Friday 18 September 2015

Smarts Update: Bacteria and Schizophrenia: When Smart Communities Collide

My new book Smarts devotes a chapter to the intelligent behavior of some of the smallest living things among us, the bacteria. It tells the story of James A. Shapiro, one of the leading bacterial geneticists of the last century, who helped change the way we think about bacteria, among the oldest forms of life and the most successful. They can be found in the thermal vents of the deepest deeps and at the outer reaches of the atmosphere. As they live and die they re-cycle vital elements from sea, soil, rock, and air, which helps maintain the global temperature within a range conducive to life. There are so many species with so many different attributes that no one can say how many kinds there are or what they can do.  

About thirty-five years ago, Shapiro began to revise the then accepted story that bacterial genes are the sole directors of bacterial behavior. He began to ask how bacteria interact with each other in nature.  How do they process information, how do they sense and respond to their environments? His observations forced him to these startling conclusions: they rewrite their own genes, and they behave intelligently. Though bacteria are tiny and utterly brainless, in their natural social groups they find food, evade enemies, create means of transport unavailable to single cells, make peace and war: in other words, they make choices. It appears their information exchange system is as global as ours. Like us, they can do things as communities that they cannot do as individuals.

Shapiro’s work fits within a larger body of ideas about how evolution works—not just by successful competition to the death, but also through cooperation, collaboration, and symbiosis, and above all through the sharing of information by all kinds of different living things, mostly in the form of molecules. In the real world, as opposed to the lab, bacteria live  as communities among communities -- amid fungi, viruses, plants, and beasts. Like us, they prey on others and in turn are preyed upon. Viruses called phages can insert themselves into a bacterial cell and take over its replication system, using the bacterium to copy themselves. These phages carry bits and pieces of genes from one host to another, altering genomes as they go, sometimes altering attributes in a way that proves useful or otherwise. In other words, phages constitute a genetic information transport system. Records of such viral invasions can be seen in every genome, plant, animal or human. The inserted genetic bits are copied every time a cell splits, and sometimes they even jump around to new positions which can also generate new attributes. This is not purposeful tinkering, like human genetic engineering, but it is genetic engineering nonetheless. Over the long haul of evolutionary time it allows all of us living things to “learn” from the experience of others.

But our relations with bacteria are broader than the odd bacterial gene insinuating into our cells thanks to some invading virus. We also cooperate and fight with living bacterial communities every minute of the day. They colonize us first as we pass through the birth canal. Over time, they populate our mouths, guts, skin, hair, every part of us. We help them by providing warm and safe conditions, they help us to digest food, get rid of wastes, and fight off other invaders. We call the communities that live in us and on us microbiomes. Recent studies have shown that these microbiomes affect everything about us from the state of our guts to the state of our minds. When our communal relationships go awry, our health will go too.   

Apparently, healthy people enjoy just the right balance of these cooperative life forms.

Some of us in the West, especially the libertarians, think of human beings as individuals, as if each of us sprang fully formed from Zeus’s head as did the Goddess Athene. In that worldview, we humans are supposed to be subject only to our own wills, and are able to make moral choices. But Shapiro’s science presents a different picture, an embedded, entangled one. Individuals cannot survive without their community of communities and these interactions, which go every which way, shape everything about us, from the cut and thrust of our intelligence to our emotions.

The most intriguing new offerings from some of Shapiro’s colleagues suggest that even major psychiatric disorders may be triggered by imbalances among the communities that constitute our microbiomes. If they are right, they have made a great breakthrough in the struggle to relieve human suffering. Everybody has a family member or knows someone in another family who is struggling with mental illness, everything from serious depression to anxiety to schizophrenia. Who doesn't wonder why the various pills on offer don’t work very well, and certainly don’t cure? And why has no one been able to nail down the cause of schizophrenia, for example, even 100 years after it was first described?

For me, these questions are more than a little personal.

For one thing, I grew up about two blocks from the home of Dr. Abram Hoffer, a pioneer of modern psychiatry who sought to uncover the brain chemistry of schizophrenia, even trying to recreate analogous states with the use of LSD.

For another, two of my closest friends lost their son to depression via suicide. 

And finally, two years ago, a life-long friend was killed by a schizophrenic.

We were sandbox friends. Our fathers were medical colleagues who had known each other since they were kids. Our mothers were friends too. Our families went to the same lake every summer and gathered together on the same beach or went to each others’ cabins to play when it rained. When I had kids, my husband and I took them to that same lake every summer and when my friend built a  cottage for his family on a neighboring body of water, he took my children out on his boat the way his father and uncles used to take me. His Dad passed away when we were teenagers. It was terrible for him and for his siblings, and it wasn’t easy for me either. His father had been my favorite doctor and he had been trying to get rid of my asthma by injecting me with dilute substances that my immune system overreacted to. He worked his whole life from before dawn to after dusk to take care of our city’s sick children, especially those crippled physically, cognitively, or emotionally.

When their son was born, my friend and his wife gave him his father’s name. It is a Jewish tradition to name a baby for someone who has passed away. It helps us to remember that person but there is also an element of magic to it, as if by giving the name to the baby we can also transfer the dead person's best attributes, pass his goodness forward.

It didn't work that way for my friend's son. He began to display symptoms of schizophrenia when he was in his teens. There were no special facilities in town to treat kids with such illnesses. So my friend and his wife lead awareness campaigns and raised a lot of money to build a new facility for children. They also took their son to the best specialists they could find. He would be fine for a while, but then he’d stop taking his meds, and then descend into hell.

Two years ago this summer, he went to the family cottage to visit his parents. He killed my friend with a kitchen knife. He was arrested, he was jailed, and he was sent for a psychiatric assessment. Late last spring he stood trial and was found not criminally responsible. I’ve stared and stared at the photo of him carried on all the news sites that reported on the trial because he is a ringer for my friend, his father, at the same age.

As you might imagine, when a paper appeared last month offering important new information about schizophrenia, I grabbed it. It appeared in the online journal PeerJ. It's very smart work. It examined the differences in the microbiomes found in the throats of schizophrenics and healthy controls.

The paper has nine authors, starting with Eduardo Castro-Nallar of George Washington University.  Robet H. Yolken of Johns Hopkins School of Medicine is also on the list. Yolken has been looking for correlations between the development of schizophrenia and exposure to infectious agents like fungi, viruses, or bacteria for a long time. In a review he published in 2004 with E. Fuller Torrey, he refers to, among other things, a relationship between the onset of schizophrenia and exposure to cats in early life. A 2013 study by Yolken and another group identified the “phageomes” (the viral communities that prey on bacteria) found in the throats of 41 schizophrenics and compared them to 33 controls. It turned out the schizophrenics had much higher levels of Lactobacillus phage phiadh. These levels also correlated with other immunological disorders, and with the use of a drug called valproate, “shown in animal models to alter the microbiome.” The paper suggested that using a drug to alter phage levels might affect the disease.

In this study, the authors set out to identify all the communities living in the throats of schizophrenics versus controls because, they wrote, “ The role of the human microbiome in schizophrenia remains largely unexplored.”

First, they laid out their reasoning as to why this might prove fruitful by reviewing earlier studies that suggested both genetic and environmental components to schizophrenia. One big genetic study had supported the theory that schizophrenia either causes, or is a product of, immune dis-regulation. They referred to other studies that have shown that microbiomes “modulate” the immune response, that the balance of these groups can effect intestinal conditions such as “Crohns and other Inflammatory Bowel Diseases and also… the development of system immune diseases such as rheumatoid arthritis, Type I diabetes and allergic diseases.” They mentioned studies that have shown that gut biota “affect brain development” and “modulate cognition” and that changes in the balance of various microorganisms in the gut have an impact on “anxiety-like and depression-like behaviors and have been linked to neuro-developmental disorders such as autism spectrum disorder and multiple-sclerosis.”

Then they got down to business. They described how they identified every life form and its relative representation in the throats of 16 schizophrenics versus 16 controls. They matched the controls to the schizophrenics in every way (age, gender, race, socioeconomic status, smoking). They took swabs from the backs of their throats and identified the things growing on those swabs by means of a “shotgun metagenomic analysis.”

They discovered that the various bacteria, viruses and fungi living in the schizophrenics differed distinctly from those in healthy controls. Schizophrenics had more species, more evenly spread, whereas healthy controls had fewer species, with a few that were dominant.

In particular, the schizophrenics had more lactic acid bacteria, especially Lactobacillus gasseri, which was 400 times more abundant in schizophrenics than in controls. Because of the differences in the species and distribution of  microbes, they concluded that certain kinds of signaling pathways were also more abundant in schizophrenics than in controls, pathways related to “environmental information processing, particularly transport systems.” As the authors put it, “L. gasseri has been shown to modulate the immune system by altering the function of dendritic cells, enterocytes, and components of innate immunity.”

What do these differences mean? Are too many species evenly spread in a microbiome the cause of schizophrenia? Or are they the result? The study could not address those questions. Clearly a lot of work remains to be done. But at least one group of researchers is heading down a very smart path.

Stay tuned for more.

And eat your probiotics every day.

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