# [Book Review] "I Contain Multitudes" by Ed Yong

I have read this book once before, just before I went to university, and I found it immensely enlightening at the time. Now I return to it as an older man, and find it has lost a lot of its shine. I don't know if this is reflective of my loss of naivete, or increase in biological knowledge.

Core Thesis
-----------

The subject of this book is the microbiome. This is the community of micro-organisms (although it's almost all focused on bacteria with a small amount of emphasis on viruses) that live around us, on us, and inside us.

The book is mostly a long series of interesting investigations into the microbiomes of humans and animals. What is implied (and sometimes said outright) is that biologists have neglected studying it.

The history of the study of microbiology is explored in detail. As I am not a huge fan of scientific history literature I mostly skimmed this but I expect it would be interesting to many people. Some key points here are the origins of the focus on microbes as pathogens and parasites, and how this idea has changed to focus more and more on symbiosis over time. We need our microbes and they need us!

Microbes do not have the same properties when it comes to genes as do large organisms. They can and do frequently exchange genetic material with other microbes. This means that in a microbiological community, the set of all genes present is more important than the set of specific microbes.

### Holobionts and their Hologenomes

This culminates in the concept of the "hologenome". This is the set of genes in both an organism and its microbes, which are together referred to as a "holobiont". Hologenomes have some properties common to mere "genomes", such as the construction of biological pathways (which are like manufacturing lines, the product of one reaction being the starting-point of the next) using genes from many different bacteria and the host.

On the other hand, genomes of macroscopic organisms are generally static, only changing upon being transferred to the next organism. Hologenomes contain the "core" genes of the main organism, and it's necessary symbionts. Other genes are part of slow-changing microbes, and others still are ephemeral. Microbial genes are subject to different types of natural selection depending on their relationship to the host.

This perspective is genuinely very interesting. It's a different way of thinking about organisms and their bacterial communities, and I think it's the strongest part of the book.

Cool Facts
----------

One thing this book certainly doesn't lack is cool facts about biology. Honestly some of these things are so cool and interesting that if you're a sucker for cool biology facts it's worth reading the book just for these. Here's a selection:

*   The human body contains more bacterial cells than human ones, but there are 500 times more different genes in the bacteria than in your own genome
*   Human gut mucus has an incredibly high concentration of bacteriophage viruses (which infect bacteria) embedded into it, which help prevent gut bacteria from invading the body.
*   Babies' immune systems actively suppress themselves to allow for bacteria to colonize them after birth. They then learn to tolerate these bacteria in the gut.
*   Human milk contains special sugars (HMOs) which induce lots of bacteria to behave differently in the guts of infants. They also seem to prevent infection of human cells by bacteria in cultures.
*   The Hawaiian bobtail squid is able to use tiny water currents to filter bacteria from the water, detect as few as *five* cells of a specific type of bacteria (*Vibrio fischeri*), and then cultivates them in special organs. It uses these to produce light to hide its own shadow from creatures underneath it.
*   *Paracatenula* worms are >50% bacteria, and 90% of their body is a bacteria-holding organ called the trophosome. They can regrow a head from a trophosome but not the other way round.
*   *Wolbachia*, a group of symbiotic bacteria, are only passed from female insects to their descendants. This means males are reproductive dead ends. *Wolbachia* have taken to sterilizing males, to killing them so their sisters can eat them, to feminizing them.
*   Lots of insects just die if they're deprived of microbes. Unlike human bacteria which live in the gut, these actually live inside the cells of the insects.
*   There are two species of wasps which appear to be reproductively isolated from each other (i.e. individuals from one species cannot breed with those from another) entirely due to having different bacteria living in them.
*   One sort of parasitic wasp has a *domesticated virus* in it's own genome. It produces this virus when it parasitizes its host and releases it into the host's tissue.
*   A type of caterpillar which is parasitized by a different wasp can fight back. It does this by having its own symbiotic bacteria release a virus (which is dormant in the bacteria's genome) to kill the wasp's symbiotic bacteria.

The takeaway here is that symbiotic bacteria (and particularly in insects) fall into the Floridaman reference class. Everything is possible and only a fool expects to be unsurprised. These are all pretty well-sourced and not too significant to the overall thesis so I'll save the fact-checking and follow-ups for later.

Medical and Ecological Interventions
------------------------------------

Ed Yong did a good job of finding the actual researchers in the field and talking to them. This is good. But researchers love to talk about their next project, and find settled science to be terribly boring. Many of these projects are thus highly speculative, and a fairly high proportion are medical.

Some of the findings are uncontroversial, like the fact that bacteria-free mice (and humans) are generally not healthy. Bacteria in the gut are necessary for digestion.

Lots of them are, well, *not* uncontroversial.

### Oh Dear God We're Doing Autism

One of the first examples given is of research by Paul Patterson and Sarkis Mazmanian. Patterson gave pregnant mice a compound to mimic viral infection, attempting to create mouse models of schizophrenia (based on the fact that flu infections in pregnant mothers are linked to schizophrenia). The resulting mice showed behaviour which sort of resembles both schizophrenia and autism.

More remarkably, transferring samples of gut microbiota from autistic children to sterile mice (in this case sterile refers to having no microbiome, not to reproductive capability) seems to replicate the symptoms. But feeding a bacteria (*B. fragilis*) to these mice seemed to cure most of their symptoms! While Mazmanian has continued to produce papers, interest in *B. fragilis* has petered out. Mazmanian has also not been able to replicate the results in humans.

That's not to say that autistic people don't have different microbiomes, which is fairly well-documented. It just appears that an altered microbiome isn't the only factor in play. This wasn't surprising to me on reading the book.

### Faecal Transplants And Beyond

*C. difficile* causes terrible infections of the gut. They're most common *after* antibiotic treatment, as *C. diff* is generally more resilient to antibiotics than the rest of the gut microbiome. This means that treatments using antibiotics are often ineffective. Unless all of the *C. diff* is removed and the gut reset, it is likely to return.

In this case, one of the major treatments is the rather unpleasant method of faecal transplant. Some faeces is taken from a healthy individual and put into the gut (through colonoscopy or a slow-dissolving pill) of the sick person. This has a ~95% (!) success rate, and is now standard practice. The FDA tried to stop faecal transplants for a bit because we all know their attitudes towards improving people's lives but it is still in common usage.

*C. diff* is an ideal target for microbiome-based interventions. We know the exact bacterium responsible. It is a case of an attractor in the microbiome-landscape characterised by an extreme lack of diversity. It occurs almost entirely due to outside influences on the gut (rather than human genetics). Most microbiome-based interventions are much less hard to get right.

### Eliminating Dengue Fever

Dengue fever is carried by mosquitoes. When infected by a certain type of *Wolbachia*, the mosquitoes can no longer carry dengue fever. This *Wolbachia* can be introduced to mosquito populations to reduce the impact of dengue fever. When the book was written, this was in very early stages, now it has been rolled out to regions encompassing over 6 million people.

The website for this project says that "In areas where *Wolbachia* is self-sustaining at a high level, there have been no dengue outbreaks". This sounds remarkable but how many areas have actually met that criteria? Givewell do not have an effectiveness assessment for them, but I have found an assessment of their effectiveness from an australian consulting firm. It seems they have definitely released a lot of mosquitoes but the nature of their intervention makes it difficult to assess actual cases of dengue averted.

### Diet-dependant Interventions

Cows can't normally eat *Leucaena*. But they can be given a gut microbe which can remove the toxins. This has been a success story in Australia, which now uses it as a major feedstock. This works because the cows consistently eat *Leucaena*, which gives the microbes something to eat.

Similar trials have occurred in humans who are prone to kidney stones (and other stones). The cause is oxalate in the diet, but giving these people a supplement of *Oxalis* bacteria, which can break down oxalate, generally fails. This is because people who are oxalate-sensitive don't eat oxalate, and the bacteria starve.

Obesity is linked to changes in gut microbiome. Transferring gut microbes from a non-obese mouse to an obese one can make it thinner compared to a diet-matched control, but this only happens when that controlled diet is high-fibre. The same seems to be true of humans. With perfect control over gut microbes, we can influence obesity, but in reality lots of that control comes from the diet.

The microbiome is not magic. The microbes in it respond to changes in their environment, and for gut microbes, that's our diet. Unfortunately the dietary advice remains the same. This also explains the lack of microbiome-associated cures for the laundry list of diseases associated with the microbiome.

### Microbiome → Health

From my first reading, I recalled the presence of enormous amounts of claims as to how the microbiome influences health, and how manipulating the microbiome might change our health. I was quite excited to have either the thrill of discovering them anew or the thrill of tearing them down.

I was surprised to find that the book didn't contain many concrete claims of this nature. Instead there was a large amount of existing research in models, and a few quite strange studies which just seem odd (microbes reducing the symptoms of depression in people with IBD? what about the IBD itself??). I think this is partially a failure of my memory, but partially a failure of the book.

I can't fault the book for making actually wrong statements, but I can fault it for giving off incorrect impressions. It feels like trying to analyse some lawyer's testimony on a client's character, mentioning his time spent going to churches, which when investigated turns out to be true, but only because he's a cleaner or something. The concrete claims are all basically true, but more banal that I recalled.

Conclusions
-----------

I think that most of this book is a very well-written and accessible account of the microbiome, and the author does a good job of making the reader excited by it. I think that it overreaches in a lot of ways, and a reader would be wise to consider what it is claiming to be true and what is being speculated on.

The biggest issue with microbiome research is a lack of gears-level models. This is mostly due to the gigantic complexity of the topic. We have good models of certain interventions and disease states, but these are really not common. Changing the microbiome of mice can make them more or less anxious, fatter or thinner, and we don't know why.

There have only been five years since the publication. This is barely more than one generation of PhD students. Further studies on the microbiome have not made enormous progress, but that is to be expected. Whether the microbiome will be a focus of future disease treatment is unclear. The book is arguably overselling things, but part of the point of a book is to intrigue us, and to draw our attention towards things we would otherwise have ignored. That is something "I Contain Multitudes" does very well.