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Evolution, Genetics, Orthopedics, Research, Science, Stanford News

From whence the big toe? Stanford researchers investigate the genetics of upright walking

From whence the big toe? Stanford researchers investigate the genetics of upright walking

A tiny armored fish may seem like an unlikely experimental animal to someone interested in understanding how humans may have evolved to walk on two legs.

But developmental biologist David Kingsley, PhD, has made a career out of studying how changes in gene regulation in the aquatic threespine stickleback broadly affect the fish’s skeletal structure. His recent research, published today in Cell, pinpoints a stretch of DNA that controls the size of the protective bone plates sported by marine sticklebacks.

As I explained in our release:

The threespine stickleback is remarkable in that it has evolved to have many different body structures to equip it for life in different parts of the world. It sports an exterior of bony plates and spines that act as armor to protect it from predators. In marine environments, the plates are large and thick; in freshwater, the fish have evolved to have smaller, lighter-weight plates, perhaps to enhance buoyancy, increase body flexibility and better slip out of the grasp of large, hungry insects. Kingsley and his colleagues wanted to identify the regions of the fish’s genome responsible for the skeletal differences that have evolved in natural populations.

“So what?” might ask the more jaded, fish haters among us. (Don’t count me among them — I recently blogged here about my undying love for the silvery, colorful killifish that’s made an undeniable splash in the field of aging research.)

Well, it turns out that this bit of regulatory DNA controls the expression of an important protein involved in bone formation during development. What’s more, this regulatory region is shared among animals separated by millions of years of evolution, from mice to chimpanzees.

But you know who doesn’t have it? Humans. Further experiments in the Kingsley laboratory suggest that the region specifically drives expression of the protein, called GDF6, in the hind limbs of our nearest evolutionary relatives, the chimpanzee.

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Bioengineering, Evolution, Research, Science, Stanford News, Technology

Fast-forwarding evolution to select suitable proteins

Fast-forwarding evolution to select suitable proteins

4286076672_2763323a1e_zNature churns out new versions of proteins in response to environment changes or random mutations. Sometimes the new versions work better than old. Other times, not.

But now, Stanford researchers have developed a super speedy technique to test millions of versions of a certain protein to see which one works best.

A Stanford news release explains:

The researchers call their tool µSCALE, or Single Cell Analysis and Laser Extraction.

The “µ” stands for the microcapillary glass slide that holds the protein samples. The slide is roughly the size and thickness of a penny, yet in that space a million capillary tubes are arrayed like straws, open on the top and bottom.

The microcapillary glass slide, roughly the size and thickness of a penny, holds the protein samples.

The power of µSCALE is how it enables researchers to build upon current biochemical techniques to run a million protein experiments simultaneously, then extract and further analyze the most promising results.

The research was led by Jennifer Cochran, PhD, associate professor of bioengineering and Thomas Baer, PhD, executive director of the Stanford Photonics Research Center.

The system is easy to use with numerous applications, Baer said.

“Evolution, the survival of the fittest, takes place over a span of thousands of years, but we can now direct proteins to evolve in hours or days,” Cochran said in the release.

Previously: Proteins from pond scum revolutionize neuroscience, Study shows toothed whales have persisted millions of years without two common antiviral proteins and Computing our evolution
Photo by Alexander Boden

Aging, Evolution, Genetics, Research, Science, Stem Cells

The war within: In our aging bodies, the “fittest” stem cells may not be the ones that ensure our survival

The war within: In our aging bodies, the "fittest" stem cells may not be the ones that ensure our survival

ageAnti-aging research has been in the news lately: for instance, here, here and (less recently and less frivolously) here.

Albert Einstein College of Medicine researcher Nir Barzilai, MD, who’s spearheading the groundbreaking anti-aging trials referred to in these articles, is far from frivolous. I remember really liking a talk he gave at Stanford a few years ago about his ongoing study of super-old Ashkenazis, at a symposium sponsored by Stanford’s Glenn Laboratories for the Biology of Aging.

Now, Tom Rando, MD, PhD, the director of Glenn Labs at Stanford, has co-authored a thought-provoking review in Science that advances a theory of why we age.

It’s not the only theory. Judy Campisi of the Buck Institute for Research on Aging, for example, has explored the detrimental activities of differentiated cells gone wrong within our tissues. The older the tissue, the wronger the cells in it go.

Rando and his co-author, Baylor College of Medicine regenerative-medicine expert Margaret Goodell, PhD, come at aging from the opposite end of the spectrum: stem cells, the least-differentiated cells in the body. In particular, Rando and Goodell target the aging-associated actions of so-called somatic stem cells, which reside in virtually all (and, probably, actually all) of our tissues and whose fates are restricted to spawning only cell types that belong in those tissues. While we’re growing up, those somatic stem cells are the reason why: They divide to generate the differentiated cells that bulk us up. Once we’ve matured, they mostly hang back, springing into action to replace tissue lost to injury or to wear and tear.

Radiation, noxious foreign substances, and plain old existence wreaks sporadic damage on somatic stem cells by triggering genetic mutations or by altering the cells’ epigenetic settings, the patterns of chemical stop-and-go signs that variously switch the 20,000-odd genes in each cell’s genome on or off. These insults pile up as life’s pages turn. Eventually, Rando and Goodell write, a curious, Darwin-like natural selection occurs among our tissue-resident stem cells.

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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

K man - 560

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

Stanford Medicine Resources: