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Evolution, Genetics, Microbiology, Pregnancy, Research, Science, Stanford News, Stem Cells

My baby, my… virus? Stanford researchers find viral proteins in human embryonic cells

My baby, my... virus? Stanford researchers find viral proteins in human embryonic cells

Wysocka - 560

One thing I really enjoy about my job is the opportunity to constantly be learning something new. For example, I hadn’t realized that about eight percent of human DNA is actually left-behind detritus from ancient viral infections. I knew they were there, but eight percent? That’s a lot of genetic baggage.

These sequences are often inactive in mature cells, but recent research has shown they can become activated in some tumor cells or in human embryonic stem cells. Now developmental biologist Joanna Wysocka, PhD, and graduate student Edward Grow, have shown that some of these viral bits and pieces spring back to life in early human embryos and may even affect their development.

Their research was published today in Nature. As I describe in our press release:

Retroviruses are a class of virus that insert their DNA into the genome of the host cell for later reactivation. In this stealth mode, the virus bides its time, taking advantage of cellular DNA replication to spread to each of an infected cell’s progeny every time the cell divides. HIV is one well-known example of a retrovirus that infects humans.

When a retrovirus infects a germ cell, which makes sperm and eggs, or infects a very early-stage embryo before the germ cells have arisen, the viral DNA is passed along to future generations. Over evolutionary time, however, these viral genomes often become mutated and inactivated. About 8 percent of the human genome is made up of viral sequences left behind during past infections. One retrovirus, HERVK, however, infected humans repeatedly relatively recently — within about 200,000 years. Much of HERVK’s genome is still snuggled, intact, in each of our cells.

Wysocka and Grow found that human embryonic cells begin making viral proteins from these HERVK sequences within just a few days after conception. What’s more, the non-human proteins have a noticeable effect on the cells, increasing the expression of a cell surface protein that makes them less susceptible to subsequent viral infection and also modulating human gene expression.

More from our release:

But it’s not clear whether this sequence of events is the result of thousands of years of co-existence, a kind of evolutionary symbiosis, or if it represents an ongoing battle between humans and viruses.

“Does the virus selfishly benefit by switching itself on in these early embryonic cells?” said Grow. “Or is the embryo instead commandeering the viral proteins to protect itself? Can they both benefit? That’s possible, but we don’t really know.”

Wysocka describes the findings as “fascinating, but a little creepy.” I agree. But I can’t wait to hear what they discover next.

Previously: Viruses can cause warts on your DNA, Stanford researcher wins Vilcek Prize for Creative Promise in Biomedical Science and Species-specific differences among placentas due to long-ago viral infection, say Stanford researchers
Photo of Joanna Wysocka by Steve Fisch

Evolution, In the News, Research, Science

Chins make us human; new study examines why

Chins make us human; new study examines why

il-150226-ts-08When we think of what makes us human, it’s common to think of something like language or tool-making. Something that likely doesn’t pop into mind is the chin – but humans are the only species to have one! The bony prominence is missing from the skulls of Neanderthals, archaic humans, primates, and indeed all other animals. (In the photo, the skull on the left is human, and the one on the right is Neanderthal).

Scientists have puzzled for more than a century over why chins developed, and the dominant theory has been that they resulted from mechanical forces like chewing. Bones under pressure sustain tiny tears that then enable new bone to grow, much like weight lifting does to muscles. But a new study conducted by University of Iowa researchers suggests that mechanical forces have nothing to do with it: It’s more likely that chins resulted from shifting social dynamics.

The study, published in the Journal of Anatomy, capitalized on the fact that children don’t have chins either – the bone underneath their lower lip is smooth, and the prominence develops with age. The study examined nearly 40 people ranging from 3-20 years old, correlating their chin development with various forces exerted by their cranio-facial anatomy (during chewing, for example), and concluded that mechanical forces don’t play a role in chin development. In fact, those with the most mechanical force had the smallest chins.

Nathan Colton, PhD, professor of orthodontics at the UI College of Dentistry and lead author of the study, is quoted in a UI press release:

In short, we do not find any evidence that chins are tied to mechanical function and in some cases we find that chins are worse at resisting mechanical forces as we grow. Overall, this suggests that chins are unlikely related to the need to dissipate stresses and strains and that other explanations are more likely to be correct.

Instead, the researchers think that the chin results from the facial structure being rearranged as faces got smaller – human faces are 15 percent smaller than those of Neanderthals. This reduction resulted from a decrease in testosterone levels, which happened as males of the species benefitted more from interacting socially with other groups rather than fighting other males.

Robert Franciscus, PhD, professor of anthropology at UI and a contributing author on the study, also comments:

What we’re arguing is that modern humans had an advantage at some point to have a well-connected social network, they can exchange information, and mates, more readily, there’s innovation. And for that to happen, males have to tolerate each other. There had to be more curiosity and inquisitiveness than aggression, and the evidence of that lies in facial architecture.

Previously: Humans share history – and a fair amount of genetic material – with Neanderthals
Photo by Tim Schoon, University of Iowa

Evolution, Global Health, In the News, Microbiology, Nutrition, Research

A key bacteria from hunter gatherers’ guts is missing in industrial societies, study shows

392924423_860dafa0a4_oTrends like the paleo diet and probiotic supplements attest to the popular idea that in industrial societies, our digestion has taken a turn for the worse. The scientific community is gathering evidence on how the overuse of antibiotics affects our microbiome, and on what might be causing the increasing incidence gastrointestinal inflammatory disorders like Crohn’s disease and colitis. Scientists are now one step closer to knowing exactly what has changed since the majority of humans were hunter-gatherers.

Yesterday, a paper published in Nature Communications found that an entire genus of bacteria has gone missing from industrialized guts. Treponema are common in all hunter-gatherer societies that have been studied, as well as in non-human primates and other mammals. Treponema have primarily been known as pathogens responsible for diseases like syphilis, but the numerous strains found in the study are non-pathenogenic and closely resemble carbohydrate-digesting bacteria in pigs, whose digestive system is notably similar to that of humans. The genus is undetectable in humans from urban-industrial societies.

The study, led by anthropologists from the University of Oklahoma and the Universidad Científica del Sur in Peru, used genomic reconstruction to compare microbes in stool samples from two groups in Peru, one of hunter-gatherers and one of traditional farmers, with samples from people in Oklahoma. Each group comprised around 25 people. This is the first comprehensive study of the full-spectrum of microbial diversity in the guts of a group of hunter-gatherers – in this case, the Amazonian Matses people.

The researchers also sought to understand how diet affects gut health: The hunter-gatherers ate game and wild tubers, the traditional farmers ate potatoes and domestic mammals, and the Oklahomans ate primarily processed, canned, and pre-packaged food, with some additional meat and cheese.

Science published a news report discussing the findings, in which co-author Christina Warinner, PhD, an anthropologist at the University of Oklahoma, is quoted as saying:

Suddenly a picture is emerging that Treponema was part of core ancestral biome. What’s really striking is it is absolutely absent, not detectable in industrialized human populations… What’s starting to come into focus is that having a diverse gut microbiome is critical to maintaining versatility and resiliency in the gut. Once you start to lose the diversity, it may be a risk factor of inflammation and other problems.

Further research is needed to answer the next question: Is there a direct link between the absence of Treponema and the digestive health and prevalence of certain diseases (like colitis and Crohn’s) in industrialized humans? If so, this could be a valuable key to increasing our digestive health. It would also indicate that imitating a paleo diet is not enough to achieve a real “paleo gut.”

Previously: Drugs for bugs: industry seeks small molecules to target, tweak, and tune-up our gut microbes, Tiny hitchhikers, big impact: studying the microbiome to learn about disease, Civilization and its dietary (dis)contents: Do modern diets starve our gut-microbial community?, Stanford team awarded NIH Human Microbiome Project grant, and Contemplating how our human microbiome influences personal health
Photo by AJC1

Applied Biotechnology, Cancer, Evolution, Immunology, Research, Stanford News

Corrective braces adjust cell-surface molecules’ positions, fix defective activities within cells

Corrective braces adjust cell-surface molecules' positions, fix defective activities within cells

bracesStanford molecular and cellular physiologist and structural biologist Chris Garcia, PhD, and his fellow scientists have tweaked together a set of molecular tools that work like braces of varying lengths and torque to fix things several orders of magnitude too small to see with the naked eye.

Like faulty cell-surface receptors, for instance, whose aberrant signaling can cause all kinds of medical problems, including cancer.

Cell-surface receptors transmit naturally occurring signals from outside cells to the insides of cells. Molecular messengers circulating in the blood stumble on receptors for which they’re a good fit, bind to them, and accelerate or diminish particular internal activities of cells, allowing the body to adjust to the needs of the minute.

Things sometimes go wrong. One or another of the body’s various circulating molecular messengers (for example, regulatory proteins called cytokines) may be too abundant or scarce. Alternatively, a genetic mutation may render a particular receptor type overly sluggish, or too efficient. One such mutation causes receptors for erythropoietin – a cytokine that stimulates production of certain blood-cell types – to be in constant overdrive, resulting in myeloproliferative disorders. Existing drugs for this condition sometimes overshoot, bringing the generation of needed blood-cell types to a screeching halt.

Garcia’s team took advantage of the fact that many receptors – erythropoietin receptors, for example – don’t perform solo, but instead work in pairs. In a proof-of-principle study in Cell, Garcia and his colleagues made brace-like molecular tools composed of stitched-together antibody fragments (known in the trade as diabodies). They then showed that these “two-headed beasts” can selectively grab on to two members of a mutated receptor pair and force the amped-up erythropoietin receptors into positions just far enough apart from, and at just the right angles to, one another to slow down their hyperactive signaling and act like normal ones.

That’s a whole new kind of therapeutic approach. Call it “cellular orthopedics.”

Previously: Souped-up super-version of IL-2 offers promise in cancer treatment and Minuscule DNA ring tricks tumors into revealing their presence
Photo by Zoe

Cancer, Evolution, Genetics, Infectious Disease, Microbiology, Research, Stanford News

Bubble, bubble, toil and trouble – yeast dynasties give up their secrets

Bubble, bubble, toil and trouble - yeast dynasties give up their secrets

yeasty brew

Apologies to Shakespeare for the misquote (I’ve just learned to my surprise that it’s actually “Double, double, toil and trouble“), but it’s a too-perfect lead-in to geneticist Gavin Sherlock’s recent study on yeast population dynamics for me to be bothered by facts.

Sherlock, PhD, and his colleagues devised a way to label and track the fate of individual yeast cells and their progeny in a population using heritable DNA “barcodes” inserted into their genomes. In this way, they could track the rise and fall of dynasties as the yeast battled for ever more scarce resources (in this case, the sugar glucose), much like what happens in the gentle bubbling of a sourdough starter or a new batch of beer.

Their research was published today in Nature.

From our release:

Dividing yeast naturally accumulate mutations as they repeatedly copy their DNA. Some of these mutations may allow cells to gobble up the sugar in the broth more quickly than others, or perhaps give them an extra push to squeeze in just one more cell division than their competitors.

Sherlock and his colleagues found that about one percent of all randomly acquired mutations conferred a fitness benefit that allowed the progeny of one cell to increase in numbers more rapidly than their peers. They also learned that the growth of the population is driven at first by many mutations of modest benefit. Later generations see the rise of the big guns – a few mutations that give carriers a substantial advantage.

This type of clonal evolution mirrors how a bacterium or virus spreads through the human body, or how a cancer cell develops mutations that allow it to evade treatment. It is also somewhat similar to a problem that kept some snooty 19th century English scientists up at night, worried that aristocratic surnames would die out because rich and socially successful families were having fewer children than the working poor. As a result, these scientists developed what’s known as the “science of branching theory.” They described the research in a paper in 1875 called “On the probability of extinction of families,” and Sherlock and his colleagues used some of the mathematical principles described in the paper to conduct their analysis.

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Evolution, In the News, Research, Stanford News

Blond ambition: Delving into the work of Stanford biologist David Kingsley

Blond ambition: Delving into the work of Stanford biologist David Kingsley

Thanks to a tiny fish called the stickleback, Stanford developmental biologist David Kingsley, PhD, and his team uncovered the genetic basis for blond hair earlier this year.

Kingsley’s research caught the eye of the team at HHMI Bulletin, which featured his discovery in their fall issue. As described in the piece, Kingsley and fellow researcher Catherine Guenther, PhD, discovered the change in a single point in the genetic sequence outside the gene itself. The discovery prompted a question because the gene, known as KITLG, is involved in many other key processes in developing organisms. Yet Kingsley found the control for hair color acted alone.

“The genetic mechanism that controls blond hair doesn’t alter the biology of any other part of the body. It’s a trait that’s skin deep, and only skin deep,” Kingsley told HHMI.

The HHMI feature also includes a video of Kingsley – above – that provides glimpses into his lab and reveals the sources of his inspiration (as well as his penchant for purchasing telescopes).

And for a Friday giggle, check out his lab members spelling his name with their bodies here.

Becky Bach is a science-writing intern at the Office of Communications and Public Affairs. 

Previously: It’s a blond thing: Stanford researchers suss out molecular basis of hair color, Something fishy: Threespine stickleback genome published by Stanford researchers and Hey guys, sometimes less is really more

Behavioral Science, Evolution, Imaging, Neuroscience, Research, Stanford News, Surgery

In a human brain, knowing a face and naming it are separate worries

In a human brain, knowing a face and naming it are separate worries

Alfred E. Neuman (small)Viewed from the outside, the brain’s two hemispheres look like mirror images of one another. But they’re not. For example, two bilateral brain structures called Wernicke’s area and Broca’s area are essential to language processing in the human brain – but only the ones  in the left hemisphere (at least in the great majority of right-handers’ brains; with lefties it’s a toss-up), although both sides of the brain house those structures.

Now it looks as though that right-left division of labor in our brains applies to face perception, too.

A couple of years ago I wrote and blogged about a startling study by Stanford neuroscientists Josef Parvizi, MD, PhD, and Kalanit Grill-Spector, PhD. The researchers recorded brain activity in epileptic patients who, because their seizures were unresponsive to drug therapy, had undergone a procedure in which a small section of the skulls was removed and plastic packets containing electrodes placed at the surface of the exposed brain. This was done so that, when seizures inevitably occurred, their exact point of origination could be identified. While  patients waited for this to happen, they gave the scientists consent to perform  an experiment.

In that experiment, selective electrical stimulation of another structure in the human brain, the fusiform gyrus, instantly caused a distortion in an experimental subjects’ perception of Parvizi’s face. So much so, in fact, that the subject exclaimed, “You just turned into somebody else. Your face metamorphosed!”

Like Wernicke’s and Broca’s area, the fusiform gyrus is found on each side of the brain. In animal species with brains fairly similar to our own, such as monkeys, stimulation of either the left or right fusiform gyrus appears to induce distorted face perception.

Yet, in a new study of ten such patients, conducted by Parvizi and colleagues and published in the Journal of Neuroscience,  face distortion occurred only when the right fusiform gyrus was stimulated. Other behavioral studies and clinical reports on patients suffering brain damage have shown a relative right-brain advantage in face recognition as well as a predominance of right-side brain lesions in patients with prosopagnosia, or face blindness.

Apparently, the left fusiform gyrus’s job description has changed in the course of our species’ evolution. Humans’ acquisition of language over evolutionary time, the Stanford investigators note, required the redirection of some brain regions’ roles toward speech processing. It seems one piece of that co-opted real estate was the left fusiform gyrus. The scientists suggest (and other studies hint) that along with the lateralization of language processing to the brain’s left hemisphere, face-recognition sites in that hemisphere may have been reassigned to new, language-related functions that nonetheless carry a face-processing connection: for example, retrieving the name of a person whose face you’re looking at, leaving the visual perception of that face to the right hemisphere.

My own right fusiform gyrus has been doing a bang-up job all my life and continues to do so. I wish I could say the same for my left side.

Previously: Metamorphosis: At the push of a button, a familiar face becomes a strange one, Mind-reading in real life: Study shows it can be done (but they’ll have to catch you first), We’ve got your number: Exact spot in brain where numeral recognition takes place revealed and Why memory and  math don’t mix: They require opposing states of the same brain circuitry
Photo by AlienGraffiti

Big data, Evolution, Genetics, In the News, Research, Science, Stanford News

Flies, worms and humans – and the modENCODE Project

Flies, worms and humans - and the modENCODE Project

It’s a big day in comparative biology. Researchers around the country, including Stanford geneticist Michael Snyder, PhD, are publishing the results of a massive collaboration meant to suss out the genomic similarities (and differences) among model organisms like the fruit fly and the laboratory roundworm. A package of four papers, which describe how these organisms control how, when and where they express certain genes to generate the cell types necessary for complex life, appears today in Nature.

From our release:

The research is an extension of the ENCODE, or Encyclopedia of DNA Elements, project that was initiated in 2003. As part of the large collaborative project, which was sponsored by the National Human Genome Research Institute, researchers published more than 4 million regulatory elements found within the human genome in 2012. Known as binding sites, these regions of DNA serve as landing pads for proteins and other molecules known as regulatory factors that control when and how genes are used to make proteins.

The new effort, known as modENCODE, brings a similar analysis to key model organisms like the fly and the worm. Snyder is the senior author of two of the papers published today describing some aspects of the modENCODE project, which has led to the publication, or upcoming publication, of more than 20 papers in a variety of journals. The Nature papers, and the modENCODE project, are summarized in a News and Views article in the journal (subscription required to access all papers).

As Snyder said in our release, “We’re trying to understand the basic principles that govern how genes are turned on and off. The worm and the fly have been the premier model organisms in biology for decades, and have provided the foundation for much of what we’ve learned about human biology. If we can learn how the rules of gene expression evolved over time, we can apply that knowledge to better understand human biology and disease.”

The researchers found that, although the broad strokes of gene regulation are shared among species, there are also significant differences. These differences may help explain why humans walk, flies fly and worms slither, for example:

The wealth of data from the modENCODE project will fuel research projects for decades to come, according to Snyder.

“We now have one of the most complete pictures ever generated of the regulatory regions and factors in several genomes,” said Snyder. “This knowledge will be invaluable to researchers in the field.”

Previously: Scientists announce the completion of the ENCODE project, a massive genome encyclopedia

Autoimmune Disease, Evolution, Immunology, Microbiology, Nutrition, Public Health, Stanford News

Civilization and its dietary (dis)contents: Do modern diets starve our gut-microbial community?

Civilization and its dietary (dis)contents: Do modern diets starve our gut-microbial community?

hunter-gatherer cafe

Our genes have evolved a bit over the last 50,000 years of human evolution, but our diets have evolved a lot. That’s because civilization has transitioned from a hunter-gatherer lifestyle to an agrarian and, more recently and incompletely, to an industrialized one. These days, many of us are living in an information-intensive, symbol-analyzing, button-pushing, fast-food-munching society. This transformation has been accompanied by consequential twists and turns regarding what we eat, and how and when we eat it.

Toss in antibiotics, sedentary lifestyles, and massive improvements in public sanitation and personal hygiene, and now you’re talking about serious shake-ups in how many and which microbes we get exposed to – and how many of which ones wind up inhabiting our gut.

In a review published in Cell Metabolism, Stanford married-microbiologist couple Justin Sonnenburg, PhD, and Erica Sonnenburg, PhD, warn that modern civilization and its dietary contents may be putting our microbial gut communities, and our health, at risk.

[S]tudies in recent years have implicated [dysfunctional gut-bug communities] in a growing list of Western diseases, such as metabolic syndrome, inflammatory bowel disease, and cancer. … The major dietary shifts occurring between the hunter-gatherer lifestyle, early Neolithic farming, and more recently during the Industrial Revolution are reflected in changes in microbial membership within dental tartar of European skeletons throughout these periods. … Traditional societies typically have much lower rates of Western diseases.

Every healthy human harbors an interactive internal ecosystem consisting of something like 1,000 species of intestinal microbes.  As individuals, these resident Lilliputians may be tiny, but what they lack in size they make up in number. Down in the lower part of your large intestine dwell tens of trillions of  single-celled creatures – a good 10 of them for every one of yours. If you could put them all on a scale, they would cumulatively weigh about four pounds. (Your brain weighs three.)

Together they do great things. In a Stanford Medicine article I wrote a few years back, “Caution: Do Not Debug,” I wrote:

The communities of micro-organisms lining or swimming around in our body cavities … work hard for their living. They synthesize biomolecules that manipulate us in ways that are helpful to both them and us. They produce vitamins, repel pathogens, trigger key aspects of our physiological development, educate our immune system, help us digest our food and for the most part get along so well with us and with one other that we forget they’re there.

But when our internal microbes don’t get enough of the right complex carbohydrates (ones we can’t digest and so pass along to our neighbors downstairs), they may be forced to subsist on the fleece of long carbohydrate chains (some call it “mucus”)  lining and guarding the intestinal wall. Weakening that barrier could encourage inflammation.

The Sonnenburgs note that certain types of fatty substances are overwhelmingly the product of carbohydrate fermentation by gut microbes. These substances have been shown to exert numerous anti-inflammatory effects in the body, possibly protecting against asthma and eczema: two allergic conditions whose incidence has soared in developed countries and seems oddly correlated with the degree to which the environment a child grows up in is spotlessly hygienic.

Previously: Joyride: Brief post-antibiotic sugar spike gives pathogens a lift, The future of probiotics and Researchers manipulate microbes in the gut
Photo by geraldbrazell

Evolution, Genetics, Obesity, Research, Science, Stanford News

Tiny fruit flies as powerful diabetes model

Tiny fruit flies as powerful diabetes model

Seung Kim

Fruit flies in your kitchen are unquestionably annoying. But the next time you’re trying to bat one out of the air around your too-ripe apples and bananas (or maybe that’s just me?), spare a few seconds to realize how important the tiny insects have been to science. They’ve been a darling of developmental biology for decades, as researchers identified genes (subsequently shown to be shared in mammals and humans) critically important in the metamorphosis from egg to animal. Frankly, it’s hard to over-estimate their contribution to science.

Now they’re set to take up a starring role in diabetes research. Stanford developmental biologist and Howard Hughes Medical Institute investigator Seung Kim, MD, PhD, and research associate Sangbin Park, PhD, have devised a way to measure insulin levels in fruit flies at the picomolar level – the level at which insulin concentrations are measured in humans. They’ve done so by successfully tagging the fruit fly insulin-like-peptide 2, or Ilp2, with a chemical tag. Their research was published today in PLOS Genetics.

From our release:

The experimental model is likely to transform the field of diabetes research by bringing the staggering power of fruit fly genetics, honed over 100 years of research, to bear on the devastating condition that affects millions of Americans. Until now, scientists wishing to study the effect of specific mutations on insulin had to rely on the laborious, lengthy and expensive genetic engineering of laboratory mice or other mammals.

In contrast, tiny, short-lived fruit flies can be bred in dizzying combinations by the tens of thousands in just days or weeks in small flasks on a laboratory bench.

In 2002, Kim and developmental biologist Roel Nusse, PhD, surprised many researchers when they showed that fruit flies develop a diabetes-like condition when their insulin-producing cells are destroyed. Further research has been stymied, however, by the difficulty of accurately measuring circulating insulin levels in the tiny animals. When speaking to me about the research, Kim called the new technique a “breakthrough” in the field.

Unlike many previous attempts by many groups, Park found two places in Ilp2 where the tag can be placed without affecting its biological activity. This allowed Kim and Park to track Ilp2 through its life cycle, as it’s produced by neurons in the brain (this is different from humans, who make insulin in beta cells in the pancreas), secreted into the blood stream and binds to insulin receptors in cells throughout the body. Parsing the effect of each mutation on the way the body produces, secretes and responds (or not) to insulin is critical to further understand the disease and to devise new therapeutic approaches. More from our release:

Park and his colleagues then turned their attention to mutations associated with type-2 diabetes in genome-wide studies in humans. These studies don’t reveal how a specific mutation might work to affect development of a disease; they show only that people with the condition are more likely than those without it to have certain mutations in their genome. Hundreds of candidate-susceptibility genes have been identified in this way.

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