Sex may seem like all fun and games, but evolutionarily speaking, sexual reproduction has perplexed biologists for decades. It’s a question of math—why have a population in which only 50% of people can reproduce? In other words, why do men exist? Other than killing bugs and lifting heavy things that you could probably lift yourself, men, and sexual reproduction, confers an important evolutionary advantage: protection from pathogens.
The generation time of a human, other animal, or even a plant, is far greater than that of a bacterium. Think years, versus hours (or even minutes). Bacteria, and other pathogens, also acquire mutations at a much higher rate than humans per generation. Although mutating doesn’t sound like a benefit, it actually allows the bacteria to evolve as it is able to find mutations that better suit the particular environment in which it finds itself.
With bacteria acquiring new mutations so often, and evolving so rapidly, how are we humans supposed to keep up? This is where sex comes in. While we aren’t able to reproduce every hour, sexual reproduction allows us, as a species, to be constantly mixing our genetic material. Asexual reproduction, as occurs in bacteria, involves a single organism making an almost exact copy of itself. Any mutations that arise are random, and useful ones are just lucky. Sexual reproduction, on the other hand, always involves mixing information of two parents, so each generation is an opportunity for the acquisition of lots of new traits.
The idea that sexual reproduction might provide protection from pathogens is not a new one. This theory has its roots in a set of ideas known as the Red Queen Hypothesis. In Lewis Carroll’s Through the Looking Glass, the Red Queen says: “Now, here, you see, it takes all the running you can do, to keep in the same place. If you want to get somewhere else, you must run at least twice as fast as that!” In evolutionary biology, this translates to the idea that pathogens (e.g. viruses, bacteria, fungi, and parasites) and their hosts are engaged in a constant race against one another where the pathogens want to remain in their hosts and hosts want to eliminate them. Fortunately for the pathogens, they’re able to reproduce and evolve more rapidly than complex multicellular organisms like us. Each new generation, which occurs on the scale of hours, is an opportunity for a species of bacteria to acquire new mutations that could fortuitously render it less susceptible to attack from an animal’s immune system.
Multicellular organisms cannot mutate themselves on a per infection basis, so we depend on other mechanisms of battling quickly mutating bugs. The genetic variation that we, as a species, get from sexual reproduction is particularly important for the ability of our immune system to fight pathogens. In fact, the most variable set of genes in the human genome encode proteins that determine what kinds of pathogens an individual is best at fighting. This variation affords our species widespread protection from pathogens in general—even if one person is particularly susceptible to a certain viral infection, for example, the likelihood of everyone being susceptible to this virus is made extremely low by our extraordinary genetic diversity. This diversity is afforded by sexual selection that allows humans to acquire new traits with every generation.
There’s no guarantee that newly acquired traits will be useful, and many of them can be neutral, like eye color, or detrimental, like genetic diseases. Over evolutionary time, however, sexual reproduction is hypothesized to give organisms a leg up in the arms race with pathogens. So in addition to allowing you to make babies and enjoy yourself at the same time, sex may also play an important role in protecting species from extinction.
If you’re a dog person like me, you probably feel a special bond with your dog, and may even consider them as a member of your family. Though we’re unable to communicate with our dogs in the same way we communicate with other humans, many dog owners would likely agree that they feel an emotional connection to their pets. Because of these close relationships, scientists have long been interested in the evolution of domesticated dogs. Last week, the journal Science featured a number of research articles addressing longstanding questions about domesticated dogs. One of these articles investigated a possible mechanism by which we form emotional connections with our dogs, through a hormone called oxytocin.
Oxytocin is produced in the brain and acts as a powerful modulator of neuronal processes in mammals. It is specifically important in social behavior, playing crucial roles in the bonding between mothers and infants, as well as between sexual partners in species that exhibit lifelong mating behavior. The role of oxytocin in maternal/infant bonding has been well-studied in humans, and acts through a positive feedback loop. Positive feedback loops are extremely common in biology, and describe a system in which signal A promotes signal B, and signal B reciprocally promotes signal A.
Specific interactions, such as eye contact, between a mother and her infant increase oxytocin levels in the mother, and the increase in maternal oxytocin causes a corresponding increase in the infant’s oxytocin levels, which then amplify oxytocin levels in the mother. While this phenomenon is well-described between humans in an intraspecies manner, the authors of this study asked whether oxytocin-mediated bonding could be observed in an interspecies manner, specifically between humans and their pet dogs. This pairing is a great model in which to observe such interspecies interactions because humans have anecdotally described forming one-on-one relationships with their pet dogs.
To study this, the investigators looked at pairs of dogs and their owners, as well as pairs of hand-raised wolves and their owners. Wolves are the closest living relative of domesticated dogs and share many common biological features. However, because dogs, unlike wolves, have cohabitated with humans for many generations, the authors hypothesized that interspecies bonding behavior with humans would have evolved in dogs, but not in wolves.
In their first experiment, the authors observed interactions between the wolf/owner and dog/owner pairs. They specifically focused on eye contact, or gazing, as this interaction has been well-documented to stimulate oxytocin feedback loops in human interactions. They measured oxytocin levels in the urine of the dogs, wolves, or owners before and after their interactions, and also measured the duration of gazing between the animals and their owners. They found that the longer the duration of eye contact between dogs and their owners, the higher the levels of oxytocin in both the humans’ and the dogs’ urine. Interestingly, this correlation was not observed in the wolf/human pairs, supporting the idea that interspecies oxytocin-mediated bonding has evolved specifically in dogs as a function of their close evolutionary relationship with humans.
While this finding showed that gazing behavior was related to oxytocin levels in dogs and humans, it did directly not address the issue of the positive feedback loop. In other words, they showed that dog and human oxytocin levels were both elevated following extended eye contact, but not that dog oxytocin levels directly affect their owners’ oxytocin levels. To answer this question, they administered oxytocin or saline (salt water) to dogs, and then allowed them to enter a room in which their owner and two unfamiliar human volunteers were present. The investigators observed the interactions between the dogs and the humans, and measured oxytocin levels in the dogs and the humans throughout the experiment.
They found that female dogs who had received oxytocin engaged in more eye contact with their owners than the dogs who had received saline, and that the owners of the oxytocin-treated female dogs had significantly increased levels of oxytocin following the interaction, even though the owners had not been given oxytocin themselves. This experiment demonstrated that in female dogs, oxytocin stimulates dog/owner gazing behavior, which results in elevated oxytocin levels in the owner.
These results were not observed in male dogs, for reasons that remain unclear. Some evidence suggests that in humans, females are more sensitive to the effects of oxytocin than males. Additionally, in a small rodent called the prairie vole, oxytocin may be related to male aggression. Thus, the authors hypothesize that in their experiments, male dogs may have been exhibiting an aggressive response to the strangers in the room, limiting their interactions with their owners. In all species studied, however, the differing role of oxytocin between the sexes remains largely unknown.
Nevertheless, the results from this study indicate the bonds formed between dogs and their owners are mediated by oxytocin, the same hormone that contributes to maternal/infant bonding and lifelong sexual partners. Our feelings of affection for our dogs seem to be driven by bona fide neurological mechanism, in addition to how cute they are and how much fun they are to play with.
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.
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?
This is Durban, South Africa. Aside from being a surfing mecca, a thriving center of Zulu culture, and the largest port on the African continent, Durban (located in KwaZulu-Natal province) is the global epicenter of the HIV and tuberculosis (TB) epidemics. TB is the leading cause of death amongst South Africa's HIV-infected population, which is the largest of any country in the world. And a huge proportion of South Africa's affected population resides in KwaZulu-Natal.
I extremely fortunate to have been able to study these infections in the laboratory and the classroom as an undergraduate. But when it comes to infectious diseases, some of the hardest questions can only be answered by studying them in hard places. This was, in large part, the motivation for the founding of the KwaZulu-Natal Research Institute for Tuberculosis and HIV in Durban, and was also my motivation for moving thousands of miles away from home for two years to conduct research there. I wrote about my experience for a new magazine about science and society, called Method. Check out the excerpt below, and read the full story here. And be sure to read all of the other great content that Method has to offer.
Between 2005 and 2006, an outbreak of extensively drug resistant tuberculosis (XDR-TB) killed all but one patient at the Church of Scotland Hospital in Tugela Ferry, South Africa. The median survival time following diagnosis was a mere 16 days, and of the patients tested, all were co-infected with HIV. The situation was desperate, the fatality rates unprecedented, and the community unprepared for an outbreak of this magnitude. Though this calamity sent shockwaves through the TB and HIV research communities, the situation was not unique. XDR-TB had been detected in all of South Africa’s nine provinces, all of its neighboring countries, and dozens of other countries across the globe. HIV was fueling the TB epidemic, and Africa was the only region of the world in which TB incidence was on the rise. No new TB drugs had been discovered in nearly 40 years. Effective vaccines against HIV or TB infection remained a dream.
More than 8,000 miles away, in Chevy Chase, Maryland, American researchers at the Howard Hughes Medical Institute (HHMI), the largest private funder of academic biomedical research in the United States, were meeting to discuss their international program. At this meeting, Dr. Bruce Walker, an HHMI investigator who leads an HIV research lab at Harvard Medical School, proposed using a model similar to what has historically worked for HHMI in the United States: investing in individual investigators who were doing great work in biomedical science.
“But,” Dr. Walker recalls, “In a place like Africa, truly transformative support would require establishment of critical infrastructure and a critical mass of investigators.” Indeed, this meeting identified two important and intricately related problems in the developing world: the desperate need for cutting edge biomedical research, and the rarity of sites in which to conduct such research...Read more
Reprinted with permission from Method Quarterly.
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.
By: Zuri Sullivan
Sorry, kids, but if you kiss a frog, it’s highly unlikely that he’ll turn into a prince. The most you’ll probably get out of it is some icky frog skin slime on your mouth. That may sound terrible, but a new study published in Antimicrobial Agents and Chemotherapy suggests that some components of icky frog skin can have some unexpected benefits for our health.
As you might imagine, frogs are pretty distantly related from humans, and consequently, their immune systems work quite differently from ours. One thing we have in common, however, is that we both produce molecules specialized for killing bacteria, called antimicrobial peptides (AMPs). Humans produce lots of AMPs in their guts— last week, I wrote a story about how the helpful bacteria in our guts manage to survive in the face of these harsh molecules, while dangerous bacteria don’t. Unlike humans, frogs and other amphibians produce AMPs in their skin. To a certain extent, you could say they wear their immune systems on their backs.
Scientists haven’t quite figured out all of the ways that AMPs actually kill bacteria, but if the bacteria are susceptible to them, they work incredibly well. So from the bacteria’s perspective, AMPs are pretty nasty. From biomedical scientists’ perspective, however, this means that AMPs from a variety of species may be able to be used to treat bacterial infections when our own AMPs are inadequate.
This was the focus of the study I mentioned above, led by principal investigator David Craik at the University of Queensland in Australia. His research group wanted to know whether frog AMPs could be used to treat Staphylococcus aureus infection. You may know of Staphylococcus aureus by its more colloquial nickname, Staph. Staph infections are a major problem in hospitals, and the widespread use of antibiotics has led to the emergence of antibiotic resistant staph, also known as MRSA (for methicillin resistant Staphylococcus aureus). Antibiotics are great, but when misused or overused, they can promote the emergence of antibiotic resistant bacteria, necessitating the development of new antibiotics. It’s a vicious cycle, but AMPs could be new weapons in our anti-bacterial arsenal.
Can you really take AMPs from frog skin and use them to treat a staph infection? In mice, the answer seems to be yes. Dr. Craik’s group isolated AMPs from frogs, and studied their chemical structure. If they’d had to run out and catch a frog every time they wanted to do an experiment, the study would have taken forever, so they synthesized molecules that were very similar to the frog AMPs. These synthetic AMPs were then used to treat Staph-infected mice. Surprisingly, they worked! And not only that, but when they tested the compounds to find out if they were toxic to the mice, they seemed to be safe.
This doesn’t mean you should go out and lick a frog next time you’re feeling sick. As Helen and I tried to illustrate before, findings in mice need a lot of work to be extrapolated to humans. We know that a drug’s effect on mice is not always the same as its effect on humans, so clinical trials, despite being absurdly costly and tedious, are really important to make sure our drugs have the effects we want them to. AMPs are also expensive and difficult to synthesize, and scientists will need to find easier ways of making them if they want to try to use them to treat human infections.
Don’t give up on frog AMPs yet, though. With time, scientists may be able to turn them into real treatments for human infections. And in the meantime, you can put them to good use by applying the old Russian method of dipping a frog in unpasteurized milk to keep it from spoiling.
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.
Biology is complex—very, very, very, very, very complex—and because of this, simplification is incredibly important. Many experiments are conducted by breaking down a complex system and studying its constituent parts, manipulating specific components (or “variables,” in science slang) to understand how they impact the system as a whole. For example, to understand how viruses replicate within their animal hosts, scientists often study how the virus replicates in animal cells grown in an incubator, instead of the whole organism. As a consequence, scientific knowledge accumulates in tiny increments—each study answers a small, but specific question. When we amass sufficient answers to simple questions, we learn something new about a complex biological system.
This strategy of deconstruction and reconstruction has led to a number of important scientific discoveries, but it comes at a cost. Findings made in smaller systems can’t always be extrapolated to the larger system. Sometimes, these findings are really exciting, and they tempt us to jump to conclusions because of their potential impact on the larger system. This presents a major challenge to science reporters: keeping a story exciting at its beginning while resisting the temptation for overstatement. Some stories in the media meet this challenge better than others, but like all news, science news should be taken with a grain of salt—a scientist’s interpretation of his or her findings and their potential impact on society can vary widely from the interpretations of reporters.
As a case study for this idea, we investigated a recent high-profile story about the relationship between temperature and catching the common cold. The original study, published last month in the Proceedings of the National Academy of Sciences by a team of investigators headed by the laboratory of Akiko Iwasaki, an investigator of Howard Hughes Medical Institute and Professor of Immunobiology at Yale University, investigated the effect of temperature on protective immune responses to rhinovirus, the predominant causative agent of the common cold.
“It’s been known since the 1960s that the virus replicates better at nasal cavity temperature, which is around 33 to 35 degrees Celsius,” said Dr. Ellen Foxman, a post-doctoral fellow at Yale University who was the primary author of the study. Core body temperature for humans is 37 degrees Celsius (98.6°F), but inhaling cool air brings the temperature in our noses down to about 33-35 degrees Celsius (91.4-95°F)—the temperature at which rhinovirus grows best. By exploring the role of specific immune responses in a cell system, the study found that the temperature difference in viral replication was caused by a temperature-dependent difference in immune responses. Turns out, key immune responses against rhinovirus don’t work as well at 33-35 degrees as they do at core body temperature, so the virus is able to replicate more.
Given the implications of these findings (particularly that we should always listen to our moms and bundle up in cold weather), this study was covered widely by the media, with such headlines as “Common cold ‘prefers cold noses’” and “Common cold really is triggered by cold weather”.
“Some of the headlines went further than we did in our study,” says Ellen. “We didn’t actually study weather at all. Or people going out in the cold.” This was apparent in the original research findings, but many journalists bit into the cold weather/cold virus relationship. “To really make that claim, in terms of a clinical research study, you’d need to have two groups of people, normalize them, put some people in the cold…all that we didn’t do. So some people took it a bit further than we would have.”
This study wasn’t conducted in humans or in animals for that matter. It was done in a system where cells that live on a dish in an incubator in a lab are infected with the virus and are grown at different temperatures. Organisms are a lot more complicated than cells in a dish, making it difficult to extrapolate the findings from the study to a complex organism like a human. The relevance of these studies in humans is not currently known. This was seen as a limitation in other mainstream articles that covered the study, but was never fully discussed. On another note, the study looked at temperatures of 33-35°C compared to 37°C. The temperature of the human nasal cavity during winter could reach far below 33°C. Studies exploring how the immune responses functions below 33°C have not been done. Far from invalidating their results, however, the controlled system in which the experiments were performed is a major strength of the research. It demonstrated that the slight shift in the temperature dampens the immune response to the virus. Because inhaling cold air results in cooling of the nasal cavity temperature, the study implies that the cold weather could lead to more virus replication in human nose.
“After we isolated the primary cells, everything was identical about them, except for a few hours of incubation at different temperatures. So, it’s not the same as studying it in a person…but in a person, there are so many variables that you can’t control, that you can’t analyze. That’s the advantage of doing something in a laboratory. You can control everything except for one variable at a time and see how this variable affects the immune response, and thereby the infection.” This high degree of control is an indispensable component of the scientific method—without it, results are extremely difficult to interpret because outcomes cannot necessarily be attributed to a single variable. In order to show cause and effect, scientists need to ask straightforward questions under tightly controlled conditions. This control allowed for the discovery of what Ellen sees as the most important implication of the study.
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.
By: Zuri Sullivan
It has come to our attention that many people are concerned about deoxyribonucleic acid (DNA) in their food, and that more than 80% of Americans support “mandatory labels on foods containing DNA,” according to a study conducted by the Oklahoma State University Department of Agricultural Economics. The study found that more people supported mandatory labeling on foods containing DNA than supported a tax on sugared sodas, a ban on the sale of marijuana, a ban on the sale of foods with trans fats, or a ban on the sale of unpasteurized milk.
Ilya Somin, a Professor of Law at George Mason University, discussed these findings in a recent blog post on washingtonpost.com. In his post, Somin addresses the dangerous intersection of widespread ignorance about science with mistrust of public policy amongst the American electorate. Our purpose here is to address some of the scientific misinformation leading to these concerns.
DNA is a molecule that stores all the information necessary for life. Along with a related molecule, ribonucleic acid (RNA), it is one of a group of macromolecules, or building blocks, that make up all known living organisms. Other groups of macromolecules include proteins, carbohydrates, and lipids (or fats). The information encoded in DNA, however, is required for building all of these molecules. In short, DNA is essential for life.
All living organisms, from single-celled bacteria to large, complex, multicellular organisms like us, are built from cells that contain DNA. Even fossils, like this 400,000 year-old skeleton contain DNA. All of the food that we eat, provided that it came from a living organism, contains DNA. Vegetables, fruits, meats, dairy, pizza—all of it contains DNA. The only thing in your refrigerator that doesn’t contain DNA is the refrigerator itself. If we were to label all foods containing, DNA, therefore, we’d need to label every single food. Not only would that be wasteful, but it would also be meaningless. In fact, I’d be in support of labeling any foods that don’t contain DNA. I’m not sure what that would be, maybe rocks or something?
The purpose of Because Science is two-fold. First, we think science is awesome and we want everyone else to think science is awesome, too. But more importantly, we want to help people to better understand the science that impacts their daily lives. While we felt a bit of an imperative to write this quick piece about following the publication of this study, we are always open to suggestions based on concerns or misunderstandings about science. So if there’s a scientific topic you’d like to know more about, send us an email and let us know!
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.
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.