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Microbiology, Research, Science, Stanford News

Tiny balloon-like vesicles carry cellular chatter with remarkable specificity, say Stanford researchers

Tiny balloon-like vesicles carry cellular chatter with remarkable specificity, say Stanford researchers

6292985963_bbc06df590_z“BRUSH YOUR TEETH,” I bellowed up the stairs last night at my (seemingly deaf and clueless) children for what seemed like the one-millionth time since their birth. “Surely there has to be a better way,” I pondered, as I trudged up the stairs to deliver my threatening message in person.

The cells in our bodies don’t have the option to, however reluctantly, leave their metaphorical couch and wag their fingers under the noses of their intended recipients. And yet, without a fail-safe method of communication among distant participants, the orderly workings of our bodies would screech to a halt.

Now biologists Masamitsu Kanada, PhD, and Christopher Contag, PhD, have published in the Proceedings of the National Academy of Sciences an interesting and revealing glimpse into one tool cells can use to do the job: tiny balloon-like vesicles capable of delivering a payload of protein or genetic information from one cell to another. As Contag and Kanada explained to me in an email:

Extracellular vesicles are nanosized little containers of information that are produced by most, if not all, cells in the bodies of plants, animals and humans. From many studies it is apparent that adding vesicles from one cell type to another can affect the behavior of the recipient cells, both in a culture dish and in the living body, even across species from plants to animals and presumably humans.

We wanted to assess, under controlled sets of conditions, which biomolecules within vesicles transfer the most information most efficiently. We learned that the process is complex, and that a biomolecule in one type of vesicle is transferred in a way that affects other cells, but the same molecule in another type of vesicle may not affect cell function.

In other words, Contag, who co-directs Stanford’s Molecular Imaging Program, and his colleagues found that not all these vesicles are created equal. Some, whose outer layer was derived from the cell’s external plasma membrane (these are known as micro-vesicles), handily delivered both protein and DNA to recipient cells. Others, with outer layers derived from internal membranes in the cell (known as exosomes), were less capable and didn’t deliver any functional DNA. Interestingly, neither kind was able to deliver RNA, which was instead swiftly degraded.

The distinction between vesicle type and function is important as researchers increasingly rely on them to eavesdrop on cellular conversations or even to deliver particular biomolecules to be used for therapy or imaging. Understanding more about how they work will allow researchers to both better pick the right type for the job at hand and to learn more about how cells talk with one another. As Contag and Kanada said:

How cells communicate across distances is relevant to mobilization of immune cells to attack pathogens, depression of immune responses by tumor cells, signaling of cancer cells to metastasize, modulation of physiological processes in intestinal cells in response to plant-derived diets and to many other biological process. Understanding this form of cell-to-cell communication will bring us closer to controlling how cells talk to one another inside the body.

Now if only I could find the right kind of vesicle to communicate with my recalcitrant children. Perhaps a helium-filled balloon with a pointed message inside could float up the stairs and pop next to their ears? On second thought, that might not be the best choice.

Previously: Researchers develop imaging technologies to detect cancer earlier, faster
Photo by Matthew Faltz

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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Genetics, NIH, Research, Science, Stanford News

Project Roadmap: Mysteries of the epigenome revealed

Project Roadmap: Mysteries of the epigenome revealed

Let’s hear it for large, international collaborations! Hot on the heels of the ENCODE Project (well, in research time anyway) comes the National Institutes of Health’s Roadmap Epigenomics Project, which is geared toward understanding how chemical tags on DNA and its associated proteins determine how each cell uses the information in the genome to develop its own identity. One of the leaders of the massive project was geneticist Anshul Kundaje, PhD, who helped to analyze the huge amounts of data generated by labs around the world as they studied more than 100 adult and fetal human tissues.

The work is published today in Nature in the form of a large package of papers. Kundaje is the first author of the main paper; Nature has also published a nice summary of all the papers in the issue and produced a musical video to explain the project.

From our release:

The problem [of picking and choosing from a genome’s worth of information] is somewhat like being handed a list of all the ingredients available in a well-stocked kitchen without any idea of how to combine them. Tossing a few of them together, willy-nilly, into a baking dish and popping it into the oven isn’t likely to yield anything edible. But with a well-written recipe telling you how much and when to mix together flour, sugar, eggs and butter, you can turn out a perfect cake or fantastic waffles.

The completion of the Human Genome Project gave biologists the list of ingredients to which every cell has access. The Roadmap Epigenomics Project outlines the recipes and shows how cells use these ingredients to generate their own special sauce. By comparing and contrasting these cellular recipes, researchers can begin to draw parallels among cell types and even predict which cells might be involved in specific traits and diseases.

As a proof of principle, Kundaje and others showed in one of the companion papers that, based on the epigenomic maps shared among cells, the immune system is likely to play a larger role in the development of Alzheimer’s disease than previously thought.

Previously: Scientists announce the completion of the ENCODE project, a massive genome encyclopedia , Red light, green light: Simultaneous stop and go signals on stem cells’ genes may enable fast activation, provide “aging clock” and Caught in the act! Fast, cheap, high-resolution, easy way to tell which genes a cell is using

Aging, Genetics, Research, Science, Stanford News

My funny Valentine – or, how a tiny fish will change the world of aging research

My funny Valentine - or, how a tiny fish will change the world of aging research

YoungFishI admit it. I have crush on a fish. The object of my affection is the African turquoise killifish – a tiny, colorful fish that lives in seasonal ponds and puddles under the hot sun of Mozambique and Zimbabwe. Because the pools dry out regularly, the fish have evolved to have a normal lifespan of only a few months. In fact, it’s one of the shortest-lived vertebrates known. It’s also zippy, territorial and (maybe it’s just me?) seemingly possessing a degree of chutzpah noticeably absent in your average goldfish.

The killifish’s compressed lifespan, plus the ease and speed with which it can be housed and bred, make it an ideal model for genetic studies of aging and longevity. But in the absence of a fully sequenced genome and little information about gene expression patterns or a way to introduce selective mutations, it’s been difficult for researchers to get a scientific handle on the slippery creature.

Today, geneticists Anne Brunet, PhD, and Itamar Harel, PhD, published a comprehensive genetic toolbox for use by researchers around the world wanting to draw parallels between humans and my tiny, finned crush. The article appears online in Cell; a charming video abstract describing their work is also available.

As I describe in our release:

Although the similarities between fish and humans may not be immediately evident, people have much more in common with the tiny, minnowlike creature than with other short-lived laboratory animals.

“This fish gives us the best of both worlds,” said postdoctoral scholar Itamar Harel, PhD. “As a vertebrate, it shares many critical attributes with humans, including an adaptive immune system, real blood and similar stem cell biology.

At the same time, its very short life span mimics those of the laboratory worms, yeast and fruit flies that until now have served as the traditional models of aging research.”

A short life span allows researchers to quickly assess the effect of genetic variations among different strains of fish. It also allows them to breed and raise hundreds of progeny for study within the span of months, rather than the many years required to conduct similar experiments in other vertebrates.

“The life span of a mouse can be as long as three to four years,” said Anne Brunet, PhD, professor of genetics. “This is close to the average length of a postdoctoral or graduate student position. This means that it would be very difficult for a researcher to conduct a meaningful analysis of aging in the mouse within a reasonable time period.”

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Aging, Ethics, Medicine and Society, Research, Science, Stanford News

Golden years? Researcher explores longevity research and the companies banking on its success

Golden years? Researcher explores longevity research and the companies banking on its success

Elderly Japanese woman for Scott blog postAlthough I haven’t had a birthday yet this year, the transition to writing 2015 on all my checks (whoops, did I just date myself there? ahem) has made me feel older. Coincidentally, I’ve also been working on an article for an upcoming issue of Stanford Medicine magazine about aging and longevity. So, yeah. I’ve been thinking a lot about the passage of time.

That’s why I was really interested to learn that Stanford bioethicist Christopher Scott, PhD, teamed up with Nature Biotechnology senior editor Laura DeFrancesco to c0-author a feature article examining the commercialization of longevity research. The article layers research advances with the rise and fall (and rise again) of companies and organizations that have tossed their hats into the anti-aging ring since the 1990s. With it, Scott and DeFrancesco paint a picture of a dynamic field on the brink of something big. As Scott explained in an email to me:

Aging research, as we knew it in the 1990s and 2000’s, is being abandoned in favor of something much more ambitious. The central features of longevity research include an embrace of big data, a pivot away from studies hoping to find aging genes, a recognition that aging is best thought of a collection of diseases, not just one disease.

I’m fascinated by how quickly this new direction has taken off, especially since classic aging research yielded so little, and became saddled with hype. Longevity research has that same feel to it, and from an ethics and policy perspective one question is whether the promise of healthy lifespans will outrun the reality of the science.

And there’s the rub. As Scott points out, it’s not enough to just live long. No one wants a prolonged, but unhealthy, old age. We need to live long and well. The concept that gained ground is “healthspan” rather than “lifespan.” And from Google’s Calico to Craig Venter’s Human Longevity, Inc , there are a lot of bright minds (and plenty of $) focused on this problem. But there’s a lot at stake.

As Scott explained:

These are highly consequential decisions (funding research, creating new companies, establishing new scientific disciplines), technological inventions, and social changes that are being pursued on the tacit assumption that such decisions, inventions, and changes do lead to a healthier, longer life and the promise of a better future. In ethics, I think these assumptions are largely unexplored and unacknowledged.

The article is a fascinating cross-section of a rapidly growing field, but, as Scott points out, there are still many questions that scientists haven’t addressed. It’s well worth the time to read, whether you’re a writer on a deadline or just a person trying to figure out how to gracefully change that “4” into a “5” on …all your paperwork.

Previously: Exploring the value of longevity with bioethicist Ezekiel Emanuel , Tick tock goes the clock – is aging the biggest illness of all? and Researchers aim to extend how long – and how well – we live
Photo by Maya Stone

Autism, Genetics, Research, Stanford News

Unlocking autism’s secrets: Stanford researchers point fingers at a brain cell dark horse

Unlocking autism’s secrets: Stanford researchers point fingers at a brain cell dark horse

Snyder smilingGeneticist Michael Snyder, PhD, has a thing for ‘omes.’ He’s studied genomes, transcriptomes, proteomes and microbiomes. Each term represents looking at something (DNA, RNA, proteins or microorganisms on a grand scale, throughout an entire organism). Most recently he’s been known for combining omics information to generate a dynamic picture of his own changing health over time (he termed the analysis a “integrative personal omics profile, or iPOP, but really, the siren call of “the Snyder-ome” is almost too great to resist).

Now he and postdoctoral scholar Jingjing Li, PhD, have turned their attention to the human “interactome,” a database that includes information about more than 69,000 protein interactions. They’ve used sophisticated algorithms to identify who in the brain is playing nicely with whom, and identified a particular group that seems to play an important role in the development of autism in a part of the brain called the corpus callosum. Importantly, the analysis points a finger at a new cell type in the brain — the oligodendrocytes. These serve as kind of a pit crew for the neurons, coating them in an insulating material to keep electrical signals between cells running smoothly. They’ve published their work today in Molecular Systems Biology.

As Snyder explained in our release:

This is our first glimpse of autism’s underlying biological framework, and it implicates a cell type and region of the brain that have not been extensively studied in this disease. Until now, we’ve suspected that autism could be the result of defects in the neurons themselves. Now it appears that the oligodendrocytes can contribute to the problem by inhibiting neuronal signaling through poor cellular differentiation and myelination.

Snyder, who also directs Stanford’s Center for Genomics and Personalized Medicine, and Li hope that the finding will allow researchers to broaden their net to the corpus callosum, which helps the two halves of the brain communicate with one another. As psychiatrist and study co-author, Joachim Hallmayer, MD, commented:

Autism is an extremely heterogeneous disease. Many genes have been implicated, but environment also plays a role. This study suggests a possible way to subdivide patients into smaller, more homogenous populations based on which genes are mutated. Some of these may be very easy to treat, based on their mechanism, while others may be much more difficult. For those in this category, it’s possible we could one day find a way to train or improve the connection between the brain’s hemispheres.

It will be fascinating to see where this research goes next. In the meantime, here’s hoping the New Year-ome treats you and yours well!

Previously: New imaging analysis reveals distinct features of the autistic brain, Omics’ profiling coming soon to a doctor’s office near you? and A conversation with autism activist and animal behavior expert Temple Grandin
Photo of Snyder by Steve Fisch

Genetics, Neuroscience, Research, Science, Stanford News

Yeast advance understanding of Parkinson’s disease, says Stanford study

Yeast advance understanding of Parkinson's disease, says Stanford study

It’s amazing to me that the tiny, one-celled yeast can be such a powerful research tool. Now geneticist Aaron Gitler, PhD, has shown that the diminutive organism can even help advance the understanding of Parkinson’s disease and aid in identifying new genes involved in the disorder and new pathways and potential drug targets. He published his findings today in Neuron and told me in an email:

Parkinson’s disease is associated with many genetic and environmental susceptibility factors. Two of the newest Parkinson’s disease genes, EIF4G1 and VPS35, encode proteins involved in protein translation (the act of making protein from RNA messages) and protein sorting (shuttling proteins to the correct locations inside the cell), respectively. We used unbiased yeast genetic screens to unexpectedly discover a strong genetic interaction between these two genes, suggesting that the proteins they encode work together.

The proteins, EIF4G1 and VPS35, have changed very little from yeast to humans. Gitler and his colleagues showed that VPS35 interacts functionally with another protein implicated in Parkinson’s disease, alpha-synuclein, in yeast, round worms and even laboratory mice. As Gitler described:

Together, our findings connect three seemingly distinct Parkinson’s disease genes and provide a path forward for understanding how these genes might contribute to the disease and for identifying therapeutic interventions. More generally, our approach underscores the power of simple model systems for interrogating even complex human diseases.

Previously: Researchers pinpoint genetic suspects in ALS and In Stanford/Gladstone study, yeast genetics further ALS research

Aging, NIH, Public Health, Research, Science, Stanford News

Tick tock goes the clock – is aging the biggest illness of all?

Tick tock goes the clock - is aging the biggest illness of all?

3821120232_d1452b4109_zIt’s an uncomfortable truth that aging is the single biggest risk factor for many chronic diseases. It’s also completely out of our control. (The alternative is, well, not so fun to contemplate.) But although we all think we’d like to live longer, longevity in and of itself is not necessarily a good thing. Living longer rapidly loses its appeal if you’re too sick or feeble to really enjoy your extra “golden” years.

But researchers from many scientific disciplines are now working to understand how and why our bodies tend to break down as time passes. The Trans-NIH Geroscience Interest Group (a group of researchers from numerous NIH institutes) interested in aging held a summit in 2013 to explore mechanisms of aging and identify common themes that could serve as research targets. The thought is that understanding, and slowing, aging may be an efficient way to tackle many chronic diseases simultaneously.

Now the group, which includes Stanford geneticist Anne Brunet, PhD; neurologist Tony Wyss-Coray, PhD; and Thomas Rando, MD, PhD, has released the conclusions of the summit and outlined a plan for the work that lies ahead. (Rando is the director of the Glenn Center for the Biology of Aging at Stanford.) Many of the findings focus  on a concept called “healthspan,” which designates the portion of a person’s lifespan in which he or she is relatively healthy and fully functional. From the Cell article:

While life expectancy continues to rise, healthspan is not keeping pace because current disease treatment often decreases mortality without preventing or reversing the decline in overall health.  Elders are sick longer, often coping with multiple chronic diseases simultaneously.  Thus, there is an urgent need to extend healthspan.

The researchers identified seven intertwined “pillars of aging” for targeted research, including adaptation to stress, stem cells and regeneration, metabolism, macromolecular damage, inflammation, epigenetics and a concept called proteostasis, which describes the intricate dance in which proteins are made, transported and degraded within a cell. They suggest the creation of an Aging Research Initiative that works to merge the emerging field of geroscience with research on chronic disease and to search for therapeutic interventions that could extend both lifespan and healthspan.

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Aging, Men's Health, Research, Science, Stanford News, Stem Cells

Viva la hedgehog! Signaling protein also shown to be important in prostate growth

Viva la hedgehog! Signaling protein also shown to be important in prostate growth

6111053153_5b14f4570d_zOk, so it may *appear* that this post is just an excuse to post a cute hedgehog picture. After all, who could resist that little face? But this is really meant to be a quick shout-out to Stanford developmental biologist Philip Beachy, PhD, who has shown yet again that the signalling protein called hedgehog is critically important during many aspects of development.

In Beachy’s latest work, published earlier this week in Nature Cell Biology, he and his colleagues show that the precise control of when and where the hedgehog protein is made dictates the branching of tubules in the adult prostate (you may remember other recent work from Beachy’s lab about the role that hedgehog plays in bladder cancer, and what that could mean for patients). The findings of the current research suggest that aberrant hedgehog signalling could play a role in the prostatic hyperplasia, or non-cancerous enlargement of the prostate, which often happens as men age.

Previously: Drug may prevent bladder cancer progression, say Stanford researchers, Cellular culprit identified for invasive bladder cancer, according to Stanford study and Bladder infections – How does your body repair the damage?
Photo by Tiffany Bailey

Genetics, Pediatrics, Research, Science, Stanford News

Move over CRISPR, there's a new editor in town: Stanford-devised approach cures hemphilia in mice

Move over CRISPR, there's a new editor in town: Stanford-devised approach cures hemphilia in mice

A lot of attention has been paid lately to the idea of genome editing. This technique allows researchers to precisely modify an animal’s DNA to replace one version of a gene with another, or to add a working copy for a mutated gene. An approach called CRISPR/Cas9 in particular has garnered interest with its ease of use, ability to modify multiple genes, and relatively quick turnaround time when making specific strains of laboratory animals like mice for study.

Now pediatrician and geneticist Mark Kay, MD, PhD, has published  in Nature a new way to conduct genome editing that could give CRISPR a run for its money because it could be both safer and longer-lasting than other methods. As described in our press release:

The approach differs from that of other hailed techniques because it doesn’t require the co-delivery of an enzyme called an endonuclease to clip the recipient’s DNA at specific locations. It also doesn’t rely on the co-insertion of genetic “on” switches called promoters to activate the new gene’s expression.

Inclusion of endonucleases and promoters run the risk of a gamut of adverse effects in the recipient, from cancers if the promoter turns on the wrong gene in the genome to an unwanted immune response geared toward the foreign proteins. The researchers in Kay’s lab, including postdoctoral scholar and study lead author Adi Barzel, PhD, found a way around their use, and showed that it worked to enable mice with hemophilia to produce a missing blood clotting factor:

The technique devised by the researchers uses neither nucleases to cut the DNA nor a promoter to drive expression of the clotting factor gene. Instead, the researchers hitch the expression of the new gene to that of a highly expressed gene in the liver called albumin. The albumin gene makes the albumin protein, which is the most abundant protein in blood. It helps to regulate blood volume and to allow molecules that don’t easily dissolve in water to be transported in the blood.

The researchers used a modified version of a virus commonly used in gene therapy called adeno-associated virus, or AAV. In the modified version, called a viral vector, all viral genes are removed and only the therapeutic genes remain. They also relied on a biological phenomenon known as homologous recombination to insert the clotting factor gene near the albumin gene. By using a special DNA linker between the genes, the researchers were able to ensure that the clotting factor protein was made hand-in-hand with the highly expressed albumin protein.

As Kay, who is also a member of the Stanford Cancer Institute, the Stanford Child Health Research Institute and Stanford Bio X, explained, the integration of the clotting factor gene is key to the successful treatment (other clinical trials involving gene therapy for hemophilia rely on the expression of a free floating, unintegrated gene in the nucleus):

The real issue with AAV is that it’s unclear how long gene expression will last when the gene is not integrated into the genome. Infants and children, who would benefit most from treatment, are still growing, and an unintegrated gene could lose its effectiveness because it’s not copied from cell to cell. Furthermore, it’s not possible to re-administer the treatment because patients develop an immune response to AAV. But with integration we could get lifelong expression without fear of cancers or other DNA damage.

Previously: Gene “editing” could correct a host of genetic disorders, Policing the editor: Stanford scientists devise way to monitor CRISPR effectiveness and Both a doctor and a patient: Stanford physician talks about his hemophilia

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