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Evolution, Fertility, Pregnancy, Research, Science, Stanford News, Stem Cells, Videos

Viral RNA essential for human development, say Stanford researchers

Viral RNA essential for human development, say Stanford researchers

Viruses are tricky, but we humans may be trickier still. Stanford stem cell biologists Vittorio Sebastiano, PhD, and Jens Durruthy-Durruthy, PhD, published a study today in Nature Genetics indicating that the genetic remnants of ancient viral infections that still linger in our genome are essential to early human embryonic development.

As Sebastiano explained in our release:

We’re starting to accumulate evidence that these viral sequences, which originally may have threatened the survival of our species, were co-opted by our genomes for their own benefit. In this manner, they may even have contributed species-specific characteristics and fundamental cell processes, even in humans.

The researchers, who talk about their work in the video above, relied on a new RNA sequencing technique to investigate the expression of what are called long-intergenic noncoding, or lincRNAs. These molecules don’t contain protein-making instructions, but instead affect the expression of other genes. They’ve been implicated in many important biological processes, including the acquisition of a developmental state called pluripotency that is necessary for a fertilized egg to develop into the cells and tissues of a growing fetus.

More from our release:

They identified more than 2,000 previously unknown RNA sequences, and found that 146 are specifically expressed in embryonic stem cells. They homed in on the 23 most highly expressed sequences, which they termed HPAT1-23, for further study. Thirteen of these, they found, were made up almost entirely of genetic material left behind after an eons-ago infection by a virus called HERV-H.

[…] After identifying HPAT1-23 in embryonic stem cells, Sebastiano and his colleagues studied their expression in human blastocysts — the hollow clump of cells that arises from the egg in the first days after fertilization. They found that HPAT2, HPAT3 and HPAT5 were expressed only in the inner cell mass of the blastocyst, which becomes the developing fetus. Blocking their expression in one cell of a two-celled embryo stopped the affected cell from contributing to the embryo’s inner cell mass. Further studies showed that the expression of the three genes is also required for efficient reprogramming of adult cells into induced pluripotent stem cells.

I can’t stop marveling at the close ties we have with viruses. It makes me think of the words of Michael Corleone in The Godfather: “Keep your friends close, and your enemies closer.” As Durruthy-Durruthy told me, “It’s fascinating to imagine how, during the course of evolution, primates began to recycle these viral leftovers into something that’s beneficial and necessary to our development.”

Previously: My baby, my… virus? Stanford researchers find viral proteins in human embryonic cellsMastermind or freeloader? Viral proteins in early human embryos leave researchers puzzled  and Species-specific differences among placentas due to long-ago viral infection, say Stanford researchers
Video by Christopher Vaughan/Stanford Institute for Stem Cell Biology and Regenerative Medicine

Evolution, Infectious Disease, Microbiology, Pediatrics, Pregnancy, Research, Stanford News

Mastermind or freeloader? Viral proteins in early human embryos leave researchers puzzled

Mastermind or freeloader? Viral proteins in early human embryos leave researchers puzzled

and_virus_makes_four_fullI’m filing this finding firmly under the category of “Things I’m glad I didn’t know when I was pregnant.” (Other items include the abject terror of letting your teen get behind the steering wheel of a car for the first time, and the jaw-dropping number of zeros that can appear in a college financial aid package.) Recently, Stanford researchers found that the earliest stages of human development – those that occur within days of fertilization – may take place in a stew of viral proteins that lie in wait tucked inside the human genome. What do the viral proteins do? Who knows! Why are they popping up when we’re (arguably) at our most vulnerable? No idea!

Ugh. Like there’s not enough to worry about while growing another human inside your body.

I’m not being entirely fair here. Developmental biologist Joanna Wysocka, PhD, and graduate student Edward Grow, were some of the first researchers to show that ancient viral DNA sequences abandoned in our genome after long-ago infections can and do make viral proteins early in human development. I wrote about their finding on this blog earlier this year.

My article in the most recent issue of Stanford Medicine magazine expands on this story, describing how they made their finding and their future plans to learn more about our viral co-pilots. As I explain:

The finding raises questions as to who, or what, is really pulling the strings during human embryogenesis. Grow and Wysocka have found that these viral proteins are well-placed to manipulate some of the earliest steps in our development by affecting gene expression and even possibly protecting the embryo’s cells from further viral infection.

I’m often struck by how much parenting is like research. It’s a (seemingly) never-ending, but very rewarding, job. And for both, there’s clearly always lots to learn. As I write:

So, who’s in charge here? Us or the viruses? Or is there no longer any distinction? There’s certainly been plenty of evidence showing that humans are far from free operators when it comes to, well, pretty much anything. Our bodies are teeming masses of bacteria, viruses and even fungi that are collectively known as the microbiome. Many of these microorganisms, which are 10 times more numerous than our own cells, are essential to a healthy life, such as the gut bacteria that help us digest our food.

“What we’re learning now is that our ‘junk DNA,’ including some viral genes, is recycled for development in the first few days and weeks of life,” says [study co-author and former Stanford stem cell researcher Renee Reijo-Pera], who is now on the faculty of Montana State University. “The question is, what is it doing there?”

Previously: Stanford Medicine magazine tells why a healthy childhood mattersMy baby, my…virus? Stanford researchers find viral proteins in human embryonic cells and Species-specific differences among placentas due to long-ago viral infection, say Stanford researchers
Photo of Joanna Wysocka by Misha Gravenor

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

Chimps and humans face-off in Stanford study on inter-species variation

Chimps and humans face-off in Stanford study on inter-species variation

wysocka_illustration (6)Our nearest primate relative, the chimpanzee, shares much of its genome with us. And yet, despite the astounding similarities in our DNA sequences, it’s not difficult to discern the face of one species from the other.

Developmental biologist Joanna Wysocka, PhD, researches, among other things, how human faces are formed during early embryonic development. She and graduate student Sara Prescott compared gene expression patterns between humans and chimpanzees in the hopes of identifying not just what makes us recognizably human, but also how human faces also differ among themselves.

They describe their work, which was published today in Cell, as a kind of “cellular anthropology” that can illuminate important genomic tweaks in our recent evolutionary past. In particular, they found that the critical differences between the two species lie not in the DNA sequence of the genes themselves, but in when and where (and to what levels) the genes are made into proteins during development. These changes have led to important, human-specific adaptations. As Wysocka explained in our release:

We are trying to understand the regulatory changes in our DNA that occurred during recent evolution and make us different from the great apes. In particular, we are interested in craniofacial structures, which have undergone a number of adaptations in head shape, eye placement and facial structure that allow us to house larger brains, walk upright and even use our larynx for complex speech.

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Cardiovascular Medicine, Evolution, Genetics, Research, Science

Ethiopian gene offers potential help for hypoxia

Ethiopian gene offers potential help for hypoxia

8494671414_5bc71743c8_zGene therapies have been developed for color blindness, Parkinson’s, SCID, and muscular dystrophy, among others. Now there soon could be another to add to the list: hypoxia, or oxygen deprivation.

In a study published in PNAS, researchers investigated how mice with lower levels of the endothelin receptor type B (EDNRB) gene – a gene that is present among Ethiopians, who evolved to live at high elevations where oxygen levels are low – fare in hypoxic conditions. It found that even with five percent oxygen, lower than you’d find atop Mount Everest, the mice with the gene alteration survived. They managed to get oxygen to their vital organs with the help of several “downstream” genes that are regulated by EDNRB.

According to a press release, these three heart-specific genes “help heart cells perform crucial functions such as transport calcium and contract. The finding provides a direct molecular link between EDNRB levels and cardiovascular performance.”

The implications of this work are described in the release by senior author Gabriel Haddad, MD, professor and chair of pediatrics at UC San Diego School of Medicine: “In addition to improving the health of the more than 140 million people living above 8,000 feet, information on how Ethiopians have adapted to high altitude life might help us develop new and better therapies for low oxygen-related diseases at sea level — heart attack and stroke, for example.” Haddad and his team are now testing therapeutic drugs that inhibit ENDRB.

Previously: Near approval: A stem cell gene therapy developed by Stanford researcher, Using genetics to answer fundamental questions in biology, medicine, and anthropology and “It’s not just science fiction anymore”: ChildX researchers talk stem cell and gene therapy
Photo by mariusz klozniak

Dermatology, Evolution, Pediatrics, Research, Science, Stanford News, Surgery

To boldly go into a scar-free future: Stanford researchers tackle wound healing

To boldly go into a scar-free future: Stanford researchers tackle wound healing

scarshipAs I’ve written about here before, Stanford scientists Michael Longaker, MD, and Irving Weissman, MD, are eager to find a way to minimize the scarring that arises after surgery or skin trauma. I profiled the work again in the latest issue of Stanford Medicine magazine, which focuses on all aspects of skin health.

My story, called “Scarship Enterprise,” discusses how scarring may have evolved to fulfill early humans’ need for speed in a cutthroat world:

“We are the only species that heals with a pathological scar, called a keloid, which can overgrow the site of the original wound,” says Longaker. “Humans are a tight-skinned species, and scarring is a late evolutionary event that probably arose in response to a need, as hunter-gatherers, to heal quickly to avoid infection or detection by predators. We’ve evolved for speedy repair.”

Check out the piece if you’re interested in reading more about this or learning how scarring happens, or why, prior to the third trimester, fetuses heal flawlessly after surgery. (Surprisingly, at least to me, many animals also heal without scarring!)

Previously: This summer’s Stanford Medicine magazine shows some skinWill scars become a thing of the past? Stanford scientists identify cellular culprit, New medicine? A look at advances in wound healing and Stanford-developed device shown to reduce the size of existing scars in clinical trial
Illustration by Matt Bandsuch

Evolution, Genetics, Research, Science, Stanford News

Kennewick Man’s origins revealed by genetic study

Kennewick Man's origins revealed by genetic study

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One day in 1996, on the banks of the Columbia River near Kennewick, Washington, two men found a human skull about ten feet from shore. Eventually, the nearly complete skeleton of an adult man was unearthed and found to be nearly 9,000 years old.

Since that find, controversy has swirled as to whether the man was an ancestor of Native American tribes living in the area, or was more closely related to other population groups around the Pacific Rim. A study published in 2014, based in part on anatomical measurements, concluded that the skeleton, known as the Kennewick Man, was more likely related to indigenous Japanese or Polynesian peoples.

Now Stanford geneticists Morten Rasmussen, PhD, and Carlos Bustamante, PhD, working with Eske Willerslev, PhD, and others at the University of Copenhagen’s Centre for GeoGenetics have studied tiny snippets of ancient DNA isolated from a hand bone. They’ve compared these DNA sequences with those of modern humans and concluded that the Kennewick Man (known to many Native Americans as the Ancient One) is more closely related to Native American groups than to any other population in the world.

The findings are published today online in Nature, and they’re likely to reignite an ongoing controversy as to the skeleton’s origins and to whom the remains belong.

As Rasmussen said in our press release:

Due to the massive controversy surrounding the origins of this sample, the ability to address this will be of interest to both scientists and tribal members. […]

Although the exterior preservation of the skeleton was pristine, the DNA in the sample was highly degraded and dominated by DNA from soil bacteria and other environmental sources. With the little material we had available, we applied the newest methods to squeeze every piece of information out of the bone.

Increasingly, such methods of isolating and sequencing ancient DNA are being used to solve millennia-old mysteries, including those surrounding Otzi the Iceman and a young child known as the Anzick boy buried more than 12,000 years ago in Montana.

Bustamante explained in the release:

Advances in DNA sequencing technology have given us important new tools for studying the great human diasporas and the history of indigenous populations. Now we are seeing its adoption in new areas, including forensics and archeology. The case of Kennewick Man is particularly interesting given the debates surrounding the origins of Native American populations. Morten’s work aligns beautifully with the oral history of native peoples and lends strong support for their claims. I believe that ancient DNA analysis could become standard practice in these types of cases since it can provide objective means of assessing both genetic ancestry and relatedness to living individuals and present-day populations.

Previously: Caribbean skeletons hold slave trade secrets,  Melting pot or mosaic? International collaboration studies genomic diversity in Mexico and  On the hunt for ancient DNA, Stanford researchers improve the odds
Photo, of bust showing how Kennewick Man may have looked, by Brittany Tatchell/Smithsonian (bust by StudioEIS; forensic facial reconstruction by sculptor Amanda Danning)

Biomed Bites, Evolution, Genetics, Research, Science, Videos

One mutation, two people and two (or more) outcomes: What gives?

One mutation, two people and two (or more) outcomes: What gives?

Welcome to Biomed Bites, a weekly feature that introduces readers to some of Stanford’s most innovative researchers. 

Tweak a piano string and you’ve created a different note. Tweak a gene and no one knows exactly what might happen. Perhaps the resultant protein is completely defective. Perhaps the same change does nothing in me but turns your world upside down. Who knows?

One Stanford researcher is working to demystify some of that variability, an endeavor that could lead to big changes in the development of therapies for diseases such as cancer. Daniel Jarosz, PhD, assistant professor of chemical and systems biology and of developmental biology, describes his work in the video above:

We all know there are many mutations associated with disease, for example, that give rise to that disease in some patients, yet there are other patients that have the same mutations and don’t have any effects. We’d really like to understand that…

The clinical benefits of this work are potentially very large.

For example, Jarosz said he and his team study why some tumor genes are able to evolve rapidly to evade chemotherapy. With a greater understanding of what conditions cause rapid evolution — and drug resistance — they can more easily evaluate new therapies.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: From finches to cancer: A Stanford researcher explores the role of evolution in disease, Computing our evolution and Whole genome sequencing: The known knowns and the unknown unknowns

Evolution, Global Health, Medical Education, Research, Stanford News

Stanford med student/HHMI fellow investigates bacteriophage therapy as an alternative to antibiotics

Stanford med student/HHMI fellow investigates bacteriophage therapy as an alternative to antibiotics

IMG_5145 croppedSecond-year medical student Eric Trac isn’t one to shy away from a challenge. Trac’s family is from Vietnam and he didn’t speak much English as a child, but Trac and his mother overcame this hurdle by practicing English and studying together every night until the early morning hours so he could do well at school. Now, just 12 years later, Trac is a Howard Hughes Medical Institute (HHMI) fellow taking on a new kind of challenge: investigating an alternative to antibiotics.

Many people think that antibiotics are the only way to kill bacteria, but this isn’t true. “Before we used antibiotics, we used bacteriophages,” Trac said. “Just like viruses attack people, bacteriophages attack bacteria. In other words, bacteria can get sick as well.”

Bacteriophages have been used since the early 1900s in countries like France, Poland and the U.S. to treat diseases such as cholera and dysentery. But interest in bacteriophage therapy, and its use, declined in the West after antibiotics were discovered in the 1920s. Now that bacteria are becoming increasingly resistant to antibiotics, researchers in the West are taking interest in the decades of bacteriophage research that continued in Eastern Europe and the former Soviet Union long after antibiotics became popular elsewhere. Unfortunately, many of these studies don’t meet the scientific standards (e.g., double blind studies, experimental controls) that Western drug research requires.

So, for his year-long HHMI project, Trac and his mentors, bioengineer and physicist Stephen Quake, PhD, and pediatric pulmonary expert David Cornfield, MD, will test bacteriophage therapy — with the required scientific protocols — to see if it could be a viable, and safe alternative to antibiotics. His project will focus on two common bacteria, Pseudomonas aeruginosa and Staphylococcus aureus, that can cause life-threatening infections, especially in people with cystic fibrosis. “The need for alternative ways to kill these two bacteria is great,” Trac said.

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Evolution, Genetics, HIV/AIDS, Immunology, Infectious Disease, Research, Stanford News

Study: Chimps teach people a thing or two about HIV resistance

Study: Chimps teach people a thing or two about HIV resistance

I, personally, have never had trouble distinguishing a human being from a chimp. I look, and I know.

But I’m not a molecular biologist. Today’s sophisticated DNA-sequencing technologies show that the genetic materials of the two species, which diverged only 5 million or so years ago (an eye-blink in evolutionary time), are about 98 percent identical. Think about that next time you eat a banana.

One major exception to that parallelism: a set of three genes collectively called the major histocompatibility complex, or MHC. These genes code for proteins that sit on the surfaces of each cell in your body, where they serve as jewel cases that display bits of proteins that were once inside that cell but have since been chopped into pieces by molecular garbage disposals, transported to the cell surface and encased in one or another of the MHC proteins. That makes the protein bits highly visible to roving immune cells patrolling our tissues to see if any of the cells within are harboring any funny-looking proteins. If those roving sentry cells spot a foreign-looking protein bit, they flag the cell on whose surface it’s displayed as possibly having been infected by a virus or begun to become cancerous.

Viruses replicate frequently and furiously, so they evolve super-rapidly. If they can evade immune detection, that’s groovy from their perspective. So our MHC has to evolve rapidly, too, and as a result, different species’ MHC genes  diverge relatively quickly.  To the extent they don’t, there’s probably a good reason.

Stanford immunologist and evolutionary theorist Peter Parham, PhD, pays a lot of attention to the MHC genes. In a new study in PLOS Biology, he and his colleagues have made a discovery that may prove relevant to AIDS research, by analyzing genetic material found in chimp feces. Not zoo chimps. Wild Tanzanian chimps. As I noted in a news release about the study:

The wild chimps inhabit Gombe Stream National Park, a 13.5-square-mile preserve where they have been continuously observed from afar since famed primatologist Jane Goodall, PhD, began monitoring them more than 50 years ago.

One thing that sets the Gombe chimps apart from captive chimps, unfortunately, is a high rate of infection by the simian equivalent of HIV, the virus responsible for AIDS.

The study’s lead author, postdoc Emily Wroblewski, PhD, set up shop in a corner of Parham’s lab and extracted DNA from fecal samples legally obtained by other researchers (close contact with the animals is prohibited). Each sample could be tied to a particular Gombe-resident chimp. RNA extracted from the same sample indicated that chimp’s infection status.

Parham, Wroblewski and their colleagues found that one particular MHC gene came in 11 different varieties – astounding diversity for such a small collection of chimps (fewer than 125 of them in the entire Gombe). Surprisingly, one small part of one of those 11 gene variants was nearly identical to a piece of a protective version of its human counterpart gene, a version that seems to protect HIV- infected people slowing HIV progression to full-blown AIDS.

Why is that important? Because any piece of an MHC gene that has maintained its sequence in the face of 5 million years of intense evolutionary pressure must be worth something.

Sure enough, fecal samples from chimps with that MHC gene variant, so strikingly analogous to the protective human variant, had lower counts of virus that those from infected chimps carrying other versions of the gene.

You can believe that scientists will be closely examining the DNA sequence contained in both the human and chimp gene variant, as well as the part of the MHC protein that DNA sequence codes for. Because it must be doing something right.

Previously: Revealed: Epic evolutionary struggle between reproduction and immunity to infectious disease, Our species’ twisted family tree and Humans share history – and a fair amount of genetic material – with Neanderthals
Photo by Emily Wroblewski

Evolution, Parenting, Pediatrics, Research, Women's Health

Just when did it begin to “take a village to raise a child”?

9640826608_e65589c650_zImagine a prehistoric human mother raising her baby outside of any community or family structure, with no help from others. It sure doesn’t fit with my idea of the “village” that raises a child, a phrase I often associate with romantic notions of pre-modern lifestyles. But according to a study done by University of Utah anthropologist Karen Kramer, PhD, if you go far back enough in human evolution, mothers raised their young alone and didn’t feed or care for them past weaning (which happened around 5 or 6 years of age!).

The study, published in the Journal of Human Evolution and interestingly titled “When mothers need others: The impact of hominin life history evolution on cooperative breeding,” examines how humans transitioned into family and community patterns of child rearing. It suggests that the earliest cooperative groups were formed by a mother and many of her children, with older ones helping rear younger siblings; after this was established, other adults were incorporated, probably when bands of mothers with their offspring teamed up. As women became better at reproducing, they needed the extra help.

As noted in a University of Utah press release, this is different from the predominating theories among anthropologists, which point to cooperation among adults. Kramer also comments:

Human mothers are interesting. They’re unlike mothers of many other species because they feed their children after weaning and others help them raise their children. As an anthropologist, I live and work in traditional societies where, like other researchers, I have observed many times that it takes a village to raise a child. Not only do mothers work hard to care for their young, but so do her older children, grandmothers, fathers and other relatives. But this wasn’t always the case.

The consequences for health likely factored into the “economic decision making” that Kramer modeled in her study – children reared cooperatively were more likely to survive, and I imagine mothers garnered more than a few benefits from extra pairs of eyes, ears, hands, and feet, as well.

And another thing this study shows us: Some of the same decisions that parents weigh today – how many children to have, which kind of help to recruit in raising them, and what kind of balance between kids and other pursuits will optimize health – are really not so novel.

Previously: Computing our evolution and Revealed: Epic evolutionary struggle between reproduction and immunity to infectious disease
Photo by Jaroslav A. Polak

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