Sex > Food for Male C. Elegans

By: Helen Beilinson

Caenorhabditis elegans, or simply C. elegans, are small nematodes (worms) that are one of the most popular organisms used to study animal biology. There are many reasons for this: they replicate quickly and they are easy and inexpensive to care for. But the most fascinating fact is that each individual worm has a set number of cells that each has a specific position and function. Each of the cells can be followed from its conception to its final location. In the 1980’s, Sir John Sultson was one of the first scientists to track each of the worm’s cells throughout development to create one of the first maps of cell lineage. Since then, many researchers have continued to follow up on Sultson’s studies, leading to the belief that C. elegans’ cell lineage map had been completed. So, it came as a big surprise to the field when a group out of London discovered two new neuronal cells in the male worms.

Although C. elegans are sexually dimorphic, like humans, they are not divided into males and females. Instead, they are made up of hermaphrodites that can self-fertilize and males that can only fertilize the hermaphrodites. Males and hermaphrodites have different reproductive behaviors to reflect their reproductive patterns. Male worms need to learn how to optimally locate mating partners, which they accomplish through a process called sexual conditioning. It was previously known that males are attracted to hermaphrodites by sensing their pheromones or by directly sensing them with their tails. A recent study in the journal Nature identified two previously undescribed male-specific neurons that are necessary for sexual maturation.

This finding came as a surprise. Because they are self-perpetuating, hermaphroditic worms are easy to maintain, and are consequently more widely studied than male worms. When studying males, most scientists have focused on physically obvious attributes, such as the worms’ tails, not their brains. However, when these authors looked more closely at male worms’ brains, which had been thought to contain 383 neurons, they found that they contained 385. They called these neurons mystery cells of the male, or MCMs. To identify the function of MCMs, the authors explored other cells that the MCMs interact with. They found that these cells are a component in a loop of interactions between neurons that function in regulating mating experiences by modulating behavior. Specifically, the MCMs are necessary for a male-specific switch in puberty, in which they respond to chemical signals differently after sexual conditioning. This sexual conditioning functions to make the males suppress cues from the environment that indicates presence or absence of food in favor of sex. While hermaphrodites will always migrate towards areas with good food and migrate away from dangerous areas without food, sexual conditioning causes males to go away from areas with good food or go towards areas with bad food if there are potential mates in those locations. In effect, males prioritize sex over food.

To test this hypothesis, the authors set up the following experiment. C. elegans tend to avoid salt-rich environments, because high salt is usually an indication of food scarcity. The authors placed potential mates into a salt-rich environment and placed either hermaphrodites or males outside of this salt-rich location. They found that hermaphrodites, before and after sexual conditioning, will always avoid salt locations. However, the males will avoid the salt location before sexual conditioning, and will enter the salt-rich area after sexual conditioning. If the authors remove the MCMs from sexually conditioned males, they no longer enter the salt-rich area after sexual conditioning. The authors conclude that male C. elegans suppress their knowledge of the risk of no food for the benefit of potentially mating.

This phenomenon makes sense. Hermaphrodites are capable of self-fertilization, so in order to procreate, they need any other worms around and need to prioritize their health to be good parents. Males, on the other hand, absolutely need another partner to reproduce. The health of the male is not as critical in producing viable children as is their partners, the hermaphrodites. Thus, they can risk putting sex before food.

When the authors tried to find the origin of the MCMs during C. elegans’ development, they found that they arise from glial cells. Glia are cells that reside next to neurons and provide structural and functional support to neurons with which they are associated. However, during sexual maturation, some of the worms’ glial cells begin to start expressing neuronal proteins and develop into MCMs. Hermaphrodites do not have the glial precursors of the MCMs, so these cells, from the beginning of the male worms’ lives, are male-specific. This is the first case found in non-vertebrates where neurons develop from glial cells.

The discovery of these new neurons links developmental and anatomical differences between males and hermaphrodites to their sex-specific behaviors. It’s fascinating that the behavioral patterns of these worms is quite literally hard-wired in their minds, as opposed to something they have learned and apply to a situation. These findings are also a testament to how many new discoveries are happenstance and often come from re-observing something that’s right under your own nose. 

Some future kids will have three parents to embarrass them

By: Helen Beilinson

In each cell of our bodies, DNA is stored in two places. The nucleus contains nearly all of our genetic material, storing information that ranges from our hair color to how quickly we can break down the food we eat. A few genes are stored in an organelle called the ‘mitochondrion’, known more colloquially as ‘the powerhouse of the cell’. Mitochondria are predominantly in charge of generating their cell’s supply of chemical energy (hence their nickname), but are also involved in a variety of other tasks, such as cell growth and cell death.

Despite being involved in so many functions, mitochondria only have 37 genes (as opposed to the 25,000 in the nucleus). This may sound insignificant, but these genes are critical in ensuring that cells are happy and function properly. Consequently, defects in the function of mitochondria can have major effects on our health, resulting in a set of disorders called mitochondrial diseases. These include Leber’s hereditary optic neuropathy (LHON), which causes loss of vision at early ages and progressive loss of vision due to optic nerve degeneration, and mitochondrial myopathy, a muscle tissue disease. Fifteen percent of mitochondrial diseases are caused by mutations in mitochondrial DNA (the remaining are due to nuclear DNA mutations or other causes).

Mitochondrial diseases are treatable. However, current therapies are predominantly directed toward alleviating symptoms and in order to provide more comfort to the patient. These therapies don’t actually eliminate the cause of the symptoms— particularly mutated mitochondrial DNA. Why is it so hard to target the cause of mitochondrial diseases? Mitochondria are incredibly abundant; nearly half the space inside of heart muscle cells is taken up by mitochondria, and each liver cell contains up to 2000 individual mitochondria. So to target the cause of mitochondrial disease, one would need to eliminate the problem in the original mitochondria that gave rise to the lifetime supply present in all the cells of our bodies. Luckily, scientists have found a trick to do just that.

All of this potentially mutated mitochondrial DNA is inherited from our mothers, because the female egg, unlike sperm, contains all the mitochondria that the offspring will inherit. If a woman’s eggs contain only unhealthy or mutated mitochondria, the egg will usually be killed before it can further develop into a fetus. This is a common protective strategy used to eliminate fertilized eggs with any number of defects that could cause disease in the fetus. There are rare cases where the fetus will continue to birth with such inherited diseases. Luckily, accumulated knowledge about mitochondrial diseases and advancements in cellular biology have led to an invention that helps prevent infertility in women with defective mitochondria and protects their children from inheriting mitochondrial diseases.

This method, called three-parent in vitro fertilization (TPIVF), is essentially a twist on in vitro fertilization, where an egg is mixed with a sperm in a dish, outside of a body, and this fertilized egg is then implanted into a woman’s uterus. Unlike traditional in vitro fertilization, however, fertilized eggs generated through TPIVF contain DNA from three parents (hence the name). In this method, the nucleus from an egg with healthy mitochondria is removed and replaced by the nucleus from an egg with unhealthy mitochondria. This egg, composed of the mitochondrial DNA of parent A and the nuclear DNA of parent B, is then fertilized by sperm of parent C. In this way, a woman whose eggs contain mutated mitochondria is still able to conceive a child whose nuclear DNA is half her own.

At the beginning of February, the United Kingdom became the first country to legalize this method of in vitro fertilization. As early as January of next year, children will be born with three biological parents. As wonderful as this method is at preventing disease and infertility, it raises a lot of ethical issues, which are the predominant reason as to why TPIVF hasn’t been legalized in countries other than the UK.  Allowing for such extreme genetic modification of offspring opens the door to acceptance of “designer babies”. The idea of designer babies is that with advancements in basic cellular biology, people may start wanting to manipulate the genetic make up of their future children to personally select for features such as blue vs. brown eyes, curly vs. straight hair, etc. To my knowledge, in vitro fertilization, be it two or three parent, has thus far only been used to allow couples experiencing infertility or those whose offspring have a high risk of debilitating disease to give birth to healthy children. However, there will always be the question of whether such manipulations will lead to something more extreme.

TPIVF is an incredible advancement that highlights how far cellular, genetic, and developmental biology have come. Nevertheless, with great power comes great responsibility (thanks, Voltaire). It will definitely be interesting to see where our new abilities to genetically modulate offspring will lead.

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.