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Biomed Bites, Genetics, Medicine and Society, Microbiology, Research, Science, Videos

From yeast to coral reefs: Research that extends beyond the lab

From yeast to coral reefs: Research that extends beyond the lab

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

John Pringle, PhD, focused most of his career on yeast. Easy to culture in the lab, yeast offer scientists a malleable model to learn about all types of cells, including human cells.

As a professor of genetics, he still does a bit of that. But now, his heart is focused on saving the world’s coral reefs – no small task given that these living ecosystems are vulnerable to temperature changes, carbon dioxide concentrations and overfishing.

Pringle’s research concentrates on a small sea anemone known as Aiptasia pallida, as he explains in the video above:

We picked an experimental system that has huge advantages over the corals themselves and we try to learn basic things about their molecular and cellular biology that will help us with the more complex and less experimentally tractable system of the reefs.

Just as with his yeast work, the lessons learned from the anemones are directly applicable to human well-being. “Corals are important to hundreds of millions of people around the world for livelihood and for the beauty they bring and the food they provide,” he says. “We have the hopes that by doing basic research, we’ll contribute to an understanding of how coral reefs might be preserved.”

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

Previously: Bubble, bubble, toil and trouble — yeast dynasties give up their secrets, Yeast advance understanding of Parkinson’s disease, says Stanford study and My funny Valentine — or, how a tiny fish will change the world of aging research

Biomed Bites, Microbiology, Research, Videos

Long a mystery organelle, the primary cilium is giving up its secrets

Long a mystery organelle, the primary cilium is giving up its secrets

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

Picture a bacterium or a sperm cell — it has a flapping flagella, a hair-like structure that some species, and cells, use to move. There’s a different type of structure that protrudes out of the cells of many mammals called a primary cilium. Unlike flagella, this structure doesn’t move. Instead it receives mechanical and chemical signals from surrounding cells.

The primary cilium and its function is the focus of Max Nachury, PhD, an assistant professor of molecular and cellular physiology. His team is applying research on the cilium to learn more about a group of hereditary diseases characterized by a malfunctioning cilium such as Bardet-Biedl syndrome. Patients with BBS are often obese, have extra fingers or toes and have poor vision.

“These multi-symptomatic disorders caused by a defect in cilium function are really things we understand very poorly,” Nachury says in the video above. “We hope that our basic research can then feed back into the basic understanding of this disorder.”

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

Previously: Clues about kidney disease from an unexpected direction, Parent details practical ways to get care and support for your child’s rare disease and New search engine designed to help physicians and the public in diagnosing rare diseases

Autoimmune Disease, Cancer, Infectious Disease, Microbiology, Nutrition, Stanford News

Getting to the good gut: how to go about it

Getting to the good gut: how to go about it

In a blog post a few years ago I wrote, The Good Gutwith misplaced parenthetical self-assuredness:

Anybody who’s ever picked up an M&M off the sidewalk and popped it into his or her mouth (and, really, who among us hasn’t?) will be gratified to learn that the more germs you’re exposed to, the less likely you are to get asthma … hay fever and eczema.

I soon learned to my surprise, if not necessarily to my embarrassment, that virtually nobody – at least nobody over 6 – cops to having stooped-and-scooped as I routinely did as a kid on what I called my “lucky-sidewalk” days.

But those M&Ms may have been the best pills I ever took.

Stanford microbiologists Justin Sonnenburg, PhD, and Erica Sonnenburg, PhD, (they’re married) have written a new book, The Good Gut, about the importance of restocking our germ-depleted lower intestines.

Massive improvements in public sanitation and personal hygiene, the discovery of antibiotics and the advent of sedentary lifestyles have taken a toll on the number and diversity of microbes that wind up inhabiting our gut. According to The Good Gut, we need more, and more varieties, of them. And we need to treat them better. The dearth of friendly microorganisms in the contemporary colon is due not just to a lack of bug intake but to a lack of fiber in the modern Western diet. Indigestible to us, roughage is the food microbes feast on.

The Good Gut packages that message for non-scientists. “We wanted to convey the exciting findings in our field to the general public,” Justin Sonnenberg recently told me. “We’d noticed we were living our life differently due to our new understanding. We were eating differently and had modified both our own lifestyle and the way we were raising our children.”

In simple language, the Sonnenburgs explain how the pieces of our intestinal ecosystem fit together, what can go wrong (obesity, cancer, autoimmunity, allergy, depression and more), and how we may be able to improve our health by modifying our inner microbial profiles. Their book includes everything from theories to recipes, along with some frank discussion of digestive processes and a slew of anecdotes capturing their family’s knowledge-altered lifestyle.

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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

Ebola, Global Health, Infectious Disease, Microbiology, Research

Can a single drug outsmart many kinds of viral invaders?

Can a single drug outsmart many kinds of viral invaders?

blue virus

We’ve got plenty of effective antibiotics – maybe even too many– to knock off bacteria we don’t like. But when it comes to viruses, it’s a different story, Stanford infectious-disease specialist Shirit Einav, MD, and postdoc Elena Bekerman, PhD, write in a recently published perspective piece in Science.

“Although hundreds of viruses are known to cause human disease, antiviral therapies are approved for fewer than 10,” the authors write, before going on:

[Antiviral drugs that interfere with crucial viral enzymes] have shown considerable success in the treatment of HIV and hepatitis C virus… infections. However, this approach does not scale easily and is limited particularly with respect to emerging viruses against which no vaccines or antiviral therapies are approved.

Which is too bad, because viruses can be nasty. Not to mention creepy: They’re master puppeteers when it comes to manipulating us into submission. They can’t even replicate on their own. The little body-snatchers need our own cells, which they break into, bamboozle, and bully into producing copies of themselves and then squirting them out so they can infect other cells and, with luck, other people.

A partial list of merging and re-emerging viruses for which there are no decent treatments includes dengue, estimated to infect 400 million people each year; SARS and MERS, responsible for outbreaks of severe acute respiratory syndromes; and Ebola, which, as everybody now knows, caused an ongoing epidemic in Africa.

Developing antiviral drugs is a huge challenge. It takes, on average, more than $2 billion and about a decade, plus or minus a couple of years, to develop a new drug targeting just one single type of virus, Bekerman and Einav write. To make things worse, these nano-villains evolve even faster than bacteria do.

Einav’s research has been taking a different tack. She’s working on drugs that, instead of gumming up this or that viral enzyme (at least until it mutates into a form the drug can’t gum up), interfere with the activity of components in our cells that the viruses absolutely depend on for their own survival and replication. There are already drugs, many of them already approved for far different indications such as cancer, that can do just that – without, however, disabling our own cells so much that the cure becomes worse than the disease.

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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

Ethics, Genetics, History, In the News, Medicine and Society, Microbiology, Stanford News

Stanford faculty lend voices to call for “genome editing” guidelines

Stanford faculty lend voices to call for "genome editing" guidelines

baby feetStanford law professor Hank Greely, JD, and biochemist Paul Berg, PhD, are two of 20 scientists who have signed a letter in today’s issue of Science Express discussing the need to develop guidelines to regulate genome editing tools like the recently discovered Crispr/Cas9. Researchers are particularly concerned that the technology could be used to alter human embryos. From the commentary:

The simplicity of the CRISPR-Cas9 system enables any researcher with knowledge of molecular biology to modify genomes, making feasible many experiments that were previously difficult or impossible to conduct. […]

We recommend taking immediate steps toward ensuring that the application of genome engineering technology is performed safely and ethically.

We’ve written a bit here before about the Crispr system, which essentially lets researchers swap one section of DNA for another with high specificity. The potential uses, for both research or therapy, are touted as nearly endless. But, as Greely pointed out in an email to me: “Making babies using genomic engineering right now would be reckless – it would be unknowably risky to the lives of those babies, none of whom consented to the procedure. For me, those safety issues are paramount in human germ line modification, but there are also other issues that have sparked social concern. It would be prudent for science to slow down while society as a whole discusses all the issues – safety and beyond.”

The list of others who signed the commentary reads like a veritable who’s who of biology and bioethics. It includes Caltech’s David Baltimore, PhD; U.C. Berkeley’s Michael Botchan, PhD; Harvard’s George Church, PhD; and George Q. Daley, MD, PhD; University of Wisconsin bioethicist R. Alta Charo, JD; and Crispr/Cas9 developer Jennifer Doudna, PhD. (Another group of scientists published a similar letter in Nature last Friday.)

The call to action echos one in the 1970s in response to the discovery of the DNA snipping ability of restriction endonucleases, which launched the era of DNA cloning. Berg, who shared the 1980 Nobel Prize in Chemistry for this discovery, organized a historic meeting at Asilomar in 1975 known as the International Congress on Recombinant DNA Molecules to discuss concerns and establish guidelines for the use of the powerful enzymes.

Berg was prescient in an article in Nature in 2008 discussing the Asilomar meeting:

That said, there is a lesson in Asilomar for all of science: the best way to respond to concerns created by emerging knowledge or early-stage technologies is for scientists from publicly-funded institutions to find common cause with the wider public about the best way to regulate — as early as possible. Once scientists from corporations begin to dominate the research enterprise, it will simply be too late.

Previously: Policing the editor: Stanford scientists devise way to monitor CRISPR effectiveness and The challenge – and opportunity – of regulating new ideas in science and technology
Photo by gabi manashe

Immunology, Microbiology, Research, Stanford News

Drugs for bugs: Industry seeks small molecules to target, tweak and tune up our gut microbes

Drugs for bugs: Industry seeks small molecules to target, tweak and tune up our gut microbes

bacterial cytoplasmMy first encounter with microbiologist Justin Sonnenburg, PhD, came when I was researching “Caution: Do Not Debug,” an article I wrote five years ago for Stanford Medicine about the astonishing microbiotic superorganism that beats within the human gut.

According to the Human Microbiome Project, the typical healthy person is inhabited with trillions of intestinal microbes. A person typically hosts 160 or so species of gut bacteria. This bug collection carries its own “shadow genome” consisting of hundreds of times as many genes, in all, than our own measly 20,000 or so human ones.

In exchange for the three square meals a day we provide them, our microbial moochers do lots of good things: From my article:

[O]ur commensal microbes 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.

Since I wrote that piece, the list of microbial good deeds has continued to grow. As Sonnenburg pointed out recently in a review article in CELL Metabolism, “Starving our Microbial Self,” our resident microbes are producing hundreds or thousands of little drug-like compounds. For example: Short-chain fatty acids, generated by our gut bacteria from starches and fiber in our diet, downregulate inflammation.

Quoted in a just-published feature in Nature Biotechnology, “Drugging the Microbiome,” Sonnenburg elaborates:

Might a lack of dietary fiber lead directly to autoimmune and inflammatory diseases? That’s the view of Justin Sonnenburg, a Stanford microbiologist. “A reduction in short-chain fatty acid production… is what happens when you get rid of dietary fiber, and [leads to] increasing inflammatory responses of the host immune system,” he says. “And it’s this simmering state of inflammation that the Western immune system exists in that’s really the cause of all the diseases that we’ve been talking about. … You can just imagine that if you get rid of these important regulatory molecules, and the immune system becomes a little bit pro-inflammatory across a large population, you’re going to see increases in things like cancer, heart disease, allergies, asthma and inflammatory bowel disease.”

While they’re indispensable, our gut microbes can do bad things, too. Research has implicated them in the production of certain metabolites implicated in deleterious effects, with potential involvement in conditions ranging from heart disease to autism to Parkinson’s to colon and liver cancer, according to the Nature Biotechnology feature.

Either way, it’s going to be well worth our while to learn everything we can about the details of the ecosystem of one-celled creatures who call us “home.”

Previously: Civilization and its dietary (dis) contents: Do modern diets starve out our gut-microbial community?, The future of probiotics and Researchers manipulate microbes in the gut
Photo by Duncan Hull

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

Biomed Bites, Microbiology, Research, Science, Videos

By investigating cells, researchers can “stumble” on the next big thing in medicine

By investigating cells, researchers can "stumble" on the next big thing in medicine

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

Tobias Meyer, PhD, was hooked on biology when he learned humans are made out of cells — 10 trillion distinct little entities, joining together to make a human. (“The way to remember this number is that it is approximately the same as the number of dollars in the American debt,” Meyer suggests in the video above.) He goes on to say:

What fascinated me is that each of these individual cells is really something like a small computer that senses the environment — for example hormones it senses but also pathogens like bacteria or even stress.

Then it processes that information, which makes it do things like secrete, divide, or move. So my lab is particularly interested in this question of how cells integrate all these important signals.

Now chair of the Department of Chemical and Systems Biology at Stanford, Meyer and his team try to decipher how the cells that make up the human body work together:

For example, we recently found a receptor that senses calcium in cells that has not been found before. We were able to show this is important in many different systems like immunology and now many drugs companies are using it to develop drugs they didn’t have before.

For Meyer, the takeaway from his experience in biomedical research is clear: “By doing fundamental research, we often stumble accidentally on a big thing that can have a big impact later in human health.”

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

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