The Evolution of Human Violence

By: Helen Beilinson

Why are humans violent?

This is a dense question that has been heavily debated for centuries. There are, very simply, two camps—nature and nurture. The former has been popularized by the seventeenth-century philosopher Thomas Hobbes, who argued that the natural state of man is one of violence and independent perpetuation, that humans are naturally, inherently violent. On the other hand, Jean-Jacques Rousseau retorted, nearly a century later, that individuals are not born violent or peaceful, but instead, are molded by their environments. Outside of philosophy, social scientists have tackled this distinction by focusing on the nurture side, analyzing how sex, age, race, and socio-economic status can influence an individual’s propensity towards violence. In a recent issue of Nature, Spanish scientist José Mariá Gómez and colleagues took to answering this question from a different, unique angle—evolution.

 Lethal conspecific violence, or violence occurring between members of the same species, is not unique to humans, from infanticide in primates and dolphins to horses and hamsters attacking their own. The prevalence of aggression throughout mammals, and its high inheritability, questions whether evolution has shaped human violence due to intraspecies violence being an adaptive strategy for survival. To address this question, the authors of this study used comparative methods from evolutionary biology to quantify the levels of violence in 1,024 mammalian species, including those that are currently extinct. They assessed causes of death in over 4 million instances, defining the level of lethal violence in a species as the probability of dying from intraspecific violence compared to other causes.

 Out of the analyzed species, nearly 40% had instances of conspecific lethal violence, with, on average, 0.30% of deaths within a population occurring at the hands of those in the same species. The authors calculated phylogenetic signals of related species to analyze the evolution of lethal aggression in mammals. This signal is essentially a measure of how lethally violent a particular species is in comparison to other closely related species. They found that lethal violence was entirely absent from some species, like bats and whales, and was more frequent in other groups, such as primates. Lethal violence was at similar levels in closely related species, speaking to its heritable aspect.

 Within primates, one of the most notoriously violent groups of animals, there were differences in levels of violence, indicating violence’s evolutionary flexibility. While chimpanzees were highly violent, bonobos were tamer. This observation drove the authors to ask whether other factors could influence violence within a species. The authors subsequently scored the analyzed species for territoriality and social behavior, two traits that could drive aggression. They found that social, territorial animals had high levels of lethal violence than solitary, non-territorial species.

 Studying the evolution of and phylogenetic signals for lethal violence in mammals as a whole provided a basis for studying the violence in humans. In addition to the animal species studied, 600 human populations were analyzed, ranging in time across human history, from the Paleolithic era (~2 million to 10,000 years ago) to the present.

 We emerged from the primate line, with a long evolutionary history of higher-than-average levels of conspecific lethal violence, so it is unsurprising that at the origin of our species, human lethal violence accounted for 2% of all deaths, six times higher than the reconstructed mammalian value. Additionally, we as Homo sapiens are both social and territorial, trains with stronger tendencies towards lethal violence in mammals.

 Over human history, the estimates of lethal violence vary greatly. Although Paleolithic estimates were close to 2% of deaths were due to lethal aggression, estimates rose as high as 15-30% in various times throughout history, peaking about 3,000-5,000 years ago. Today, levels of lethal violence have decreased markedly. The authors claim that socio-political organization was a significant factor in the changes in violence. They found that there was a correlated rise in violence when human moved from pre-societal organizations, including bands and tribes, to more modern organizations like chiefdoms and states. However, although high population densities in most mammalian species drive lethal aggression, in humans, population increases were consequences of successful pacification, leading to less violence.

 Although the news is packed daily with stories of human-on-human violence, today, less than 1 in 10,000 deaths (about 0.01%) are due to lethal violence. Based on the model put forth by Gómez, this translates to humans being about 200 times less violent today that can be predicted by our evolutionary past. Even a lethal violence rate of 0.01% is too high; there is a lot of social and political work that needs to be done to lower this incidence as much as possible, ideally to zero. A violent past and phylogenetically inherited lethal violence have set up modern humans to be naturally violent creatures, nevertheless, it is clear that culture, be it social or political, can strongly influence and modulate levels of aggression in a population.

Timing Decomposition with Microbes

By: Helen Beilinson

The last decade has seen many new discoveries that have revolutionized science. Arguably, one of the most influential of these advances has been the appreciation of the impact of microorganisms on human health. In particular, the important roles played by the bacteria, viruses, and other bugs (collectively called the microbiota) that live in or on us, continue to be enumerated. Numerous elegant studies have characterized changes that happen in a person’s microbiota throughout the course of a regular year, during the progression of an infection, or even how a space environment can affect the composition of bacteria in our gut. Recently, a group from the University of California, San Diego explored the changes in bacterial composition during a different phase of life—corpse decomposition.

It might sound a bit gruesome, but the decay of once living things is critical for the cycling of nutrients on earth. The completion of this task requires an extensive arsenal of microbial and biochemical activity. Previous studies had shown that decomposition occurs in a somewhat predictable, stepwise fashion. It was also known that bacteria and other microorganisms are critical for this natural process to occur properly. However, the details of this process were not well understood. The authors of this specific study wanted to know if the environment an organism inhabits dictates the microbial decomposers, whether these microbes come from the host or the environment, and how a decomposed organism changes the environment around it.

To answer these questions, the authors determined the composition of the communities of microorganisms in decaying mice and humans in various environments. Using human cadavers might sound a bit grisly, but it’s important. Mice are good models of various human diseases and are great tools to study many aspects of biology and organismal biochemistry. However, human and mice are still two different organisms, and human subjects were required in this study to verify that their findings in mice matched what occurs in humans. The use of human cadavers is important for the implications and potential applications of this study, as it may be the newest tool in forensic science... but I’m getting ahead of myself.

To identify the families that make up the microbial communities in their samples, the authors utilized a precise technique, 16S rRNA sequencing. This technique takes advantage of the fact that there are some genes that are pretty similar in bacteria that are closely related, and grow more different the less related they are. By sequencing all the microbes, the authors are able to group them into their families and compare how similar or different the microbial populations are between different experimental groups.

An exciting preliminary piece of evidence these authors observed is that the previously described stages of decomposition followed hand in hand with a very precise and dynamic microbial community. The microbes present on day 1 are different from those that emerge on day 4 which again are different from those on day 10. At every stage, between day 1 and day 71, the microbial communities were unique. Perhaps surprisingly, when the authors changed the location of where their mouse specimen was decomposing, there was no effect on the microbial decomposers! A microbial community from a mouse decomposing in a desert environment on day 7 was almost identical to that from a mouse decomposing in a forest on day 7. Seasons also did not significantly impact microbial populations. These same data were obtained using human cadavers.

Based on the latter piece of information, one might expect that if microbial decomposers are more or less the same in different environments, which these decomposers would come from within the host itself. However, the authors found that the soil is the primary source of the microbes, even if the soil type and environment is different. It’s important to note that 16S rRNA sequencing is not the best technique for identifying specific microbes. It is mostly used to identify families of microbes that are closely related. Families of microbes tend to have similar functions, meaning they can carry out similar reactions. These data together imply that because specific microbes carry out specific reactions and that there is a predictable change in microbes over the course of decomposition, one could predict that the biochemical changes carried out by microbes can be tracked in sequential steps during the course of decomposition.

To further explore this question, the authors examined biochemical reactions taking place in the abdomen of the decaying specimen. They found that indeed, throughout the process of decomposition, there are specific reactions that can be detected at each step. The biochemical reactions that take place correlate almost perfectly with the presence of particular microbes that can carry out this process. Interestingly, the authors were also able to show that the soil around decomposing organisms also has such post-death dating properties, in that the products of the biochemical reactions occurring in the organism seep into the soil surround it, changing its chemical properties. The products produced, such as nitrate and ammonium, are used by plants to grow. Although it is a tad ghastly to think about, mammalian decomposition is important for the cycle of life on Earth. The products of decomposition allow for plants to grow which feed the living mammals.

Although now a fairly simple technology, sequencing of the microbiota of an organism has been an incredibly powerful tool in the biomedical sciences. This study has shown that another, perhaps surprising, field that may benefit from this technology is forensic science. Although there are technologies in place to help forensic scientists identify when a person has died, these are often not very precise. This paper’s methods were able to distinguish time of death with a one to two day accuracy based on the microbes found in that body and the biochemical reactions occurring. The microbes around us clearly have a constant influence on our lives: from our birth to our death, microorganisms make us who we are.

Where did life on Earth come from?

By: Zuri Sullivan

This fundamental question fascinates and frustrates scientists and non-scientists alike, and scientists across many fields have spent centuries trying to answer it. In biology, for example, we address this question through the study of evolution. This particular branch of biology allows scientists to draw inferences about past organisms through examining certain characteristics of current organisms. By comparing and contrasting the species that exist today, and investigating their relationships to one another over evolutionary time, biologists can make predictions about what some of Earth’s earliest life forms may have looked like.

These predictions are made possible through our understanding of natural selection, which is the process by which random variations that make an organism more likely to survive and reproduce are passed on to subsequent generations, gradually becoming more frequent in the population. In other words, natural selection is “survival of the fittest.”  Through this process, advantageous variation in very simple systems slowly gave rise to more complex ones. From single-celled organisms like bacteria slowly emerged more complicated single-celled organisms, like yeast. From this class of organisms, called single-celled eukaryotes emerged simple multicellular organisms, of which sea sponges are a modern example. Gradually, over hundreds of millions of years, increasing layers of complexity were built upon one another, giving rise to the diverse array of highly sophisticated organisms (including ourselves) that we observe today. This doesn’t necessarily mean that simpler life forms haven’t been able to survive over all of these millions of years (in fact, the vast majority of living organisms today are unicellular). Rather, evolutionary biology tells us that the common ancestor of all extant organisms was a single-celled organism that could have resembled some of the bacteria we see today.

The insights we gain from evolutionary biology are extremely powerful, but the question of the origin of the original life form upon which all this sophistication was built remains elusive. However, a recent study published in Nature Chemistry, led by John Sutherland of the UK Medical Research Council, provides important clues as to how this original life form could have emerged. Now you may be wondering—if we’re talking about the origins of life, and biology is the study of life, then why were chemists investigating this question? In order to understand how life began, it is necessary that we examine the individual building blocks that are needed for life, and organic chemistry provides the tools necessary to study these building blocks.

So what are these most fundamental building blocks for life? They’re called macromolecules, and include nucleic acids (like DNA or RNA), proteins, lipids (or fats), and carbohydrates. Each of these macromolecules is made of even smaller building blocks: nucleic acids are made of nucleosides, proteins of amino acids, fats from fatty acids, and carbohydrates from monosaccharides (simple sugars). The names aren’t important, but the fact that life is built upon macromolecules, which are built from small precursor molecules, transforms our question about the origin of life from the realm of biology to the realm of chemistry. Instead of asking, “where did life on Earth come from?” the more fundamental question is “how were the building blocks of life first assembled?”

Chemists have been asking this question experimentally since the 1800s, and have made a number of important discoveries. Chemists have figured out ways that amino acids, complex sugars, and certain nucleosides could be synthesized from the simplest possible building blocks that are believed to have been on Earth before life emerged. Scientists interested in these questions often refer to the hypothetical composition of pre-life molecules and water as the “primordial soup.” The issue with these studies, however, has been that the complex reactions needed to produce each macromolecule were incompatible with the reactions needed to synthesize other macromolecules. In other words, no one has been able to create a set of conditions under which all of life building blocks could be synthesized. 

This is the problem that the Sutherland lab set out to address—are there a set of conditions under which all of these macromolecule precursors could have been synthesized? Using three simple molecules that could have existed on Earth before life began, the group showed how the combination of water and ultraviolet radiation from sunlight could have produced a set of chemical reactions that gives rise to building blocks for the carbohydrates, lipids, proteins, and nucleic acids that we know today. As it was put in a commentary that covered this study, the Sutherland group uncovered “a primordial soup that cooks itself.”

As is always the case in science, this study led to more questions than it did answers. One caveat to their complex synthesis reaction is that certain molecules needed to be added at particular times in the reaction. Returning to the soup analogy, the recipe would have relied on a cook standing over the pot and slowly adding certain ingredients at the right moment. The authors of the study put forth an additional hypothesis to address this, suggesting that rainfall could have introduced these molecules at the right moment in the synthesis reaction. Seems plausible, but I’m not a chemist.

Humanity’s uphill battle against antibiotic resistance

By: Zuri Sullivan

Antibiotic resistance is a public health crisis that has received lots of attention recently, and for good reason. One only need read Maryn McKenna’s essay in Medium to understand the gravity of the situation. The advent of antibiotics in the 20th century, in addition to improvements in sanitation and other medical advances, saw a doubling of life expectancy in the United States. If widespread antibiotic resistance were to render these miracle drugs virtually useless, we could return to the dismal reality of our grandparents’ childhood, where apparently innocuous infections like strep throat could spell a death sentence.  And for every antibiotic currently on the market, there exist bacteria that are resistant to it.

So how does antibiotic resistance arise? The emergence of antibiotic resistance is actually a real-time illustration of evolution. When Charles Darwin published On the Origin of Species in 1859, he put forth the theory of natural selection, which became the basis for what we now call evolutionary biology. The basic principle is as follows:

  • Variation arises amongst organisms due to random genetic mutations
  • The environment that organisms are exposed to determines whether this mutation is beneficial (makes them more fit, or able to reproduce) or detrimental (makes them less fit)
  • When a mutation confers a fitness benefit, the organisms that possess this mutation reproduce more, passing down the variation to their offspring
  • Thus, over generations, beneficial mutations become more frequent in the entire population

Antibiotic resistance is an example of a variation that could arise in a population of bacteria. When the population is exposed to antibiotics, this mutation confers a fitness benefit to the mutant. The antibiotic kills the non-mutant bacteria, while the mutant survives, and gives rise to mutant offspring. Not only can resistant bacteria spread antibiotic resistance genes to their offspring, but they can also pass them to their neighbors through a process called horizontal gene transfer. Over time, the entire population of bacteria becomes resistant to the antibiotic. When this happens inside a person’s body, it can mean that the drugs that their doctor prescribes to treat an infection may not be effective.

The gravity of the situation is clear—antibiotic resistant infections account for about 23,000 deaths per year in the US alone, and are estimated to cost us as much as $35 billion annually. Though the problem is obvious, the solution is much less so. Many have been proposed, from restricting the use of antibiotics in agriculture, (the vast majority of antibiotics sold in the US are bought by the agriculture industry), limiting the inappropriate use of antibiotics in medicine, to reducing antibiotic treatment regimens to the lowest level possible to improve a patient’s health. The most obvious solution, and the one scientists have been working on since antibiotic resistance was first described in 1940, is discovering new antibiotics.

Unfortunately, this endeavor has produced limited success. In the past 50 years, there has only been one new class of antibiotics introduced into clinical practice; the overwhelming majority of antibiotics developed in the last several decades have been variations on existing compounds. And for most new drugs, resistance arises so quickly that antibiotic-resistant bacteria can be detected in the population years before the antibiotic even hits the market. It would seem that humans are fighting a losing battle against bacteria.

A glimmer of hope came earlier this year, when researchers from Northeastern University published a study in Nature describing the discovery of a new antibiotic without detectable resistance. The new compound, teixobactin, was found to be effective against a number of disease-causing bacteria, including Staphylococcus aureus (staph) and Mycobacterium tuberculosis (TB). Not surprisingly, this discovery generated a lot of excitement in the scientific and medical communities. But some wonder whether the development of resistance against new and exciting drugs is just a matter of time.

The answer could come from a surprising source: bacterial DNA isolated from the remains of woolly mammoths, massive, now-extinct relatives of modern elephants who walked the earth during the Pleistocene Epoch over 30,000 years ago. A 2011 study in Nature described the detection of bacterial antibiotic resistance genes in samples isolated from woolly mammoths and other ancient animals from the Pleistocene. Based on what I’ve told you already, this seems crazy. After all, antibiotic resistance is driven by the use of antibiotics, and humans have only been using antibiotics for about 100 years. So why would bacteria from 30,000 years ago be evolving resistance to antibiotics?

It turns out that humans weren’t the first organisms to realize that antibiotics are a good way to kill bacteria. Bacteria themselves were the original inventors of antibiotics, and they’ve been using them to kill each other for millions of years. That’s right—our modern antibiotics are the product of millions of years of interbacterial warfare. Humans only discovered antibiotics in the 20th century, but bacteria have been using them for much longer than that. For as long as these weapons have existed, their targets have been devising ways to evade them. If resisting antibiotics is a fundamental component of what it means to be a successful bacterium, can antibiotic resistance ever really be eliminated? 

Cheaters never prosper, not even bacteria

We all know that cheating is wrong, but some people do it anyway. I know I had my fair share of classmates growing up who would try to copy my homework (perils of being a nerd). Big or small, cheating has consequences. If you’re caught peeking at someone’s answers while taking a test, you’ll probably get a zero.

The existence of consequences for cheating makes sense in the context of social cooperation— rules and laws facilitate our happy coexistence, and thus need to be enforced. It turns out that the phenomenon of social cooperation isn’t unique to humans. Biologists have also observed that animals living in groups can have complex social structures that are regulated by rules to prevent cheating, and “police” who enforce the rules. In ant colonies, for example, worker ants are policed (link) by occasional violent attacks to prevent individual workers from cheating. In this case, cheating means a single worker ant reproducing more than would be good for the colony as a whole. By policing these cheaters, the overall harmony of the colony is maintained.

While scientists have long known that animals exhibit cooperative behavior, a recent study published in Proceedings of the National Academy of Sciences showed that bacteria do the same thing. A team led by Dr. Peter Greenberg from the University of Washington studied social behavior in a species of bacteria called Pseudomonas aeruginosa. All social groups need a means of communication. Humans use language, among other things, to communicate with one another. In P. aeruginosa (and, in fact, all bacteria), communication is mediated by a process called quorum sensing.

In a legislative body, quorum refers to the minimum number of members that must be present at a meeting to make its proceedings valid. Bacteria are able to sense quorum, or how many bacteria of the same species around them, by sending out molecules that can then be recognized by special receptors on other bacteria. If you’re an individual bacterium, these receptors tell how many of your buddies are nearby by detecting the concentration of these quorum sensing molecules. When quorum sensing is intact, the entire population of bacteria benefits by being able to coordinate their behavior. If there’s a certain valuable resource around, like a nutrient, the whole population benefits if the nutrient is equally shared. In order to make sure they share equally with each other, the bacteria need to be able to sense how many other bacteria are around, which they accomplish through quorum sensing.

Unfortunately, this system is subject to cheating. After all, these nutrients are really yummy to the bacteria, and they don’t always want to share. It’s like if you brought a bunch of cupcakes to school to celebrate your birthday, but then realized that the cupcakes are delicious and you’d actually just rather sit at home and eat them all yourself. P. aeruginosa is able to cheat when it loses the ability for quorum sensing. This occurs by random a mutation event, but subsequently allows an individual bacterium to take up nutrients and reproduce independently of its buddies. This is great for the cheater (the bacterium that loses the ability for quorum sensing), but bad for the population as a whole, so the population needs a way of controlling this cheating behavior.

 It turns out that cooperating P. aeuroginosa, those that don’t cheat and maintain the capacity for quorum sensing, police the activity of the cheaters by producing a toxic molecule called cyanide. The same gene that mediates quorum sensing is also implicated in the detoxification of cyanide. So cheaters are punished for their behavior by losing the ability to break down cyanide produced by cooperators. The cheaters die, the cooperators prosper, and all is right with the world. 

Male Odor Bride

By: Ross Federman

If you have ever been sexually attracted to someone, you likely know how powerful a feeling it can be.  You may have also made the discovery that the person you’re attracted to smells really great.  And while you find that they smell amazing, your friends may not always react the same way.  Why is this? The answer is surely a laundry list of factors that we don't understand fully and plenty that we don't even know exist yet.  However, some of how this process works has been studied, and indeed much of what you’re smelling are pheromones—chemicals secreted in sweat and other bodily fluids that have purportedly evolved to attract mates. Several studies have found a fairly significant link between how attractive a potential partner’s pheromones are and how well their combined genetic codes would render their offspring in fighting disease. Evidence really does seem to suggest that one is more attracted to those that will make their future children together healthier.

Although we are very adept at battling infections in general, one of the most powerful aspects of our immune system is its ability to adapt and focus its power on a very specific virus, bacteria, fungus, or toxin that has invaded the body, and to remember that same target if it ever shows up again.  There are two analogous molecules in mammalian immune systems known as the Major Histocompatability Complexes one and two (MHC I/MHC II) that allow little bits and pieces of these pathogens to be "presented" to other components of your immune system.  Under the right confluence of events these bits and pieces of proteins presented by MHC I and II trigger your adaptive immune response to know what to look for.  For example, if some punk kid in a red t-shirt sneaks into a black tie charity gala to get free food and drinks, the MHCs would basically show the red t-shirt to other cells, training them to look for it amongst the crowd.  I can't underscore enough how incredibly important the activity of MHC I and II is to your immune system.

The MHC proteins are made by various genes in the HLA family, and these HLA genes are the most diverse in the entire human genome.  That is to say, within the human population, there are many more varieties of MHC proteins than any of the other proteins that your genome codes for.  Each MHC has its own unique ability to present various types of peptides (which are chopped up bits of larger proteins) to your immune system.  In this case, these peptides are considered "antigens" by your immune system, small molecular signatures that allow for specific recognition, much like the red t-shirt on the moocher in the example above.  And while each unique MHC can present a wide variety of peptides and antigens, no single MHC can do this for all possible peptide antigens.  To answer this, we have evolved to each have several copies of HLA genes instead of just one.  This gives us the ability to try to cover as wide a range as possible in what our immune system can recognize and mount an attack against.

At the population level, this variety is crucial.  It ensures that the human race will have a spectrum of susceptibility to any given pathogen, so that even the worst mega pandemic virus will find some humans whose MHC molecules will present the viral antigens so efficiently that they will (hopefully) survive.  Essentially, evolution has given us the ability, as a whole species, be more suited to survive these horrible occurrences like the plague, the 1918 flu, and countless other similar events that undoubtedly occurred before recorded history.

But back to you and the awesome kids you'd have with that person that smells delicious and you’re finding yourself attracted to.  You and your partner each have a unique set of HLA genes creating a unique blend in ability to present various different antigens.  When you and your mate have very different MHC molecules, your offspring will ultimately get an even greater variety, and since HLA diversity has been so evolutionarily beneficial to our immune systems, our bodies seemed to have developed the ability to pick up on this as a cue.  Thus, we find a far more attractive scent or odor from a potential mate whose HLA genes differ from our own.  So it appears that our senses have been evolutionarily tuned to help us find sexual partners that will give our offspring a survival advantage when it comes to fending off disease, though it is still mysterious as to how this phenomenon occurs at a molecular level.

So take a second to forget about all of the crazy things going on in your head and your body when flirting, dating, or just meeting someone for the first time.  If you find yourself drawn to their scent, it could very well be nature's way of saying, "Hey if you two have kids, they'll have well equipped immune systems to fend off disease."  And with the lower and lower numbers of parents vaccinating their children recently, it might not be such a bad idea to keep this mind.

Sisterhood of the Traveling Genes

By: Helen Beilinson

Unlike humans, bacteria reproduce asexually (yet another reason why I’m happy I’m not a bacterium). This means that one bacterium splits itself into two, giving rise to two daughter cells. The two asexual offspring have the same genome as their one parent. Although keeping the same genome as your parent has a lot of benefits (moms always know best), it can also lead to problems; the lack of new genes sometimes makes it hard for bacteria to adapt to changing environments. Luckily for them, bacteria have found lots of ways of acquiring new genes to survive new environments. One such strategy is getting genes from other bacteria through a process called ‘horizontal gene transfer’ (as opposed to ‘vertical gene transfer’ where parents give genes to their offspring). Horizontal gene transfer doesn’t just occur between bacterial species—it has also happened between bacteria and eukaryotes, which are much more complex organisms. And recently, scientists from the University of Washington found that horizontal gene transfer has brought bacterial genes into animal genomes.

The researchers, led by Joseph D. Moungos, published a study in a recent issue of Nature. They found a bacterial gene called Tae that has repeatedly entered eukaryotic lineages through horizontal gene transfer. Many bacteria have Tae proteins, which function as antimicrobials to kill other bacteria. To do this, Tae breaks down the layer of protection that surrounds the bacteria, called the cell wall. The bacteria that Tae targets actually have two cell walls—an inner wall and outer wall. Tae goes in between the two walls and breaks down a sugar-rich structural protein called peptidoglycan. By targeting peptidoglycan, Tae essentially makes the two cell walls collapse in on each other, killing the bacteria. This group found that at least six times in history, eukaryotes have gotten this gene from bacteria to use as their own. When they looked at the animal versions of the proteins, termed Dae, they discovered that their function in animals is the same as in bacteria; Dae proteins are antimicrobial agents that target peptidoglycan.

The experiments initially showing that Dae has antimicrobial function were performed in a test tube, outside an actual organism. To investigate whether Dae has antimicrobial function within organisms, this study looked at an animal that got Tae from bacteria—the deer tick. Deer ticks can spread the bacteria that cause Lyme disease, which results in fevers, headaches, and rashes, and can lead to more serious symptoms if untreated. Borrelia burgdorferi is one bacterium that can cause Lyme disease in humans. It moves from person to person by living in ticks and transmitted through tick bites. To see if Dae works as an antimicrobial in deer ticks, the scientists removed the Dae protein from the deer ticks and looked for changes in the amount of B. burgdorferi. Turns out that without Dae, deer ticks have more B. burgdorferi. Dae restricts the population size of B. burgdorferi can get in the deer tick by killing the bacteria.

 Collectively, bacteria harbor heaps of antimicrobial peptides. This group looked at one such protein in a defined animal species. If one protein has been transferred to eukaryotic genomes six times in the species that they looked at, this implies that with the thousands of other antimicrobial peptides and thousands of other animals, it is highly probable that many other bacterial genes have been transferred into animals. Who knows, maybe it wouldn’t be so bad being a little bacterial.

Mycobacterium tuberculosis: Man’s Best Frenemy

By: Zuri Sullivan

Modern humans arose in Africa around 200,000 years ago. For an estimated 70,000 years of our history, we have co-existed with a bacterium called Mycobacterium tuberculosis (M. tb). M. tb is most notable for being the causative agent of tuberculosis (TB) disease, which kills 1.5 million people each year. However, this is only the tip of the iceberg when it comes to the ways that M. tb has influenced our biology.

We’ve developed an intimate relationship with M. tb over the last 70 millennia of our coexistence. The bacteria live inside immune cells in our lungs, and rely on us for survival. Our immune systems work to control the growth of M. tb when we become infected. If this immune response is unsuccessful, we can die from the infection.

In short, our survival and the survival of M. tb are deeply intertwined with one another, with each species attempting to subvert the other’s efforts to kill it. This arms race between a host (humans) and a pathogen (M. tb) is sometimes referred to host-pathogen co-evolution, and in the case of M. tb, it’s been going on for quite a long time.

Fighting off M. tb isn’t the only thing humans have been doing for the last 70,000 years, however. We migrated out of Africa, learned agriculture, formed nations, fought wars, made major technological advances, and fought lots of other pathogens. A history class can teach you how these and other events throughout human history have affected us as a species, as smaller populations, and as individuals. A new study published in Nature Genetics explores how major historical events have influenced our old frenemy, M. tb.

The study of human history often relies on primary sources, like ancient texts stored in archives. Unfortunately, bacteria haven’t learned to write, and scientists have only known about them for a few hundred years, so researchers studying the history of bacteria need to rely on other sources of information.  This is where deoxyribonucleic acid (DNA) comes in. You can learn more about DNA here, but the bottom line is that DNA is how information is stored in biology.

How did the researchers use this information to study the history of M. tb? When DNA is passed down from one generation to the next, small changes, or mutations, occur. It works a lot like the game of telephone, which lots of people play in elementary school. One person comes up with a silly message, and whispers it in the ear of the person next to them. That person whispers what they heard to the person next to them, and so on, until it gets back to the original message sender. The fun of the game is in seeing how much the message has changed, or mutated, as it traveled around the circle. Mutations in DNA accumulate in a similar way, but unlike the game of telephone, geneticists can quantify the changes and estimate when in history they occurred. This allowed the researchers in this study to read the DNA of M. tb like a historical text.

The team of researchers, representing 45 institutions on six continents, collected the largest assembly of a single strain of M. tb ever described: 4,987 samples from 99 countries. Using this massive collection, they traced the history of this M. tb strain over the last 6,000 years. The researchers looked at the similarities between the different bacterial samples to find out how related they were to one another. They identified seven distinct groups within the strain of M. tb, kind of like seven different families descended from one ancestor. They were able to plot the seven different groups, called clonal clusters (CC), on a geographic map because they knew exactly where each sample had come from.

Their map showed that this particular strain of M. tb had arisen in East Asia, and that certain CCs had spread to the islands of Polynesia and Micronesia, while others spread westward to Russia and Eastern Europe. The timing of this spread suggests that these CCs were likely transmitted along the Silk Road. Some CCs were present only in East Asia, the United States, and South Africa, suggesting that they were spread by immigration, rather than transmission along trade routes.

So the information in M. tb’s DNA showed how human migration has influenced the bacteria—what else can we learn from it? In addition to identifying the seven CCs of closely related bacteria, the researchers also tracked periods of overall expansion and contraction in the bacterial population. As in their first analysis, they looked at mutations in DNA. Because they occur at quantifiable rates, researchers can estimate when mutations occurred by comparing the number of observed mutations to the known mutation rate. In doing so, they generated a timeline for the expansion and contraction of this strain of M. tb.

Our close relationship with M. tb would suggest that this bacterial timeline would look a lot like the timeline of human history, and indeed, this is what the researchers found. The first major expansion in the bacterial population occurred around 200 years ago, coinciding with the Industrial Revolution. This was a time of major expansion in the human population as well, so a concomitant expansion in M. tb makes sense. The second M. tb growth spurt coincided with World War I, when people from different corners of the world were interacting with each other and likely spreading the bacteria. After this expansion, they noted a major drop in M. tb population around the 1960s, the period when the use of anti-M. tb drugs became widespread. For the first time in our history, humans had a secret weapon against the bacteria, and the findings from this study show that we were winning. Unfortunately, this downward trend was recently interrupted.  With the onset of the global HIV epidemic, the researchers observed a renewed growth in the M. tb population, reflecting the known positive influence of HIV on M. tb transmission.

 Part of the reason that we study human history is that the lessons from the actions of previous generations can inform our own decision-making. Studying bacterial history may be able to help us in a similar way. And because M. tb remains a major public health threat in many parts of the world, understanding how our actions impact its spread may help us to save the millions of lives that are affected by it.

The Other Sputnik: The First Known Virophage

By: Helen Beilinson

For every organism on earth, there are a multitude of viruses that can infect it. Every. Single. Organism. There are viruses that infect everything from bacteria to fish to humans, and anything in between. I’m going to tell you about one of my personal favorite viruses, Sputnik.

But first, let me introduce our host, the amoeba. Amoebae are single celled organisms, more closely resembling our cells than those of bacteria. Unlike humans, they don’t have an extensive immune system that protects them from harmful pathogens in their environment. Their main mechanism of protection is ‘eating’ things in their environment and breaking them down, in a process called ‘phagocytosis’. Although this defense works great often enough, there is not much the amoeba can do to protect itself once it’s infected with a virus.

One such virus is the Mamavirus. Mamavirus is a HUGE virus at around 750 nm in diameter. This may seem small, but that’s about half the size of the bacterium E. coli and it’s almost eight times as large as the infamous influenza virus. You can even see it under a regular light microscope, the kind of microscope used in many high school science labs, compared to most other smaller viruses that you need a high powered microscope to see them. It was first found almost seven years ago living inside amoeba in a cooling tower. Mamavirus lives and replicates in the cytoplasm of amoeba, where it sets up a “replication factory” that takes over the cell. This replication factory is where the virus replicates its DNA genome and makes the proteins necessary to build the outer shell in which it keeps its genome. Once Mamavirus replicates to a high degree, the viruses break down the amoeba cell, a process called ‘lysis’, to be released. As I’m sure is clear, this isn’t a great fate for the amoeba who has little defense against the virus once it starts replicating. That’s where Sputnik comes in.

Sputnik is a very small DNA virus, only about 50 nm in size, about fifteen times smaller than Mamavirus. It became fairly famous after its discovery as the first known virophage, a virus that infects viruses. That’s right—Sputnik is a virus that infects viruses. In fact, it infects Mamaviruses. Although Sputnik can infect amoeba on its own, it’s not that great at replicating by itself. However, when the amoeba is also infected with Mamavirus, Sputnik replicates like crazy. It takes over Mamavirus’ replication factory, which is a perfect little nook for the smaller virus to replicate. Although it might sound kind of unpleasant to be infected with two viruses at once, it’s actually a benefit for the amoeba. By hijacking the Mamavirus’ machinery, Sputnik reduces the ability for the big virus to replicate and make proper virions (or virus particles). It can reduce the Mamavirus load up to 70% and decreases amoeba lysis by threefold. Turns out the old proverb “the enemy of my enemy is my friend” really is the case with the amoeba and Sputnik.

Since the discovery of Sputnik, many more virophages have been discovered, which predominantly attack the large viruses that infect amoeba and zooplankton (a marine microorganism). Virophages have increased our knowledge of the deep complexity of the microbial world. As these critters are essentially brand new to our understanding, there is still a lot to learn about how they influence our ecosystems. There has been an ongoing battle amongst scientists about whether or not viruses are living things. Without getting too much into the details of things, the major point of contention is whether we can consider something living if it has to live within another organism’s cells to replicate. Maybe we need to reconsider whether we should classify viruses are living organisms or not. If they can also be infected with viruses, just like us and our pets and the bacteria that live in our guts—why can’t they be alive?

Why don’t we kill our microbiota?

By: Zuri Sullivan

If you didn’t already know that humans are colonized by trillions of bacteria, that these bacteria make up much more of our bodies than our own cells, and that they play an important role in our physiology, health, and disease, then you probably didn’t read Helen’s piece about the microbiota and defense against viruses. The “microbiota” refers to the collection of microorganisms that live in and on our bodies. A search for “microbiota” returns close to 14,000 academic papers. To call this a current hot topic would be a massive understatement. Why are scientists so excited about the microbiota? First, major technological advances have allowed scientists to begin unraveling the complex community of bacteria, fungi, and viruses that colonize our bodies. Additionally, mounting evidence suggests that the microbiota can influence nearly every aspect of our physiology, which raises important questions about its interactions with other cells and tissues in our bodies. 

There’s a lot to be learned about the microbiota and its functions, but one of the biggest unanswered questions in the field is why all of these bacteria are overlooked by our immune system. Most of us know the immune system as the mechanism by which our body eliminates disease-causing agents, or pathogens. These pathogens are bacteria, viruses, and fungi—the same organisms that make up the microbiota. One of the biggest unanswered questions regarding the microbiota is why our immune system doesn’t eliminate our own microbial population, but does eliminate those microbes that are pathogenic. The initiation of an immune response against an invading species relies on the detection of pathogen associated molecular patterns (PAMPs). PAMPs are molecular structures that are present in microorganisms, but not in host cells. For example, a particular sugar-like molecule, lipopolysaccharide (LPS) is present on the surface of some bacteria, but absent from mammalian cells. Thus, by targeting attacks against cells that have LPS, the immune system can efficiently target a wide array of bacteria without risking damage to host cells. In addition to being distinctly non-mammalian, another critical feature of PAMPs is that they are conserved amongst microbes. This means that PAMPs tend to be molecules that serve critical functions for microbial survival, and thus they are seen in an array of microbial species, including pathogens (microbes that make us sick) and commensals (microbes that have neutral or beneficial effects on our health). This raises an important conundrum: if the immune system recognizes PAMPs that are common to all microbes, why don’t we attack commensals?

A paper published last week in Science provides an exciting clue to how our commensal bacteria survive some of the host’s innate defenses. They looked at antimicrobial peptides, which are chemicals made by immune cells that can directly kill bacteria. They’re like antibiotics made by your own body, and they are an important innate defense mechanism against bacterial infection. The team of researchers asked whether commensal bacteria might be resistant to antimicrobial peptides, which would allow them to survive in the host. Their hypothesis was that commensal bacteria that are adapted to live in our bodies might have evolved mechanisms to tolerate antimicrobial peptides, while pathogens have not.

They found that a common commensal species, Bacteroidetes thetaiotamicron  (B. theta) was more resistant to a particular antimicrobial peptide than pathogenic bacteria. Next, they identified the B. theta gene that was responsible for antimicrobial peptide resistance, a gene called LpxF. They then asked what role this gene played in the ability of this commensal organism to survive the host immune response to a pathogenic bacteria.

This was an important question, because it illustrates an important principle about how the microbiota helps us protect ourselves from pathogenic bacteria. When we’re infected with an intestinal pathogen, gut immune cells detect the infection and induce many defense mechanisms, one of which is the secretion of antimicrobial peptides. These antimicrobial peptides need to be able to target the pathogen, while sparing the commensals that provides other benefits to the host. Thus, by having a gene that confers resistance to antimicrobial peptides, the commensal has an advantage over the pathogen in the context of an immune response.

This was borne out in an experiment wherein the researchers added two different bacterial strains to the intestines of germ-free mice (mice who are raised to not have their own microbiota): wild-type (normal) B. theta or B. theta that were lacking LpxF (a mutant strain), and therefore lacked resistance to antimicrobial peptides. They then infected these mice with a known pathogen, Citerobacter rodentium. They found that while the LpxF mutant strain of B. theta was outcompeted by the pathogen, the wild-type B. theta survived the immune response.  

The findings of this study illustrate two important principles. First, they provide a mechanism that explains how a commensal bacterium survives a host defense mechanism that is directed against all bacteria. Second, they show that this survival mechanism helps commensal microbes compete with pathogens for colonization of the gut. These principles are relevant to both the continued understanding of the role of the microbiota in host defense, and in understanding the co-evolution of the immune system and commensal microbes. This co-evolutionary relationship, whereby our evolved mechanisms for eliminating bacteria are resisted by commensals that have evolved to live in our bodies, is important for the continued study of the microbiota and its impacts on our health. 

Where did tuberculosis come from?

By: Zuri Sullivan

Could the ancestors of this adorable seal have been the source of tuberculosis in the Americas? A recent study published in Nature says it’s possible. A team of geneticists from institutions throughout North America, South America, and Europe, used a comparative genomics approach to try to solve the mystery of the origins of modern M. tuberculosis in the New World.

Mycobacterium tuberculosis (M. tb) is a bacterium that causes tuberculosis disease (TB).  TB is the second leading cause of infectious mortality in the world, after HIV, resulting in over 1 million deaths per year. In 2014, the global TB epidemic is largely concentrated in the developing world, but it was only about 50 years ago that the United States was battling its own TB epidemic in New York City.

In fact, the history of TB stretches back to the beginning of human history. The exact date of the origin of TB is still an active question in research, but evidence suggests that the M. tb complex (MTBC) emerged up to 70,000 years ago in Africa and has been co-evolving with humans since then. What remains a mystery, however, is how M. tb spread from the Old World (Africa, Europe, and Asia) to the New World (the Americas). Perhaps the most obvious explanation would be that European settlers brought M. tb with them when they colonized the New World. And there’s a strong precedent for this—the devastating effects of the introduction of pathogens to natives of the New World by European colonists have been an important feature of colonial history. In the case of TB, however, this explanation doesn’t hold up—Bos, et al. isolated M. tb genetic material from three ancient Peruvian skeletons that date back to approximately 1,000 years ago, long before European settlers landed in the New World, but more than 10,000 years after the land bridge across the Bering Strait had been inundated.

This finding set up an interesting conundrum: how did M. tb travel from the Old World to the New World a millennium before humans did so? To answer this question, the authors turned to a comparative genomics approach, analyzing the genomes of mycobacteria from various sources and looking at differences between them to try to determine evolutionary relationships between them. Using a next-generation sequencing technique called Illumina, they analyzed the sequences of M. tb DNA isolated from the Peruvian skeletons, as well as 259 other genomes from human and animal strains of mycobacteria. They then identified single nucleotide polymorphisms (SNPs) present in the various mycobacterial isolates. SNPs are single changes in the genetic code that arise randomly. When they confer a survival advantage to the organism they become evolutionarily selected for. The evolutionary history of a set of organisms can thus be inferred by this type of analysis. This allowed researchers to infer how closely related the different isolates were based on which SNPs they had in common.

Their results were surprising—the ancient Peruvian M. tb isolates were more closely related to animal strains of mycobacteria than to other human strains. In particular, they shared many SNPs with Mycobacterium pinnipedii, a strain of mycobacteria that infects seals and sea lions. Based on these findings, they concluded that the presence of M. tb in the New World could have come from a zoonotic (animal to human) transfer of M. pinnipedii from seals to humans living in ancient coastal communities that hunted these animals.

While it’s currently impossible to go back in time and understand how modern diseases arose, genetic approaches to studying pathogen evolution provide important clues about the history of pathogens and their co-evolution with humans. It is well-documented that ancient pathogens, like M. tb and Plasmodium (the causative agent of malaria) have played an important role in the evolution of our own immune systems. Thus, by unraveling the history of these tiny organisms, we may be able to learn more about how we evolved to fight them.

Is the human immune system driving HIV to become less virulent?

By: Zuri Sullivan

Humans are extremely diverse. We have different skin colors, different hair colors, different personalities, different body types…in almost every characteristic, no two people are exactly the same. One of the ways in which we are most diverse, and one of the most important ways that we are diverse, is our HLA type, which stands for human leukocyte antigen. The HLA locus is actually the most polymorphic, or variable, set of genes in the human genome. Currently, the number of alleles, or types, of the two HLA classes is 9,232 for HLA class I, and 3,010 for HLA class II. Compare that to the number of skin, hair, or eye colors that exist in our species, and you can appreciate how diverse our HLA type is. From an evolutionary standpoint, this high level of diversity in our HLA alleles is crucial for the survival of our species, as HLA alleles can affect what kinds of infections or autoimmune disease we’re susceptible to. Thus, by selecting for a high level of diversity at the HLA locus, evolution has safeguarded our species against being wiped out by any one pathogen, because we each have a differential susceptibility to different pathogens.

One such pathogen is the human immunodeficiency virus (HIV), which is the leading cause of death from an infectious agent worldwide.  And indeed, there are certain HLA alleles that confer protection against HIV. In particular, two alleles, HLA-B57 and HLA-B58, are strongly associated with HIV elite control, the phenomenon by which some individuals get infected with the virus but never progress to AIDS, even in the absence of anti-HIV drugs. The presence of these protective alleles really illustrates the evolutionary utility of HLA diversity—in the absence of modern medicine, these people would likely be the only ones to survive HIV infection.

Evolution is a two way street, however, and just as viruses exert evolutionary pressure on our immune system, our immune system exerts evolutionary pressure on viruses, including HIV. That’s the subject of a paper recently published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), in which researchers from Oxford University showed that in areas with an extremely high burden of HIV, protective HLA alleles may be driving the virus to become less virulent.

What would be the advantage to the virus of becoming less virulent? In the case of viruses that kill their hosts quickly, such as Ebola, being less virulent would likely help the virus to spread. In order to infect other individuals, viruses need their host to be alive, and ideally walking around and contacting other individuals that can get infected. If a virus causes debilitating disease soon after infection, its host is less able to spread the infection to other individuals. So extremely virulent viruses, like Ebola, are actually bad for us (the host) and bad for the virus. This is why some of the most successful viruses, like rhinovirus (the cause of the common host) and influenza virus (the cause of the flu) don’t make most people extremely sick, and have managed to stick around in the population for centuries.

Another reason why a virus would become less virulent is that virulence could be a trade off for another advantage. Often when pathogens acquire mutations that allow them to resist certain evolutionary pressures, such as antibiotics or the immune system, these mutations have a fitness cost to the pathogen. But, the relative benefit of evading the immune system or antibiotics outweighs the cost of a moderate decrease in fitness. This is the hypothesis raised by Payne, et al in their PNAS paper.

They compared Botswana and South Africa, two countries with an extremely high burden of HIV, but an overall higher seroprevalence (infections per capita) in Botswana. First, they found that HIV-infected people had relatively lower viral loads than those in South Africa, suggesting that circulating viruses in Botwswana may have overall lower replicating capacity than viruses in South Africa. When they directly tested the replicative capacity of viruses isolated from 64 infected individuals in Botswana and 16 in South Africa, they confirmed that viruses from the cohort of Botswanans had lower replicative capacity. To look at whether protective HLA alleles may be playing a role in this differential viral replicative capacity, they next looked at viral mutations known to confer resistance to HLA-B57 and HLA-B58. Their results seemed consistent with their hypothesis—viruses from the Botswana cohort had a greater proportion of resistance mutations to HLA-B57 and 58 than those from the South Africa cohort. Finally, they compared a South African cohort from the early 2000s to one from 2012-13, and found that the frequency of mutations that allow HIV to escape protective HLA alleles had increased during this period, further supporting the idea that the virus is evolving resistance to these protective alleles over time.

One caveat to the findings in this study is that they were unable to find a correlation between viral replicative capacity and HLA-driven mutations. This suggests that this evolutionary relationship is more complex than was captured by their experiments, and that other factors, such as HLA diversity and antiretroviral therapy coverage, are likely important. However, other studies in South Africa have found viral replicative capacity to be correlated with the accumulation of HLA-driven mutations, supporting the overall idea that the mutations to evade the immune system come at a cost to viral fitness.

These results echo a longstanding phenomenon in the study of HIV and its close relative, siminan immunodeficiency virus (SIV), which infects non-human primates. While HIV infection in humans results in mortality rate close to 100% when untreated, many primate species, such as the African green monkey, can be infected with SIV without any apparent effect on their health. This points to the importance of host-pathogen co-evolution in disease susceptibility. HIV has infected the human population for less than a century, while SIV has been around for tens of millennia. Over that amount of time, both virus and host have evolved to resist each other without overtly killing each other. While it’s unlikely that we will see any HIV-driven evolutionary pressure on our on biology in our lifetime, it is clear our biology has placed significant pressure on the virus in its short history.