Endemic Pathogens are Making You Crazy and Then Killing You

Nobody warned you about them, but they’re destroying your mind and they’re everywhere.

In science, the process is just as important as the discoveries; improving our scientific processes will speed up our rate of discovery. Austrian philosopher Paul Feyerabend claims that contemporary research has over-indexed on processes such as the scientific method and this rigidness has restrained innovation. The crux of his book Against Method is that paradigm shifts in science stem from epistemological anarchism – epistemology refers to the formulation of beliefs. This anarchy, to any Thomas Kuhn fans, is what is necessary to achieve Kuhn’s Stage 4 phase of science, the “revolutionary phase” in which new paradigms are created. In recent decades we have placed too much importance on science being consistent, while forgetting that paradigm shifts often come from those who refute mainstream assumptions. In other words, the geniuses who generated scientific paradigm shifts were anarchists to their contemporaries. Or success came when they made mistakes, take vaccines for example.

The modern medical sense of immunity meaning "exempt from a disease" dates back to 1879, when Louis Pasteur produced the first laboratory-developed vaccine: a vaccine for chicken cholera. Pasteur happened upon his breakthrough by accident. His lab was studying fowl cholera by injecting chickens with live bacteria and recording the fatal progression of the illness. Pasteur had instructed an assistant to inject the chickens with a fresh culture of the bacteria before they both went on vacation. The assistant, however, forgot to inject the chickens before he left. When the assistant returned a month later, he finally injected the chickens with the bacteria, which was now a month old. Unlike with their typical experiments with the bacteria, this time, the chickens only showed mild signs of the disease, and survived. When they were healthy again, Pasteur injected them with fresh bacteria. The chickens did not become ill. This is how we got vaccines.

Epistemological Anarchy

Despite how popular immunology has become as a field in recent times, it's important to clarify some terminology.

A pathogen is an organism that causes disease, of which there are five main types: viruses, bacteria, fungi, worms, and protozoa. An epidemic refers to a disease spread across a local region: for example, an isolated flu outbreak in a city. We should all know what a pandemic is by now. It is an epidemic disease that has spread over a much larger area: for example, a country, a continent or the whole world. Endemic diseases have a level of permanence among a given population. Herpes viruses are globally endemic: ~ 3.7billion people for herpes simplex 1 (HSV-1) alone.

For many people, infections like HSV-1 remain asymptomatic and do not produce symptoms like the cold sores they are usually associated with. But our cultural mistake is thinking that the occasional cold sore is the main fear factor of carrying latent (dormant) infections like HSV-1. In reality, the dangers of us living with endemic diseases like HSV seem to be tied to several later-onset neurodegenerative diseases and even chronic illnesses such as cancer.

Communicable diseases spread from one person to another in many ways: contact with bodily fluids; breathing in an airborne virus; by being bitten by an insect. Noncommunicable diseases aren’t spread from person to person, they are chronic conditions that don’t seemingly stem from infection: heart disease, cancer, and diabetes, for which a complete cure is harder to achieve.

However, communicable infectious disease exposure may be causing noncommunicable chronic conditions much more than we think. There is plenty of research that demonstrates the link between infectious diseases and later health issues. For one example, new research solidifies the link between Epstein-Barr Virus (EBV), the virus that causes mono, and the chronic, debilitating neurological condition known as multiple sclerosis. The average person, while often being a carrier, is not aware of these risks.

In addition to being asymptomatic, infections can also be latent, as with the herpes virus, meaning they reside in the body for years before they flare up in a myriad of different ways. Latent pathogens, once they infect you, are with you for life.

What’s more, you have been exposed to and carry probably several, if not even dozens, of latent diseases. Maybe you had glandular fever as a kid. If so, then that Epstein-Barr virus has never left your body. Probably at least one of the herpes viruses is hanging out in your nerve ganglia. You may have Toxoplasma gondii in your brain, which can rob you of your agency and influence your risk tolerance and behavior. Have fertility issues? Maybe it’s from trichomoniasis, a sexually transmitted parasite that 1.1 million Americans carry, but hardly anyone knows about because 70% of its victims show no symptoms. Trich is linked to infertility in both men and women, though couples with fertility issues aren't always tested for it. 

The belief that the threat of infectious diseases had been conquered was widespread in the second half of the twentieth century. In 1978, one of the world’s leading authorities in communicable diseases, Robert Petersdorf, commented that he could not conceive of much of a need for many more graduates to study infectious diseases. As late as 1985, Dr. Petersdorf persevered in this belief; at the Infectious Diseases Society of America's annual meeting that year, he stated that “the millennium where fellows in infectious disease will culture one another is almost here.”

Paul W. Ewald in his book Plague Time suggests that another reason for the slowing down of research in infectious diseases was scientists relying too heavily on guidelines for identifying infectious causation set forth by Robert Koch in 1880. These postulates ultimately proved not to be true in all cases. Koch himself did not make this error – he specifically cautioned against using his guidelines as the only basis for ascribing infectious causation. Despite this, many experts assumed and postulated that infection causation could only be accepted when all of these guidelines had been met. Even if important evidence of infectious causation is available, research has often been dismissed if Koch’s postulates have not all been satisfied. This highlights Feyerabend’s point: we often need epistemological anarchy to break the reliance on dogmatic truths. In some cases, it’s the only option.

Hijacking Biology

One idea largely anarchic to the current paradigm is that endemic pathogens cause issues as broad as cancer and schizophrenia. Oddly enough, the hypothesis that viral pathogens are neurodegenerative is increasingly grounded in evidence; yet laymen are still stuck to our idea that lifestyle correlations are entirely to blame. And yes, sure, while smoking may correlate with cancer, several herpes viruses, which two-thirds of us carry, induce tumors in animal species. Wellness fanatics flinch at people smoking, but have no insight into the herpes virus permanently lodged in their brain cells.

True, it’s tough to determine whether a pathogen plays a causal role in a given chronic disease. Maybe that’s why contemporary biomedical research doesn’t go after it with the same gumption it does for other causes. Firstly, the timing delay between exposure to an infectious pathogen and a chronic disease appearing could be decades. This creates a study timing problem, which can only be solved if you have a large enough population sample in which you can correlate infectious disease antibodies and noncommunicable disease symptoms. But still, that’s not enough. Different genetic variants of infectious pathogens manifest in people differently. Furthermore, genes may play a role in the onset of a chronic illness. For example, this review links Herpes simplex 1 with the activation of a gene known to increase the risk of Alzheimer's.

Biology is hard. Such research is complex and fraught with ethical limitations. You can test a pathogen by infecting laboratory animals but not in humans, leading to conclusions about how such pathogens actually manifest in people. On top of that, we would expect pathogens to cause diseases indirectly, as well, such as via autoimmune processes induced by the pathogen. This seems to be the case for several chronic illnesses, and it makes it hard to track.

Do you suffer from anxiety? Maybe it comes from a previous exposure to cytomegalovirus. Mostly asymptomatic, cytomegalovirus is a beta-herpes virus which once it has infected you, again stays for life. Infection is associated with increased serum concentrations of cytokines (especially TNFalpha and IL-6) which are also related to mood and wellbeing. Individuals with higher CMV-specific antibody loads were more likely to be depressed, anxious, and suffer more overall psychological morbidity.

Have attachment-anxiety issues in relationships? In this study, individuals with attachment-anxiety issues had higher levels of antibodies to Epstein-Barr. Another study of college students showed those with EBV antibodies had more defensiveness and anxiety overall. EBV exposure even seems to correlate with how emotionally repressed you are as a writer. If you've never had EBV, perhaps your anxiety and depression comes from exposure to Helicobacter Pylori, or toxoplasmosis. There is a strong correlation between gastrointestinal issues and psychiatric disorders, yet psychiatrists rarely work with gastroenterologists to identify the root of the problem.

Have a child with autism in the family? Perhaps they got it from their mother's immune response to a pathogen during pregnancy. Women with high levels of antibodies to Herpes simplex 2 midway through their pregnancies were twice as likely to have a child later diagnosed with autism. A 2013 study found that women who had flu while they were pregnant were also twice as likely to have a child later diagnosed with autism.  According to this study of more than 95,000 women, pregnant women who had a fever lasting a week or longer – perhaps caused by influenza or another pathogen – were three times as likely to have an autistic child. The link is strongest in the second trimester, when a single fever is associated with a 40% increase in autism risk. Three or more fevers after the first trimester triples the risk of having a child with autism and yet, we rarely hear about it. It's likely that inflammatory chemicals such as cytokines are crossing the placenta and affecting the developing brain of the fetus, causing birth defects, chronic illnesses, and delayed psychiatric issues.

Experience manic episodes that are classified as a bipolar disorder? Maybe you got it from a Borna virus exposure. This relatively overlooked disease, also amusingly known as sad horse disease, is an infectious neurological syndrome of warm-blooded animals. Borna disease research came largely to a halt because most human studies do not focus on examining brain tissue (as samples are rarely available), but rather, blood samples, where viral loads are much lower. Luckily, research is beginning to kick back off again.

Contemporary society champions neuro-diversity and makes it taboo to consider that our psychological issues could have a biological causation. Telling someone that their mental health issues could come from pathogen exposure demeans their experience in individualistic societies. 

How many people are wasting their money on therapies focusing on the “mind” and not on treating their hijacked biology? Perhaps the time is nigh to focus more on this connection in order to develop vaccines that can literally prevent chronic diseases for which there are no cures, and which, for decades, the scientific community has blamed on genetics and lifestyle components.

An Unusual Suspect

If you’ve heard of toxoplasmosis, it is usually because pregnant women are told to avoid scooping cat litter as cat feces can infect future mothers who then pass it onto their babies. In fact this risk is massively overblown. The prevalence of Toxoplasma oocyst shedding in cats is very low (0 to 1%), even though 15 to 40% of cats have been infected with Toxoplasma at some point. This means very few cats at any one time are actually able to pass their infection directly onto people.

The real risk comes from toxoplasmosis being endemic in cattle – the numbers are shocking. As many as two-thirds of pigs and a third of dairy cows tested seropositive for toxoplasmosis, though the numbers differ across different regions. You're picking toxoplasmosis up from the meat that you eat and most likely not from directly handling your favorite feline friend. It's a shame that the CDC puts so much pressure on expecting mothers rather than addressing the fact that toxoplasmosis is so widespread in cattle. In 2020, a fascinating paper came out that demonstrated toxoplasmosis has an epigenetic signature, meaning the descendants of toxoplasmosis carriers can still have affected brains. We really can’t escape it, which is perhaps one of the reasons why Big Pharma isn’t incentivized to go after it.

It is thought that potentially up to two-thirds of people carry it, though it is more heavily prevalent in the West than the East, especially in countries with a culture for consuming undercooked meat, e.g. France with their beloved steak tartare. Cats are the definitive (originating) hosts for toxoplasmosis, and they pass it to others via their feces, which, if ingested by scavenging or grazing animals such as rodents, pigs, and cattle, can then harbor the parasite in their brain and other body tissues.

People who catch toxoplasmosis often have no symptoms. If they do, they may experience an acute infection of mild flu-like symptoms. Think about how many times you've had a cold or mild flu, perhaps one of those times it was actually from a pathogen such as Toxoplasma. After entering your system, the toxoplasmosis infection then enters a dormant phase, during which bradyzoites (slow, multiplying cell forms) create clusters within a cyst that become permanently lodged in your muscle and brain tissues. Toxoplasma gondii is occasionally also found expressed in conditions around the eyes, the lining of the lungs and also the heart.

However, the real damage happens in the brain. Toxoplasma gondii alters the molecular composition of the brain’s connections, which are known as synapses. Toxoplasma gondii is only able to reproduce in the stomachs of cats (for reasons explained momentarily). So, its evolutionary challenge has been to figure out how to get rodents into cats' stomachs. Toxoplasma has 'decided' that the best way to do this is to make rodents like the smell of cats: it is thought to rewire their motivational system through changing the association of the scent of cat urine from aversive to appealing. Toxoplasma does this through changing the motivational system by altering reward-associated neurotransmitter systems, thus making rodents more likely to be eaten.

Studies show that Toxoplasma gondii carriers have fewer proteins in the vicinity of the glutamate-releasing excitatory synapses, which make up 30-40% of the brain. Malfunctions of these synapses are associated with depression, schizophrenia and autism, among other conditions. Toxoplasmosis seropositivity was associated with a three-fold greater risk of anxiety disorders, and a seven-times greater risk of suicide attempts, especially in women over forty. People who find themselves influenced by Toxoplasma gondii find themselves with higher rates of problems with regulation of their behavior, higher rates of car accidents, higher rates of suicide attempts, due to elevated impulsivity. And importantly, it increases the risk of schizophrenia.

Two separate reviews into toxoplasmosis and schizophrenia have both found that people infected with the parasite are about 2.7 times more likely to express schizophrenic symptoms. In a sane world, we would take a bunch of the taxpayer money we spend on mental health awareness and pour it into the study of pathogens like EBV and toxoplasmosis! It gets worse. In one study, the prevalence of toxoplasmosis in particular countries appears to correlate with 23% of disease burden variability. This paper is fascinating. For noncommunicable diseases, a difference of 1% in the prevalence of toxoplasmosis corresponded to a difference of 26.33 Disability Adjusted Life Years per 100,000 inhabitants. In other words, a 1% increase in toxoplasmosis cases was associated with the loss of the equivalent of 26.33 years of full health per 100,000 people. In the paper, the prevalence of toxoplasmosis potentially explained 6.4% between countries variability in DALY.

Okay, I know, correlation does not equal causation. However, can we all agree that we should be looking more into toxoplasmosis?!

Toxic Animorphs

Why aren't we tackling pathogens like Toxoplasma with the same gumption that we tackled COVID-19? Firstly, it's probably simply too endemic for people to care. Pathogens such as Toxoplasma, Herpes and Epstein-Barr have become part of our normal way of life. Unless you have cold sores, genital herpes, or glandular fever, you may not even be aware that you carry Herpes simplex or EBV. As for toxoplasmosis, you really have no idea. Before today, you may not have even known about it. And if you want to test for it, a regular doctor will think you're insane. Tests are not easily accessible, and most toxoplasmosis tests are for acute symptomatic infections. I've worked with a doctor over the last few years to generate a blueprint of my pathogen exposure via antibody testing and have put considerable effort into reducing my HSV-1 (cold sore) viral load and much to my surprise, according to the few types of toxoplasmosis IgG antibody tests that are available (and that I have repeated) I am supposedly not a carrier.

That doesn't make Toxoplasma any less scary to me. We are all only one slice of infected dry-cured ham away from it being permanently lodged in our brains.

Without knowing the mechanism of causation, the links between infectious pathogens like Toxoplasma gondii and later noncommunicable diseases are too vague, delayed and complicated for most academic researchers to go after. But we should be going after them. We should be doing so much more than what we are doing.

However, there are also specific issues with toxoplasmosis research that have delayed the field. Remember, the definitive hosts of the pathogen are cats. However, testing on cats is a sensitive subject – so much so that, due to activist pressure, the world's leading toxoplasmosis lab in Maryland was forced to close in 2019. The lab, which opened in 1982, operated on only $625,000 of funding a year.

As this Science article above shows, the world’s leading toxoplasmosis lab was forced to close in 2019. The United States Department of Agriculture (USDA) issued guidance to ban toxoplasmosis research with cats following pressure from animal rights activists.

When I first started worrying about the lack of toxoplasmosis research going on, I considered that a path forward may be using a foreign libertarian charter city to set up an experimental lab to restart testing on cats. The utility calculation of doing this, in my opinion, massively outweighs the harm and loss of cats used in research. I write this as a staunch cat lover. However, the damage from toxoplasmosis on humans appears to be very serious, so serious that I would take on the role of the hated leader of the foreign cat-killing research lab for the sake of future generations if needed.

That was until I found this paper. The highlight of my year was stumbling across a paper entitled Intestinal delta-6-desaturase activity determines host range for Toxoplasma sexual reproduction. As mentioned previously, cats are the only definitive hosts of toxoplasmosis. The biological reasons behind this were largely unknown. That was, until now. Here, the researchers noted that cats are the only mammals that lack delta-6-desaturase activity in their intestines. Delta-6-desaturase is an enzyme required for linoleic acid metabolism. It results in cats having systemic excess of linoleic acid. By inhibiting delta-6-desaturase in mice, and supplementing their diet with linoleic acid, Toxoplasma gondii development happened in mice. Yes, by deactivating delta-6-desaturase and giving mice linoleic acid, you can, in the eye of Toxoplasma gondii, turn mice into cats.

I repeat: WE CAN TURN MICE INTO CATS.

^{Source: Di Genova et al., 2019}

This species barrier alchemy is potentially huge for the field of toxoplasmosis research. With this advance, cats’ lives can be spared and toxoplasmosis research can also become more cost-effective!! But first, we need to make people care enough and incentivize them to research it in the first place!

Plans

I am optimistic that, in the future, people will begin to grasp the link between infectious disease and chronic conditions, especially psychiatric issues. The question remains: how can we capitalize on this knowledge to drive new breakthroughs?

After thinking through these topics, the first obvious thought was that it would be useful to set up a new philanthropic foundation to focus on the intersection of neuroscience, psychiatry and immunology. The initial goal of the foundation would simply be education and outreach. How many people with psychiatric disorders have never been tested for (or treated for) the potential pathogenic causes behind their symptoms? Educating people on these topics and getting more doctors to offer the necessary blood and stool tests to rule out pathogenic causes before commencing psychiatric treatment could potentially help millions of people.

The second goal of the foundation would be to fund and incentivize research. Working with researchers in the field, we are currently compiling a list of datasets and tools that would be valuable to help us understand different disease causal mechanisms and their effects on the brain. Not all of it needs to be clinical or lab based. We have made progress simply by parsing and making correlations with already existing published research. Depending on how valuable and hard certain data are to collect, we are then pricing research questions with the goal to offer bounties or grants for those willing to take the projects on. The bounty model also offers a way for philanthropic donors to have transparency on where the foundation's investments are going. This is personally important after years of being pitched non-profits that seem to serve as hobby projects for the wives of rich men in order to organize charity galas.

After spending some time working on the bureaucratic overhead of setting up a foundation, a chance conversation with a friend resulted in the offer of doing the outreach and bounty initiative under an already existing neuroscience foundation. Another close friend is launching a Focused Research Organization to look directly at several key areas of immunology and it is also our imperative to ensure her and her team get all the necessary funding. If you are interested in funding these research areas, please reach out.

Lastly, almost all pathogen exposure harm is lessened by adequate Vitamin D levels in the blood and it is estimated that ~40% of U.S. adults are deficient in it. Before you reach out for your Vitamin D pills, know that thanks to a statistical error, general recommendations for supplementing Vitamin D daily (600 IU) are massively underestimated. Consult your doctor, but be aware of their limits and do your own research.

Editor's Note: This essay was adapted and edited from the writer's personal blog, Hard to Write.