammatical gender.


Politeness distinctions in pronouns

Finally, Galor et al. (2018) looked into the relationship between politeness distinctions in pronouns and ecological diversity, which they related to the emergence of hierarchical societies.

Linguistic traits that had reinforced existing hierarchical structures and cultural norms had conceivably emerged and persisted in these stratified societies in the course of human history. In particular, politeness distinctions in pronouns (e.g., the differential use of "tu" and "usted" in the Spanish language, "Du" and "Sie" in German, and "tu" and "vous" in French) had conceivably appeared and endured in hierarchical societies. Thus, geographical characteristics, such as ecological diversity that had been conducive to the emergence of hierarchical societies (Fenske, 2014), may have contributed to the emergence of politeness distinctions. (Galor et al. 2018, p. 2)

Galor et al. (2018, p. 32) found a significant relationship between politeness distinctions and ecological diversity in a language's homeland. A one standard deviation increase in ecological diversity corresponded to a 15 percentage point increase in the probability that the language has politeness distinctions.

I'm skeptical about the last finding. Is ecological diversity conducive to hierarchical societies? The authors refer to a study that mostly uses African data. More to the point, the study seeks to link ecological diversity to centralized states. Centralization of state power and social hierarchization are not the same thing. Japan, for instance, had a weak central state for much of its history and yet was very hierarchical, as seen in the politeness distinctions of the Japanese language.


Conclusion

Although the authors refer to work by L.L. Cavalli-Sforza, Peter Richerson, and Robert Boyd on gene-culture coevolution, they avoid discussing the possibility that selection for future orientation, gender specialization, and hierarchical politeness has influenced not only culture and language but also human biology. The coevolution they propose is simply between culture and language. It can be summed up as follows:

- Certain patterns of mind and behavior have been favored to varying degrees in different societies.

- These cultural patterns are transposed into language.

- Language then reinforces those cultural patterns: "In light of the apparent coevolution of cultural and linguistic characteristics in the course of human history, emerging linguistic traits have conceivably reinforced the persistent effect of cultural factors on the process of development" (Galor et al. 2018, p. 1).

Language is not a passive mirror of culture. It can also act upon culture. For instance, the way we perceive the future, and its relative importance to us, may be shaped by the way we speak. This is of course the Sapir-Whorf hypothesis.  In a farming society, the periphrastic future tense might make it easier to envision farming methods and technologies that pay off over the longer term. Similar arguments have been made for grammatical gender and politeness distinctions. The way we speak influences our thoughts and behavior.

Again, the authors leave it to the reader to go one step farther: patterns of mind and behavior may influence the frequencies of alleles in the gene pool.


References

Fenske, J. (2014). Ecology, trade, and states in pre-colonial Africa. Journal of the European Economic Association 12(3): 612-640.
https://www.eeassoc.org/doc/paper/20130704_190013_FENSKE.PDF 

Frost, P. (2019). The Original Industrial Revolution. Did Cold Winters Select for Cognitive Ability? Psych 1(1): 166-181
https://doi.org/10.3390/psych1010012 

Galor, O., O. Özak, and A. Sarid. (2018). Geographical Roots of the Coevolution of Cultural and Linguistic Traits (November 7, 2018). Available at SSRN: https://ssrn.com/abstract=3284239 or http://dx.doi.org/10.2139/ssrn.3284239  

Preis, T., H.S. Moat, H.E. Stanley, and S.R. Bishop. (2012). Quantifying the advantage of looking forward. Scientific Reports 2: 350
https://www.nature.com/articles/srep00350