Tuesday, October 16, 2018

The world’s simplest known animal is very poorly understood

World’s Simplest Animal Reveals Hidden Diversity
The first animal genus defined purely by genetic characters represents a new era for the sorting and naming of animals
·         By Charlie WoodQuanta Magazine on October 6, 2018

World's Simplest Animal Reveals Hidden Diversity

Two individuals from two different genera of the phylum Placozoa: Trichoplax adhaerens (left) and Hoilungia hongkongensis (right). The gross morphology and the internal structure are indistinguishable, and only genetics can tell them apart. Credit: Hans-Jürgen Osigus, ITZ Ecology and Evolution, Stiftung Tierärztliche Hochschule Hannover, Germany

The world’s simplest known animal is so poorly understood that it doesn’t even have a common name. Formally called Trichoplax adhaerens for the way it adheres to glassware, the amorphous blob isn’t much to look at. At just a few millimeters across, the creature resembles a squashed sandwich in which the top layer protects, the bottom layer crawls, and the slimy stuffing sticks it all together. With no organs and just a handful of cell types, the most interesting thing about T. adhaerens might just be how stunningly boring it is.
“I was fascinated when I first heard about this thing because it has no real defined body,” said Michael Eitel, an evolutionary biologist at the Ludwig Maximilian University in Germany. “There’s no mouth, there’s no back, no nerve cells, nothing.”
But after spending four years painstakingly reconstructing the blob’s genome, Eitel might know more about the organism than anyone else on the planet. In particular, he has looked closely enough at its genetic code to learn what visual inspections failed to reveal. The variety of creature that biologists have long called T. adhaerens is really at least two, and perhaps as many as a dozen, anatomically identical but genetically distinct “cryptic species” of animals. The discovery sets a precedent for taxonomy, the science of naming organisms, as the first time a new animal genus has been defined not by appearance, but by pure genetics.
The modern taxonomic system, little changed since Carl Linnaeus laid it out in the 1750s, attempts to chop the sprawling tree of life into seven tidy levels that grant every species a unique label. The two-part scientific name (such as Homo sapiens) represents the tail end of a branching path through this tree, starting from the thickest limbs, the kingdoms, and ending at the finest twigs, the genus (Homo) and then the species (sapiens). The path tells you everything there is to know about the organism’s relationship to other groups of creatures, at least in theory.
Ever since its discovery in the late 1800s, T. adhaerenshas been recognized as having a highly unusual body plan, and it has formally had the phylum of Placozoa (“flat animals”) to itself for almost half a century. Just one level more specific than kingdom, a phylum is a cavernous space to occupy alone: Our phylum, Chordata, overflows with more than 65,000 living species ranging from peacocks to whales to eels. Biologists have long suspected that Placozoa hid more diversity, and mitochondrial evidence strengthened that suspicion in 2004, when researchers found that short sequences from different individuals looked about as different as those of organisms from different families (one level more general than genus).
But that observation about the two Placozoa didn’t meet the accepted international standards for putting them in new taxonomic categories, which have historically been based on animals’ forms. “At the time we had just uncovered the genetic differences,” said Allen G. Collins, a co-author of the 2004 paper and a zoologist at the National Systematics Laboratory of the National Oceanic and Atmospheric Administration (NOAA). “Looking at the animals we had collected, it wasn’t discernible how they might differ morphologically.”
To finish what Collins started, Eitel and his colleagues decided to abandon the visual approach and search for defining characteristics in the placozoan genome itself.
They began by mapping out the phylum’s genetic territory with the same easy-to-sequence mitochondrial DNA Collins had used. By comparing data from this molecule, known as 16S, Eitel concluded that a particular variety of Placozoa from Hong Kong was the most distant relative of the standard strain, the genome of which had already been fully sequenced in 2008. If any group would qualify as a different species, this was the one.
He next needed to read, order and interpret the 80-odd million A, G, C and T nucleotide bases that make up the Hong Kong variant’s genome. Growing a few thousand placozoans, blending them to extract their nuclear DNA and converting the snippets of their genome into a digital format took a few weeks, but the hard work of shuffling those pieces into the right order and figuring out what each section does took four years of fiddling around with computer programs. When the team finally had a full genome ready for comparison, the payoff turned out to be worth the wait. “We expected to find differences, but when I first saw the results of our analyses, I was really overwhelmed,” Eitel said.
A quarter of the genes were in the wrong spot or written backward. Instructions for similar proteins were spelled nearly 30 percent differently on average, and in some cases as much as 80 percent. The Hong Kong variety was missing 4 percent of its distant cousin’s genes and had its own share of genes unique to itself. Overall, the Hong Kong placozoan genome was about as different from that of T. adhaerens as human DNA is from mouse DNA. “It was really striking,” Eitel said. “They look the same, and we look completely different from mice.”
So where do all those genetic changes manifest, if not in the animals’ flabby appearance?
“Even though the placozoan itself looks like a little ball of glue, it probably has cells that are doing some pretty sophisticated things,” said Holly Bik, a marine biologist at the University of California, Riverside, who studies tiny marine roundworms known as nematodes, which can also be cryptic. The Hong Kong Placozoa came from a brackish mangrove stream where large swings in temperature and salinity demand flexible body chemistry. “Physiologically, for organisms, that’s a pretty big thing to have to deal with. At the molecular level you need specific adaptations,” said Bik, who was not involved in the research.
By comparing the Placozoa variation with the average genetic differences between groups in other phyla, the German team concluded that the Hong Kong Placozoa qualified as not only a new species, but also a new genus. It might even have qualified as a new family or order in other areas of the animal tree, but to err on the conservative side, the team based their standard of genus variation on jellyfish, a genetically diverse phylum with relatively tidy divisions between levels.
All that remained was the naming. Taxonomic codes demand identifying characteristics, but don’t specify whether they should be visual or genetic, so the team picked out four genetic letters in the 16S mitochondrial genome that could uniquely differentiate the two lineages. Then, endorsed by peer review and PLOS Biology in late July, their work placed a new organism on our map of life.
The team gave their specimen the genus name Hoilungia, for a shapeshifting dragon king from Chinese mythology, and they named the species hongkongensis, for where it was collected. Similar genome-based classifications are common in the protist and bacterial worlds, and a relative handful of cryptic animal species have been named based on genetics. Namings (and renamings) that blend morphological characters with genetic ones, which recently re-classified a common houseplantSusanne Renner, a botanist at the Ludwig Maximilian University. “It’s just great.”
The researchers hope their work will make it easier for future genetic character–based naming, which is less subject to biases from attention-grabbing visual features like antlers and fins that may not accurately reflect evolutionary distance between groups. “Someone had to be the first one to fight for the right to define new general species based on genomics, and we luckily got it published,” Eitel said.
Renner says this work is the latest step in an ongoing shift toward genetic taxonomy. “It took a long time to take off and now it’s taking off,” she said. She points out that in contrast with the pages of text that can go into a formal description of a species, specifying an organism with just four letters as the German team has done lends itself to snappy efficiency. “Linnaeus would be happy to do it. He was envisioning very brief and sharp diagnoses.”
As precise as genetic classification can be however, it will likely complement traditional ways of telling animals apart, not replace them. Observing visual features doesn’t require years of a lab’s time. Even for other cryptic animals like nematodes, which can’t be raised in captivity, genetic techniques may find limited use. “For me, working with a single nematode worm, there’s never going to be enough DNA isolated from an individual to use some of these technologies,” Bik said.
But for cryptic animals that researchers can cultivate, genetic sequencing may be the perfect spotlight for illuminating the shaded parts of their evolutionary tree. Eitel said he learned a lot from the process of analyzing the H. hongkongensis genome and predicts that sequencing the next variant—a project already underway—will take months, not years. “There will probably be dozens of new species popping up in the future,” he said. “And more to come, because we’re constantly sampling.”
Reprinted with permission from Quanta Magazine, an editorially independent publication of the Simons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

Worm brain 302 neurons not understood

The Connectome Debate: Is Mapping the Mind of a Worm Worth It?
Scientists have mapped a tiny roundworm's entire nervous system. Did it teach them anything about its behavior?
·                     By Ferris Jabr on October 2, 2012

Credit: The OpenWorm Project, image generated by neuroConstruct
In the 1970s biologist Sydney Brenner and his colleagues began preserving tiny hermaphroditic roundworms known as Caenorhabditis elegans in agar and osmium fixative, slicing up their bodies like pepperoni and photographing their cells through a powerful electron microscope. The goal was to create a wiring diagram—a map of all 302 neurons in the C. elegans nervous system as well as all the 7,000 connections, or synapses, between those neurons. In 1986 the scientists published a near complete draft of the diagram. More than 20 years later, Dmitri Chklovskii of Janelia Farm Research Campus and his collaborators published an even more comprehensive version. Today, scientists call such diagrams "connectomes."

So far, C. elegans is the only organism that boasts a complete connectome. Researchers are also working on connectomes for the fruit fly nervous system and the mouse brain. In recent years some neuroscientists have proposed creating a connectome for the entire human brain—or at least big chunks of it. Perhaps the most famous proponent of connectomics is Sebastian Seung of the Massachusetts Institute of Technology, whose impressive credentials, TED talkpopular book, charisma and distinctive fashion sense (he is known to wear gold sneakers) have made him a veritable neuroscience rock star.

Other neuroscientists think that connectomics at such a large scale—the human brain contains around 86 billion neurons and 100 trillion synapses—is not the best use of limited resources. It would take far too long to produce such a massive map, they argue, and, even if we had one, we would not really know how to interpret it. To bolster their argument, some critics point out that the C. elegans connectome has not provided many insights into the worm's behavior. In a debate* with Seung at Columbia University earlier this year, Anthony Movshon of New York University said, "I think it's fair to say…that our understanding of the worm has not been materially enhanced by having that connectome available to us. We don't have a comprehensive model of how the worm's nervous system actually produces the behaviors. What we have is a sort of a bed on which we can build experiments—and many people have built many elegant experiments on that bed. But that connectome by itself has not explained anything."

Because a lone connectome is a snapshot of pathways through which information might flow in an incredibly dynamic organ, it cannot reveal how neurons behave in real time, nor does it account for the many mysterious ways that neurons regulate one another's behavior. Without such maps, however, scientists cannot thoroughly understand how the brain processes information at the level of the circuit. In combination with other tools, the C. elegans connectome has in fact taught scientists a lot about the worm's behavior; partial connectomes that researchers have established in the crustacean nervous system have been similarly helpful. Scientists are also learning how to make connectomes faster than beforeand to enhance the information they provide. Many researchers in the field summarize their philosophy like this: "A connectome is necessary, but not sufficient."

"Some people say we don't know anything about how C. elegans's brain works and I am like, 'Yes, we do!'" says Cornelia Bargmann of The Rockefeller University, who has studied the nematode for more than two decades and attended the Columbia debate. "A lot of what we know about C elegans's rapid behaviors we have learned through and with the connectome. Every time we do an experiment, we look at those wiring diagrams and use them as a starting point for generating hypotheses."

(An in-progress 3D reconstruction of the C. elegans connectome. Dots represent the cell bodies of neurons; long lines represent the neurons' axons and dendrites. Credit: The OpenWorm Project, image generated by neuroConstruct)

Early birds
As soon as Brenner and his colleagues at the University of Cambridge completed the 1986 draft of the C. elegans connectome, a few things became clear. First, scientists were able to label every one of the 302 neurons as either a sensory neuron (one that collects information from the environment, such as temperature or pressure); a motor neuron that controls muscles; or an interneuron, which connects the two. Scientists had already identified some neurons as motor or sensory by destroying them with lasers and observing what abilities the worm lost or retained. With the connectome, they could categorize all of C. elegans's neurons by referencing the number and types of connections between them. On average, sensory neurons make more presynaptic connections (sites where neurons spit out chemical messages) and fewer postsynaptic connections (where neurons receive chemical messages) because sensory neurons are mainly in the business of sending information to other cells. Motor neurons show the inverse trend. Each type of neuron constituted about one third of the C. elegans nervous system. The wiring diagram also allowed scientists to immediately identify how a neuron of interest was linked to other neurons. If a researcher zapped a neuron near the worm's head and discovered that the nematode no longer inched toward food, he could look up that neuron in the connectome and see exactly how it was connected to motor neurons.

In the 1980s, as a postdoctoral student in Brenner's lab, Martin Chalfie—now at Columbia University—used the C. elegans wiring diagram to explain one of the worm's behaviors: He identified the specific neural circuits responsible for the worm's tendency to wriggle backward when poked on the head and to squirm forward when touched on the tail. "The connectome was absolutely critical," Chalfie says. "Without it, we simply would not have known which cells were connected to which." By combining the wiring diagram with evidence from previous research, Chalfie predicted that a particular set of interneurons mediated forward movement and that another was involved in backward movement. Annihilating those neurons with lasers confirmed his predictions.

In the following 25 years researchers have continued to use the C. elegans connectome to study the worm's nervous system and behavior. In combination with genetic analysis and tools that eavesdrop on electrical activity within the worm's neurons, the connectome has helped researchers understand how C. elegans responds to temperaturechemicals and mechanical stimulation as well as how the worms mate and lay eggs. Scientists have also used the connectome to discover talents no one knew the nematode possessed: X. Z. Shawn Xu of the University of Michigan identified four neurons in the worm's body that respond to light—a surprising ability for a creature that lives between grains of soil in complete darkness. "Nearly every C. elegans neuroscience study (as long as it involves behavior) benefited from this connectome," Xu wrote in an e-mail message.

Although the C. elegans connectome has been a boon for scientists who study this nematode's behavior, the past two decades of research have also underscored the staggering intricacy of even a relatively small nervous system. "When you move onto behaviors that are more complex than a quick reflex, you're dealing with especially complicated pathways that are not immediately interpretable because they are not simple circuits—they are networks," explains Scott Emmons of Albert Einstein College of Medicine.
This past summer, in an attempt to confront some of that complexity, Emmons and his colleagues published a connectome of the male nematode's tail, which contains most of the 81 extra neurons that distinguish it from the hermaphrodite (giving the male a total of 383 neurons). It took Emmons and his team about three years to complete and publish the partial connectome: he used more or less the same techniques that Brenner relied on in the 1970s, albeit with faster computers, more powerful microscopes and digital cameras. The male C. elegansconnectome also features a crucial piece of information missing from the original draft of its counterpart: synaptic weights. The many connections between neurons are not equal in strength—the more two neurons communicate, the stronger their link becomes and the more likely one is to fire when the other fires. Neurons may also be genetically programmed to form stronger connections with certain partners as the nervous system develops.

Analyzing synaptic weights in the male nematode's connectome has already given Emmons some ideas about neural development. Some neuroscientists have proposed that genes tightly regulate the strongest connections between neurons in C. elegans, whereas weaker connections are more or less accidents—neurons hooking up with whomever they bump into. Emmons's preliminary analysis shows that homologous pairs of neurons on either side of the nematode's body form highly similar strong and weak connections, suggesting that even the weak connections are not entirely random.

Dynamic networks
Synaptic weights are just one of the many layers of information missing from typical connectomes. To understand how neural circuits work, one also needs to know whether the relevant neurons are excitatory—increasing the likelihood that linked cells fire—or inhibitory, muffling their partners instead. Further complicating things, neglected neurons shrivel in the developing brain and new neurons sprout to replace them; in the adult brain, neurons change the strength of their connections with one another daily—such flexibility is essential for learning and memory. Yet another level of complexity involves neuromodulators: certain kinds of neurotransmitters and other small molecules that linger in the fluid surrounding neurons, changing how neurons behave in ways we do not yet fully understand. A prediction about how information will flow through a particular circuit based on a wiring diagram and synaptic weights might be completely wrong if one does not know which neuromodulators are hanging around at any given time.

A good example of how a static connectome fails to capture the dynamics of living neural networks comes from research on the stomatogastric ganglion (STG), a pair of neural circuits in crustaceans—including crayfish, crabs, lobsters and shrimp—that generate rhythmic behavior in response to food. One subcircuit repeatedly constricts and dilates the pyloric region of the stomach, the foyer to the small intestines. Another subcircuit pulsates the gastric mill, a muscular pouch lined with chitinous teeth that help break down food. Mapping all the connections between the 30 neurons in the crustacean STG was an important first step toward understanding how the STG controlled the crustacean digestive system. But it was by no means sufficient. Eve Marder of Brandeis University and others have shown that the neurons in the stomatogastric ganglion do not always use the same unchanging set of connections to communicate with one another. In the presence of certain neuromodulators, a neuron that contributes to the pyloric subcircuit might switch teams, joining the gastric mill subcircuit instead by changing the tempo at which it fires.

Because any brain or nervous system is so much more complex than what a connectome by itself represents, Movshon is certainly not alone in thinking that researchers' limited resources are better devoted to other areas of neuroscience. "I'm all in favor of Seung and others," Bargmann says, "but I don't think we should have a Manhattan Project for the connectome with such a huge amount of resources. We are not quite good enough at reading them. It wasn't like the human genome project, where we knew how to sequence DNA and said, 'Yeah, let's go for it!' Scaling up connectomes is a different issue."

Oliver Hobert of Columbia, another longtime C. elegans researcher, agrees that connectomics only scratches the surface. "It's like a road map that tells you where cars can drive, but does not tell you when or where cars are actually driving," he says. "Still, connectomics of C. elegans has given us wonderful testable hypotheses in terms of how neural circuits work. What we have learned from C. elegans diagrams are not just specific worm behaviors—they are logical principles common to much of biology."

*Editor's Note: The author is a member of NeuWrite, a workshop of scientists and writers that organized the debate at Columbia.

Tuesday, October 9, 2018

 ‘Sokal Squared’: Is Huge Publishing Hoax ‘Hilarious and Delightful’ or an Ugly Example of Dishonesty and Bad Faith?

By Alexander C. Kafka October 03, 2018

Mike Nayna
James A. Lindsay, Helen Pluckrose, and Peter Boghossian, the academics who carried out a publishing hoax that targeted scholarly journals
Reactions to an elaborate academic-journal hoax, dubbed "Sokal Squared" by one observer, came fast and furious on Wednesday. Some scholars applauded the hoax for unmasking what they called academe’s leftist, victim-obsessed ideological slant and low publishing standards. Others said it had proved nothing beyond the bad faith and dishonesty of its authors.
Three scholars — Helen Pluckrose, a self-described "exile from the humanities" who studies medieval religious writings about women; James A. Lindsay, an author and mathematician; and Peter Boghossian, an assistant professor of philosophy at Portland State University — spent 10 months writing 20 hoax papers that illustrate and parody what they call "grievance studies," and submitted them to "the best journals in the relevant fields." Of the 20, seven papers were accepted, four were published online, and three were in process when the authors "had to take the project public prematurely and thus stop the study, before it could be properly concluded." A skeptical Wall Street Journal editorial writer, Jillian Kay Melchior, began raising questions about some of the papers over the summer.
Beyond the acceptances, the authors said, they also received four requests to peer-review other papers "as a result of our own exemplary scholarship." And one paper — about canine rape culture in dog parks in Portland, Ore. — "gained special recognition for excellence from its journal, Gender, Place, and Culture … as one of 12 leading pieces in feminist geography as a part of the journal’s 25th anniversary celebration."
Not all readers accepted the work as laudable scholarship. National Review took "Helen Wilson," the fictional author of the dog-park study, to task in June for her approach. "The whole reasoning behind Wilson’s study," wrote a staff writer, Katherine Timpf, "is the belief that researching rape culture and sexuality among dogs in parks is a brilliant way to understand more about rape culture and sexuality among humans. This is, of course, idiotic. Why? Because humans are not dogs."
Another published paper, "Going In Through the Back Door: Challenging Straight Male Homohysteria, Transhysteria, and Transphobia Through Receptive Penetrative Sex Toy Use," appeared in Sexuality and Culture. It recommends that men anally self-penetrate "to become less transphobic, more feminist, and more concerned about the horrors of rape culture."
The trolling trio wondered, they write, if a journal might even "publish a feminist rewrite of a chapter from Adolf Hitler’s Mein Kampf." Yup. "Our Struggle Is My Struggle: Solidarity Feminism as an Intersectional Reply to Neoliberal and Choice Feminism" was accepted by the feminist social-work journal Affilia.
Darts and Laurels
Some scholars applauded the hoax.
"Is there any idea so outlandish that it won’t be published in a Critical/PoMo/Identity/‘Theory’ journal?" tweeted the Harvard psychologist Steven Pinker.
"Three intrepid academics," wrote Yascha Mounk, an author and lecturer on government at Harvard, "just perpetrated a giant version of the Sokal Hoax, placing … fake papers in major academic journals. Call it Sokal Squared. The result is hilarious and delightful. It also showcases a serious problem with big parts of academia."
In the original Sokal Hoax, in 1996, a New York University physicist named Alan Sokal published a bogus paper that took aim at some of the same targets as his latter-day successors.
Others were less receptive than Mounk. "This is a genre," tweeted Kieran Healy, a sociologist at Duke, "and they’re in it for the lulz" — the laughs. "Best not to lose sight of that."
"Good work is hard to do," he wrote, "incentives to publish are perverse; there’s a lot of crap out there; if you hate an area enough, you can gin up a fake paper and get it published somewhere if you try. The question is, what do you hate? And why is that?"
Reviews of several of the papers "were partly conditional on claims to have done some sort of actual (very bad) fieldwork," Healy noted.
And that’s where the question of bad faith comes in.
"I am so utterly unimpressed," wrote Jacob T. Levy, a political theorist at McGill University, "by the fact that an enterprise that relies on a widespread presumption of not-fraud can be fooled some of the time by three people with Ph.D.s who spend 10 months deliberately trying to defraud it."
Karen Gregory, a lecturer in sociology at the University of Edinburgh, wrote that "the chain of thought and action that encourages you to spend 10 months ‘pulling a fast one’ on academic journals disqualifies you from a community of scholarship. It only proves you are a bad-faith actor."
Karl Steel, an associate professor of English at Brooklyn College and the Graduate Center of the City University of New York, called the trio’s work "simply not rigorous research" and described three objections to it. It is too narrow in disciplinary scope, he said. It focuses on exposing weaknesses in gender and ethnic studies, conspicuously ideological fields, when that effort would be better spent looking at more-substantive problems like the replication crisis in psychology, or unfounded scholarly claims in cold fusion or laissez-faire economics.
The trio could have reached out to colleagues in physics and other fields, but instead opted for "poor experimental design." And they targeted groups that are "likely to be laughed at anyway," showing not intellectual bravery but cowardice. "These three researchers have demonstrated that they’re not to be trusted," he said.
‘Deep Doubt’
Other online commenters said the hoax papers lack a control group of papers for comparative purposes.
Pluckrose, Lindsay, and Boghossian, reached by phone in Portland, said the papers that were rejected serve as a control of sorts. Better yet, they said, consider this meta-control thought experiment: Look at your journals and the articles they published, and see if you can distinguish them from the hoax articles. If the answer is often no, then there is your control.
Mounk, by phone, also said the control-group criticism is misguided. He called it a "confused attempt to import statistics into a question where it doesn’t apply." If the authors were claiming that their work proves that some publications are, say, 50 percent more susceptible to hoaxes than the average, or that 100 percent of articles published are nonsense because these seven articles were accepted, then you would obviously need controls. But the authors "do nothing of the sort. They demonstrate that it’s possible, with relatively little effort, to get bullshit published." It "sows deep doubt" about the nature of the academic enterprise in these disciplines.
Time will tell, the trio said, but they think the mega-hoax will effectively snuff out their academic futures. Pluckrose thinks she’ll have a hard time getting into a doctoral program, Lindsay predicted that he would become "an academic pariah," and Boghossian, who doesn’t have tenure, thinks he will be punished, and possibly fired. Still, this isn’t the first time that Lindsay and Boghossian have teamed up to mock trendy scholarship. Last year their spurious paper "The Conceptual Penis as a Social Construct" was published in the journal Cogent Social Sciences.
Meanwhile, Pluckrose and Boghossian are working on a book together, and Pluckrose is writing one on the 50-year development of grievance studies and the leftist academic culture of victimization.
If the three are exiled from academe, said Mounk, that will be unjust and a shame. Through "courage and quite a lot of work," they have shown that "clearly there’s a big corner of academia where the emperors wear no clothes." He called the hoax "a more serious contribution to our understanding of the world than many Ph.D. theses." The three of them, Mounk said, "should absolutely be celebrated."
Alexander C. Kafka is a senior editor and oversees Idea Lab. Follow him on Twitter @AlexanderKafka, or email him at alexander.kafka@chronicle.com.

Tuesday, August 28, 2018

Dads Pass On More Than Genetics in Their Sperm

Seminal research reveals that sperm change their cargo as they travel the reproductive tract—and the differences can have consequences for fertility

Katherine J. Wu


July 26, 2018

Eat poorly, and your body will remember—and possibly pass the consequences onto your kids. In the past several years, mounting evidence has shown that sperm can take note of a father’s lifestyle decisions, and transfer this baggage to offspring. Today, in twocomplementary studies, scientists tell us how.

As sperm traverse the male reproductive system, they jettison and acquire non-genetic cargo that fundamentally alters sperm before ejaculation. These modifications not only communicate the father’s current state of wellbeing, but can also have drastic consequences on the viability of future offspring.

Each year, over 76,000 children are born as a result of assisted reproduction techniques, the majority of which involve some type of in vitro fertilization (IVF). These procedures unite egg and sperm outside the human body, then transfer the resulting fertilized egg—the embryo—into a woman’s uterus. Multiple variations on IVF exist, but in some cases that involve male infertility—for instance, sperm that struggle to swim—sperm must be surgically extracted from the testes or epididymis, a lengthy, convoluted duct that cradles each testis.

After sperm are produced in the testes, they embark on a harrowing journey through the winding epididymis—which, in a human male, is about six meters long when unfurled—on their way to storage. Sperm wander the epididymis for about two weeks; only at the end of this path are they fully motile. Thus, while “mature” sperm can essentially be dumped on a waiting egg and be reasonably expected to achieve fertilization, sperm plucked from the testes and epididymis must be injected directly into the egg with a very fine needle. No matter the source of the sperm, these techniques have birthed healthy infants in four decades of successful procedures.

But scientists know genes are not the whole package. Over the course of a single lifetime, our genomes stay as they were originally written. However, how, when and why genetic instructions are followed can drastically differ without altering the manual itself—much like fiddling with the volume on a speaker without touching the wiring within. This phenomenon, called “epigenetics,” helps explain why genetically identical individuals in similar environments, such as twins or laboratory mice, can still look and act in very different ways. And things like diet or stress are capable of cranking our genes’ volume up and down.

One of the most powerful members of the epigenetic toolkit is a class of molecules called small RNAs. Small RNAs can conceal genetic information from the cellular machinery that carries out their instructions, effectively ghosting genes out of existence.

The legacy of a dad’s behavior can even live on in his child if his epigenetic elements enter an embryo. For instance, mice born to fathers that experience stress can inherit the behavioral consequences of traumatic memories. Additionally, mouse dads with less-than-desirable diets can pass a wonky metabolism onto their kids.

Upasna Sharma and Colin Conine, both working under Oliver Rando, a professor of biochemistry at the University of Massachusetts Medical School, were some of the researchers to report such findings in 2016. In their work, Sharma and Conine noted that, in mice, while immature testicular sperm contain DNA identical to that of mature sperm, immature sperm relay different epigenetic information. It turns out that sperm small RNAs undergo post-testes turnover, picking up intel on the father’s physical health (or lack thereof) after they’re manufactured, but before they exit the body. However, the exact pit stop at which these additional small RNAs hitch a ride remained unknown.

To solve the mystery, Sharma, who led the first of the two new studies, decided to track the composition of small RNAs within mouse sperm as they fled the testes and cruised through the epididymis. She and her colleagues isolated sperm of several different ages from mice, including those about to emerge from the testes, those entering the early part of the epididymis and those in the late part of the epididymis. Sharma was surprised to find that many small RNAs seemed to be discarded or destroyed upon entering the early epididymis; then, the newly vacated sperm reacquired epigenetic intel that reflected the father’s state of being, boasting a full set by the time they left the late epididymis.

There was only one possible source for the small RNA reacquisition: the cells of the epididymis—which meant that cells outside of the sperm were transmitting information into future generations.

“[The epididymis] is the least studied organ in the body,” says Rando, who was senior author on both papers. “And it turns out this tube that no one ever thinks about plays a central role in reproduction.”

To confirm that the epididymis was the culprit, Sharma’s team added a chemical marker to a set of small RNAs in the epididymis and tracked their migration. As they suspected, tiny shipments of RNAs popped off of cells in the epididymis and fused with the sperm. Each stealthy swimmer then bore these epigenetic elements all the way to its final union with the egg.

It seemed that sperm at different points along the reproductive tract had the same genetics, but not the same epigenetics. Was this difference big enough to matter? Colin Conine, who led the second of the two new studies, next tested if using immature sperm would have noticeable effects on the offspring of mice. He and his colleagues extracted sperm from the testes, early epididymis and late epididymis and injected them into eggs. All three types of sperm were able to fertilize eggs. However, when Conine transferred the resulting embryos into mouse surrogates, none derived from early epididymal sperm—the intermediate stage devoid of most small RNAs—implanted in the uterus. The least and most mature sperm of the bunch were winners—but somehow, those in the middle were burning out, even though all their genes were intact.

This was baffling to all involved. “This intermediate broken stage was really stunning,” says Rando.

At first, the researchers wondered if they had somehow isolated junky sperm doomed to be cleared from the early epididymis before reaching the ejaculate. But this didn’t seem to be the case: all three types of sperm could fertilize eggs. The only other explanation was that the defect was temporary. If this was the case, then perhaps, if fed the right small RNAs, the early epididymal sperm could be rescued.

In her work, Sharma had noted that while the epigenetic cargo of testicular sperm and late epididymal sperm differ vastly, they had a few groups in common—but these small RNAs were evicted from sperm as they entered the epididymis, then reacquired from the cells along the meandering duct. Though bookended by success, the early epididymal flop was the only stage that lacked these elements—and the only stage incapable of generating an implantable embryo.

To test if these particular small RNAs were the key to fertility, the researchers pulled small RNAs out of the late epididymis and injected them into embryos fertilized with early epididymal sperm. To their amazement, these embryos not only implanted, but also yielded mouse pups—indistinguishable from embryos fertilized by late epididymal sperm. The early epididymal sperm was defective, but not irreversibly so. This hinted that the deficiency wasn’t a fluke, but a normal part of the journey through the epididymal labyrinth. In other words, on the path to maturation, males were breaking sperm, then repairing the damage.

“It’s very bizarre to see them lose [viability] and gain it back,” says Sharma. And the utility of this back-and-forth remains entirely enigmatic. But whatever the reason, it’s clear that sperm vary enormously along the length of the reproductive tract.

Mollie Manier, a professor who studies sperm genetics at George Washington University and was not affiliated with the study, praised the rigorous nature of this “very exciting” research. “These papers really add to our understanding of [how] dads can pass non-genetic information onto their kids,” she explains. According to Heidi Fisher, a professor who studies sperm at the University of Maryland and also did not participate in the research, these “elegantly designed” experiments may also shed light on how problems with the epididymis could cause otherwise unexplained cases of male infertility.

In their future work, Rando’s group will continue to study the mouse pups generated from sperm of various ages, keeping a close lookout for any long-term issues in their health. The team also hopes to pinpoint which small RNAs are directly responsible for successful implantation—and why sperm enter this bewildering period of incompetence.

“There’s a lot of inheritance that we haven’t yet explained,” says Conine. “But animals are not just their DNA.” However, Conine cautions that different doesn’t always mean worse. Testicular and epididymal sperm from humans have helped, and continue to help, thousands around the world conceive children.

This comes with a small caveat. It wasn’t until 1978 that the first baby was successfully born of an IVF procedure—and though thousands have followed since, this generation is still young. As of yet, there’s no reason to suspect any negative consequences of in vitro versus natural conception; as this population ages, researchers will continue to keep close tabs. Since the majority of IVF procedures are performed with mature sperm that have cleared the late epididymis, Rando is not concerned.

And, in the unlikely case that there are repercussions to using testicular or epididymal sperm in these procedures, Rando remains hopeful that future work will enable scientists to restore the necessary information immature sperm might lack. Someday, addressing epigenetics may be key to enhancing assisted reproduction technology—and ensuring that sperm are as mature as they come.

Sunday, August 26, 2018

Photographer behind viral image of starving polar bear raises questions about climate change narrative

The narrative behind the viral photo of a polar bear starving, reportedly thanks to climate change, has been called into question by the National Geographic photographer who took it in the first place.
In an article for the August issue of National Geographic titled “Starving-Polar-Bear Photographer Recalls What Went Wrong,” Cristina Mittermeier talks about the intended message of the image versus the message that was received.
“We had lost control of the narrative,” she said.
“Photographer Paul Nicklen and I are on a mission to capture images that communicate the urgency of climate change. Documenting its effects on wildlife hasn’t been easy,” she wrote in the article. “With this image, we thought we had found a way to help people imagine what the future of climate change might look like. We were, perhaps, naive. The picture went viral — and people took it literally.”

The image she is referencing shows an emaciated polar bear with hardly any fur covering its bony frame. In a video that was also taken of the bear, it can be seen slowly moving through the terrain, rummaging through an empty can.
Mittermeier goes on to say that it was the language put out by the publication that led to the message being misconstrued.
“The first line of the National Geographic video said, ‘This is what climate change looks like’ — with ‘climate change’ then highlighted in the brand’s distinctive yellow. In retrospect, National Geographic went too far with the caption.”
She estimated that 2.5 billion people saw the footage: “It became the most viewed video on National Geographic’s website — ever,” she said.
From there, social media and news outlets erupted over the message that was being portrayed.
Some experts suggested a number of reason besides climate change that could’ve led to the animal’s condition, including age, illness or even injury.
Mittermeier admits that she couldn’t “say that this bear was starving because of climate change.”
“Perhaps we made a mistake in not telling the full story — that we were looking for a picture that foretold the future and that we didn’t know what had happened to this particular polar bear.”
The photographer says that her image became another example of "environmentalist exaggeration,” but added that her intentions were “clear” and that if she had the opportunity to share “a scene like this one” again, she would.