Portrait of the human as a tangled bank: A review of "I Contain Multitudes: The Microbes Within Us and a Grander View of Life"

It’s time we became friends with microbes. And not just with them but with their very idea, because it’s likely going to be crucial to our lives on this planet and beyond. For a long time most humans have regarded bacteria as a nuisance. This is because we become aware of them only when something goes wrong, only when they cause diseases like tuberculosis and diarrhea. But as Ed Yong reveals in this sweeping, exciting tour of biology, ecology and medicine which is pregnant with possibility, the vast majority of microbes help us in ways which we cannot possibly fathom, which permeate not just our existence but that of every single other life form on our planet. The knowledge that this microbial universe is uncovering holds tantalizing clues to treating diseases, changing how we eat and live and potentially effecting a philosophical upheaval in our view of our relationship with each other and with the rest of life.

Yong’s book shines in three ways. Firstly it’s not just a book about the much heralded ‘microbiome’ – the densely populated and ubiquitous universe of bacteria which lives on and within us and which rivals our cells in terms of numbers – but it’s about the much larger universe of microbes in all its guises. Yong dispels many misconceptions, such as the blanket statements that bacteria are good or bad for us, or that antibiotics are always good or bad for us. His narrative sweeps over vast landscape, from the role of bacteria in the origins of life to their key functions in helping animals bond on the savannah, to new therapies that could emerge from understanding their roles in diseases like allergies and IBD. One fascinating subject which I think Yong could have touched on is the potential role of microbes in seeding extraterrestrial life.

The universal theme threading through the book is symbiosis: how bacteria and all other life forms function together, mostly peacefully but sometimes in a hostile manner. The first complex cell likely evolved when a primitive life form swallowed an ancient bacterium, and since this seminal event life on earth has never been the same. They are involved in literally every imaginable life process: gut bacteria break down food in mammals’ stomachs, nitrogen fixing bacteria construct the basic building blocks of life, others play critical roles in the water, carbon and oxygen cycle. Some enable insects, aphids and a variety of other animals to wage chemical warfare, yet others keep coral reefs fresh and stable. There’s even a species that can cause a sex change in wasps. Perhaps the most important ones are those which break down environmental chemicals as well as food into myriad interesting and far-ranging molecules affecting everything, from mate-finding to distinguishing friends from foes to nurturing babies’ immune systems through their ability to break down sugars in mother’s milk. This critical role that bacterial symbiosis plays in human disease, health and even behavior is probably the most fascinating aspect of human-bacteria co-existence, and one which is only now being gradually teased out. Yong’s central message is that the reason bacteria are so fully integrated into living beings is simple: we evolved in a sweltering, ubiquitous pool of them that was present and evolving billions of years before we arrived on the scene. Our relationship with them is thus complex and multifaceted, and as Yong demonstrates, has been forged through billions of years of messy and haphazard evolution. For one thing, this therefore makes any kind of simple generalization about them almost certainly false. And it makes us realize how humanity would rapidly become extinct in a world suddenly devoid of microbes.

Secondly, Yong is adept at painting vivid portraits of the men and women who are unraveling the secrets of the microbial universe. Old pioneers like Pasteur, Leeuwenhoek and Koch come alive in crisp portraits (for longer ones, I would recommend Paul DeKruif's captivating classic, "Microbe Hunters"). At the same time, new pioneers herald new visions. Yong crisscrosses the globe, from the San Diego Zoo to the coral reefs of Australia to the savannah, talking to adventurous researchers about wasps, aphids, hyenas, squid, pangolins, spiders, human infants and all the microbes that are intimately sharing their genes with these life forms. He is also a sure guide to the latest technology including gene sequencing that has revolutionized our understanding of these fascinating creatures (although I would have appreciated a longer discussion on the so-called CRISPR genetic technology that has recently taken the world by storm). Yong’s narrative makes it clear that innovative ideas come from the best researchers combining their acumen with the best technology. At the same time his sometimes-wondrous narrative is tempered with caution, and he makes it clear that the true implications of the findings emerging from the microbiome will take years and perhaps decades to unravel. The good news is that we're just getting started.

Thirdly, Yong delves deeply into the fascinating functions of bacteria in health and disease, and this involves diseases which go way beyond the familiar pandemics that have bedeviled humanity throughout its history. Antibiotics, antibiotic resistance and the marvelous process of horizontal gene transfer that allows bacteria to rapidly share genes and evolve all get a nod. Yong also leads us through the reasonable but still debated 'hygiene hypothesis' which lays blame for an increased prevalence of allergies and autoimmune disorders at the feet of overly and deliberately clean environments and suburban living. He discusses the novel practice of fecal transplants that promises to cure serious intestinal inflammation and ailments like IBD and Crohn’s disease, but is also wary about its unpredictable and unknown consequences. He also talks about the fascinating role that bacteria in newborn infants’ bodies play when they digest crucial sugars in mother’s milk and affect multiple functions of the developing baby’s body and brain. Unlike proteins and nucleic acids, sugars have been the poor cousins of biochemistry for a long time, and reading about their key role in microbial symbiosis warmed this chemist's heart. Finally and most tantalizingly, the book describes potential impacts that the body’s microbiome and its outside guests might have on animal and human behavior itself, leading to potential breakthrough treatments in psychiatry. The real implications of these roles will have to be unraveled through the patient, thoroughgoing process that is the mainstay of science, but there is little doubt that the arrows seem to be pointing in very promising directions.

“There is grandeur in this view of life”, Darwin said in his magnum opus “The Origin of Species”. And just how much grandeur there exactly is becomes apparent with the realization that Darwin was dimly aware at best of microbes and their seminal role in the origin and propagation of life. Darwin saw life as an 'entangled bank' full of wondrous species: I can only imagine that he would have been enthralled and stupefied by the vision of this entangled bank presented in Ed Yong's book.

The only science equation that you should know

As I mentioned in my last post, “Chemistry”, declared Roger Kornberg in an interview, “is the queen of all sciences. Our best hope of applying physical principles to the world around us is at the level of chemistry. In fact if there is one subject which an educated person should know in the world it is chemistry.” Kornberg won the 2006 Nobel Prize in chemistry for his work on transcription which involved unraveling the more than dozen complicated proteins involved in the copying of DNA into RNA. He would know how important chemistry is in uncovering the details of a ubiquitous life process.

I must therefore inevitably take my cue from Kornberg and ask the following question: What equation would you regard as the most important one in science? For most people the answer to this question would be easy: Einstein’s famous mass-energy formula, E=mc². Some people may cite Newton’s inverse square law of gravitation. And yet it should be noted that both of these equations are virtually irrelevant for the vast majority of practicing physicists, chemists and biologists. They are familiar to the public mainly because they have been widely publicized and are associated with two very famous scientists. There is no doubt that both Einstein and Newton are supremely important for understanding the universe, but they both suffer from the limitations of reductionist science that preclude the direct application of the principles of physics to the everyday workings of life and matter.

Take Einstein’s formula for instance. About the only importance it has for most physical scientists is the fact that it is responsible for the nuclear processes that have forged the elements in stars and supernova. Chemists deal with reactions that involve not nuclear processes but the redistribution of electrons. Except in certain cases, Einstein therefore does not figure in chemical or biological processes. Newton’s gravitational formula is equally distant. Chemical reactions involve the attraction and repulsion of charges which are processes governed by the electromagnetic force. This force is stronger than the gravitational force by a factor of 10³⁶, an unimaginable number. Thus gravity is too weak for chemists and biologists to bother with it in their work. The same goes for many physicists who deal with atomic and molecular interactions.

Instead here are two equations which have a far greater and more direct relevance to the work done by most physical and biological scientists. The equations lie at the boundary of physics and chemistry, and both of them are derived from a science whose basic truths are so permanently carved in stone that Einstein thought they would never, ever need to be modified. That science is thermodynamics, and the equations we are talking about involve the most basic variables in thermodynamics. They apply without exception to every important physical and chemical process you can think of, from the capture of solar energy by plants and solar cells to the combustion of fuel inside trucks and human bodies to the union between sperm and egg.

Two thermodynamic quantities govern molecular behavior, and indeed the behavior of all matter in the universe. One is the enthalpy, usually denoted by the symbol H, and roughly representing the quantity of energy and the strength of interactions and bonds between different atoms and molecules. The other is the entropy, usually denoted by the symbol S, and roughly representing the quality of energy and the disorder in any system. Together the enthalpy and entropy make up the free energy G, which roughly denotes the amount of useful work that can be extracted from any living or non-living system. In practical calculations what we are concerned with are changes in these quantities rather than their absolute values, so each one of them is prefaced by the symbol ∆ indicating change. The celebrated second law of thermodynamics states that the entropy of a spontaneous process always increases, and it is indeed one of the universal facts of life, but that is not what we are concerned with here.

Think about what happens when two molecules – of any kind – interact with each other. It need not even be an actual reaction, it can simply be the binding of two molecules to one another by strong or weak forces. The interaction is symbolized by an equilibrium constant K_e, which is simply the ratio of the concentrations of the products of the reaction to the starting material (reactants). The bigger the equilibrium constant, the more the amount of the products. K_e thus tells us how much of a reaction has been completed, how much reactant has been converted to product. Our first great equation relates this equilibrium constant to the free energy of the interaction through the following formula:

∆G⁰ = -RT ln K_e

or, in other words

K_e = e^-∆G0/RT

Here ln is the natural logarithm to base e, R is a fundamental constant called the gas constant, T is the ambient temperature and ∆G₀ is the free energy change under so-called 'standard conditions' (the details of these are not very important for understanding the crux of the matter here). 

This equation tells us two major things and one minor thing. The minor thing is that reactions can be driven in particular directions by temperature increases, and exponentially so (that's not the same as speeding them up though; this goal is the domain of kinetics, not thermodynamics). But the major things are what's critical here. Firstly the equation says that the free energy in a spontaneous process with a favorable positive equilibrium constant is always going to be negative; the more negative it is the better. And that is what you find. The free energy change for many of biology's existential reactions like the coupling of biological molecules with ATP (the “energy currency” of the cell), the process of electron transfer mediated by chlorophyll and the oxidation of glucose to provide energy is indeed negative. Life has also worked out clever little tricks to couple reactions with positive (unfavorable) ∆G changes to those with negative ∆G₀ values to give an overall favorable free energy profile.

The second feature of the equation is a testament to the wonder that is life, and it never ceases to amaze me. It attests to what scientists and philosophers have called “fine-tuning” the fact that evolution has somehow succeeded in minimizing the error inherent in life’s processes, in carefully reining in the operations of life within a narrow window. Look again at that expression. It says that ∆G₀ is related to K_e not linearly but exponentially. That is a dangerous proposition because it means that even a tiny change in ∆G₀ will correspond to a large change in K_e. How tiny? No bigger than 3 kcal/mol.

A brief digression to appreciate how small this value is. Energies in chemistry are usually expressed as kilocalories per mole. A bond between two carbon atoms is about 80 kcal/mol. A bond between two nitrogen atoms is 226 kcal/mol, indicating why nitrogen can be converted to ammonia by breaking this bond only at very high temperatures and pressures and in the presence of a catalyst. A hydrogen bond - the "glue" that holds biological molecules like DNA and proteins together - is anywhere between 2 and 10 kcal/mol.

3 kcal/mol is thus a fraction of the typical energy of a bond. It takes just a little jiggling around to overcome this energy barrier; if you ask a chemist to predict or optimize a reaction within this range she will be extremely uncomfortable. One of the reasons drug designers have such a hard time designing drugs that will bind tightly to proteins is precisely because it's so hard to predict and control the interactions of their drugs with those proteins down to such a small number. The exponential, highly sensitive dependence of Ke on ∆G₀ means that changing ∆G from close to zero to 3 kcal/mol will translate to changing K_e from 1:99.98 in favor of products to 99.98:1 in favor of reactants (remember that K_e is a ratio). It's not even chemistry, actually, it's a simple mathematical truth. Thus, a tiny change in ∆G₀ can all but completely shift a chemical reaction from favoring products to favoring reactants.

Naturally this will be very bad if the goal of a reaction is to create products that are funneled into the next chemical reaction. Little changes in the free energy can therefore radically alter the flux of matter and energy in life’s workings. But this does not happen. Evolution has fine-tuned life so well that it has remained a game played within a 3 kcal/mol energy window for more than 2.5 billion years. It's so easy for this game to quickly spiral out of hand, but it doesn’t. It doesn’t happen for the trillions of chemical transactions which trillions of cells execute everyday in every single organism on this planet.

And it doesn’t happen for a reason; because cells would have a very hard time modulating their key chemical reactions if the free energies involved in those reactions had been too large. Just like we manage to maintain our body temperature between an alarmingly narrow window of comfort, so we also manage to maintain the sprinkling of energy in our essential cellular processes to within 3 kcal/mol. Life would be quickly put into a death trap if every time it had to react, fight, move or procreate it had to suddenly change free energies for each of its processes by tens of kilocalories per mole.

There are lots of bonds broken and formed in biochemical events, of course, and as we saw before, these bond energies can easily amount to dozens of kcals/mol. But the tendency of the reactants or products containing those bonds to accumulate is governed by these tiny changes in free energy which nudge a reaction one way or another. In one sense then, life is optimizing small changes (in free energy of reactions) between two large numbers (bond energies). This is always a balancing act on the edge of a cliff, and life has managed to be successful in it for billions of years.

Thus we all hum along smoothly, beneficiaries of a 3 kcal/mol energy window, going about our lives even as we are held hostage to the quirks of thermodynamic optimization, walking along an exponential energy precipice. And all because

K_e = e^-∆G₀^/RT

^{This is a revised version of an older post.}