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Addiction, Behavioral Science, Genetics, Neuroscience, Research, Stanford News

Found: a novel assembly line in brain whose product may prevent alcoholism

Found: a novel assembly line in brain whose product may prevent alcoholism

alcohol silhouette

High-functioning binge drinkers can seem charming and stylish. The ultimate case in point: Nick and Nora of the famed Thirties/Forties “Thin Man” film series (you can skip the ad after the first few seconds).

But alcoholism’s terrific toll is better sighted on city streets than in celluloid skyscraper scenarios. At least half of all homeless people suffer from dependence on one or another addictive drug. (My Stanford Medicine article “The Neuroscience of Need” explores the physiology of addiction.) Alcohol, the most commonly abused of them all (not counting nicotine), has proved to be a particularly hard one to shake.

Alcoholism is an immense national and international health problem,” I wrote the other day in a news release explaining an exciting step toward a possible cure:

More than 200 million people globally, including 18 million Americans, suffer from it. Binge drinking [roughly four drinks in a single session for a man, five for a woman] substantially increases the likelihood of developing alcoholism. As many as one in four American adults report having engaged in binge drinking in the past month.

While there are a few approved drugs that induce great discomfort when a person uses them drinks alcohol, reduce its pleasant effects, or alleviate some of its unpleasant ones, there’s as of yet no “magic bullet” medication that eliminates the powerful cravings driving the addictive behavior to begin with.

But a study, just published in Science, by Stanford neuroscientist Jun Ding, PhD, and his associates, may be holding the ticket to such a medication. In the study, Ding’s team identified a previously unknown biochemical assembly line, in a network of nerve cells strongly tied to addiction, that produces a substance whose effect appears to prevent pleasurable activity from becoming addictive. The substance, known as GABA, acts as a brake on downstream nerve-cell transmission.

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Genetics, In the News, Mental Health, Neuroscience, Research, Stanford News

Bright Young Mind: Stanford postdoc featured as a top young scientist

Bright Young Mind: Stanford postdoc featured as a top young scientist
100315_nobels_rajasethupathy_resizedYoung researchers don’t always get the accolades they deserve, so I was delighted to see a recent story that’s bucking this trend. This week Science News released its list of “10 scientists who are making their mark,” and Stanford neuroscientist Priya Rajasethupathy, MD, PhD, a postdoctoral research fellow in the lab of Karl Deisseroth, MD, PhD, was featured among them.

Rajasethupathy was nominated for this honor by another group of outstanding scientists: Science News polled 30 Nobel Prize winners to learn which young researchers are doing work that’s worth watching.

Rajasethupathy’s research on how memories are made and stored caught their eye because she’s found that long-term memories may leave lasting marks on DNA. (Her work “has been called groundbreaking, compelling and beautifully executed,” according to the piece.) By studying sea slugs, she and her colleagues have also identified a tiny molecule that may be involved in memory.

Now Rajasethypathy is expanding on this early work and investigating the neural circuits involved in memory recall. To do this, she’s exploring specific genetic mutations to see if they result in abnormal memory behavior. This work may offer insights into neurological disorders, she explains.

Previously: Exploring the role of prion-like proteins in memory disordersNo long-term cognitive effects seen in younger post-menopausal women on hormone therapy and Individuals’ extraordinary talent to never forget could offer insights into memory
Photo by Connie Lee; courtesy of Pryia Rajasethupathy

Cancer, Genetics, Research, Science, Stanford News

Combination therapy could fight pancreatic cancer, say Stanford researchers

Combination therapy could fight pancreatic cancer, say Stanford researchers

I’ve mentioned here before my personal connection to pancreatic cancer, which claimed the life of my grandmother. So I was excited to hear from Stanford cancer researcher Julien Sage, PhD, about some developments on the research front. Sage and postdoctoral scholar Pawal Mazur, PhD, collaborated with Alexander Herner, MD and Jens Svieke, MD, at the Technical University Munich to conduct the work, which was published today in Nature Medicine.

In our release on the study, which was done in animal models, Sage explained:

Pancreatic cancer is one of the most deadly of all human cancers, and its incidence is increasing. Nearly always the cause of the disease seems to be a mutation in a gene called KRAS, which makes a protein that is essential for many cellular functions. Although this protein, and others that work with it in the Ras pathway, would appear to be a perfect target for therapy, drugs that block their effect often have severe side effects that limit their effectiveness. So we decided to investigate drugs that affect the DNA rather than the proteins.

Mazur and Herner worked together to test whether drugs that affect the epigenetic status of a cancer cell (that is, the dynamic arrangement of chemical tags on the DNA and its associated proteins that control how and when genes are expressed) could rein in its growth without serious side effects. Many of these tags are what’s called acetyl groups, and they are added to protein complexes called histones that keep the DNA tightly wound in the cell’s nucleus. As I explained in our release:

They started by investigating the effect of a small molecule they called JQ1 on the growth of human pancreatic tumor cells in a laboratory dish. JQ1 inhibits a family of proteins responsible for sensing acetyl groups on histones. The researchers found that the cells treated with JQ1 grew more slowly and displayed fewer cancerous traits. The molecule was also able to significantly shrink established pancreatic tumors in mice with the disease. However, it did not significantly affect the animals’ overall likelihood of survival.

Mazur, who began the work in Siveke’s lab and continued it when he moved to Sage’s lab, next tested whether using JQ1 in combination with any other medications could be more effective:

“It happened that the drug that worked best was another epigenetic drug called vorinostat,” said Sage. “On its own, vorinostat didn’t work very well, but when combined with JQ1 it showed a very strong synergistic effect in both the laboratory mice with pancreatic cancer and in pancreatic cancer cells from people with the disease.”

Vorinostat works by inhibiting a family of proteins that remove the acetyl groups from histones. It has been approved by the FDA for use in people with recurrent or difficult-to-treat cutaneous T cell lymphoma. When human pancreatic cancer cells were treated simultaneously with JQ1 and vorinostat, the cells grew more slowly and were more likely to die.

Mice with established pancreatic cancers treated with both of the drugs showed a marked reduction in tumor size and a significant increase in overall survival time. Their tumors showed no signs of developing a resistance to the treatment, and the mice did not develop any noticeable side effects.

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Bioengineering, Cancer, Genetics, Stanford News

Cancer drug produced in common plant

Cancer drug produced in common plant

I knew that many of the drugs we use today were first identified in plants. What I didn’t know was in how many cases those plants are still the only source of the drug because scientists haven’t figured out how to make them in the lab.

If the only source of an effective drug is a plant that is rare, endangered, or hard to grow in the lab, that’s obviously a problem.

Elizabeth Sattely, PhD, a Stanford chemical engineer, recently tackled this problem for a popular cancer drug that comes from a Himalayan plant called the Mayapple. She managed to identify the ten drug-making enzymes in the Mayapple and insert those genes into a much easier-to-grow plant. In a story about the work, which appears today in the journal Science, I wrote:

[It] could lead to new ways of modifying the natural pathways to produce derivative drugs that are safer or more effective than the natural source.

“A big promise of synthetic biology is to be able to engineer pathways that occur in nature, but if we don’t know what the proteins are, then we can’t even start on that endeavor,” said Sattely, who is also a member of the interdisciplinary institutes Stanford Bio-X and Stanford ChEM-H.

Sattely said this is really a first step. Ultimately she’d like to get those same enzymes into yeast, which can produce high volumes of drugs in big laboratory vats.

Video by Amy Adams

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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Genetics, In the News, Pregnancy, Research, Science, Women's Health

Maternal-fetal “chimera” cells: What do they actually do?

Maternal-fetal "chimera" cells: What do they actually do?

1292733380_3e6815a6d1_zAfter a woman is pregnant, fetal cells linger in her body long after her baby is brought out into the world. They cross the placenta and congregate in her thyroid, breasts, brain, scars… and elsewhere. The phenomenon is called “fetal microchimerism,” a reference to the hybrid monster of Greek mythology that strikes me as both whimsical and menacing.

But what do these cells do? An entertaining and informative National Geographic blog post highlights a recent review study published in BioEssays that seeks to answer this question. The evidence we have so far is contradictory and messy, not yielding much in the way of patterns: Sometimes cells collect more in diseased tissues, other times in healthy ones. But when viewed through an evolutionary lens, things start to make sense, argue the paper’s authors. These cells allow a baby to inadvertently influence her mother’s body in her own interest, which is sometimes – but not always – in the mother’s interest, too.

Writer Ed Yong explains:

Some of those changes, like faster healing, benefit the mother too. Others may not. For example, foetal cells could stimulate the breast to make more milk, either by releasing certain chemical signals or by transforming into glandular cells themselves. That’s good for the baby but perhaps not for the mother, given that milk takes a lot of energy to make—mothers literally dissolve their own bodies to create it. And if the foetal cells start dividing too rapidly in the breast, they might increase the risk of cancer.

Similarly, the thyroid gland produces hormones that control body temperature. If foetal cells integrate there and start dividing, they could ramp up a mother’s body heat, to a degree that benefits her baby but also drains valuable energy. And again, if they divide uncontrollably, they might increase the risk of cancer. Indeed, thyroid cancer is one of the only types that’s more common in women than men, but is not a reproductive organ like the ovaries or breasts.

Such influences would have developed gradually over hundreds of millions of years in a subtle evolutionary contest between mother and fetus – it is in the mother’s interest for the fetus to do well, but not to monopolize all her resources, so it’s not unlikely that mothers evolved counter-measures. The paper authors don’t have any conclusions yet, but their point is that within this evolutionary framework, it makes sense that fetal cells both help and harm the mother.

Previous research on microchimerism has only asked about such cells’ presence, not their function. The paper’s authors hope to organize a workshop to test some of the hypotheses they proposed, which means gathering microchimeric fetal cells and sequencing their genes, then working out which of the mother’s genes they are activating and whether these correlate with any traits like milk production or temperature. The possibilities for further research are immense:

And then, there’s the matter of cells that travel in the other direction—from the mother to the foetus. What do they do in their new homes? These paths can get even more complicated. It’s possible that the cells from one foetus can travel into its mother, hide out, and then into a sibling during a later pregnancy. “At one point, we started trying to draw family trees, and trying to work out where all the microchimerc cells could be going,” says [co-author Athena Aktipis, PhD]. “It got really messy.”

Previously: How a child’s cells may affect a mother’s long term health
Related: The yin-yang factor
Photo by Simone Tagliaferri

Cancer, Genetics, Imaging, Precision health, Research, Science, Stanford News

You know it when you see it: A precision health approach to diagnosing brain cancer

You know it when you see it: A precision health approach to diagnosing brain cancer

BurlIf you know which virus has made a person ill, as well as whether your patient responds better to drug A or drug B, you’re in a much better position to treat them. In the world of oncology, it’s often the genetic personality of the tumor itself that determines the best treatment protocol. A tumor with one set of gene variants may be susceptible to only one of several treatments. To decide which drug to prescribe, you’ve got to know your tumor.

In some cancers, such as skin cancer, it’s easy to physically examine the tumor and easy to take a biopsy to root out the tumor’s genetic secrets. But for cancers deep in the brain, a biopsy is problematic. And without knowing more about a brain tumor, it’s harder to guess the right treatment.

Now a team of researchers, led by Stanford’s Haruka Itakura, MD, and Olivier Gevaert, PhD, have distinguished three types of brain tumors. Each type is identifiable by their appearance in MRIs and predictably associated with specific molecular characteristics. Itakura and Gevaert report their work in today’s Science Translational Medicine.

Magnetic resonance imaging revealed three distinct kinds of glioblastoma brain tumors, each of which could be associated with a different probability of patient survival and a unique set of molecular signaling pathways. The work paves the way for more precise diagnosis, better targeted therapies and personalized treatment of GBM brain tumors.

Previously: Brain imaging, and the “image management” cells that make it possibleA century of brain imaging and When it comes to brain imaging, there’s nothing simple about it
Photo by Travis

Genetics, Research, Science, Stanford News

Annoying anemones shed light on coral reef biology

Annoying anemones shed light on coral reef biology

Bleached CoralI stopped by John Pringle’s office last week to hear about what he’s been up to. A lot! As we mentioned here a few months ago, Pringle, PhD, a professor of genetics who spent the first decades of his career studying yeast genetics and cell biology, has switched gears and is looking for ways to help corals — while continuing a lifetime of basic research.

Corals and the incredibly species-rich ecosystems they support are disappearing fast in nearly every part of the world’s oceans. Coral reefs protect coastlines, sustain rich fisheries and support some of the most species-rich habitats in the world. Yet, around the world, a third of all coral has died.

The first sign of stress is a fading, or “bleaching,” of the coral that reflects the loss of photosynthetic algae that live inside the coral. In a quest to understand the molecular underpinnings of bleaching in corals, Pringle and two colleagues at Stanford helped sequence the genome of a small sea anemone that serves as a model for corals. They report their work this week in PNAS.

I asked Pringle what they’d found. But first, he wanted to tell me about his colleagues Christian Voolstra, PhD, Sebastian Baumgarten, and others at the Red Sea Research Center, in Thuwal, Saudi Arabia, where much of the experimental work and analysis took place. Pringle said the center is part of the King Abdullah University of Science and Technology, or KAUST, a six-year-old university with top researchers from around the world and a $20 billion endowment.

Although it’s easy to mistake coral for some kind of weird rock, corals are animals. But lab animals they are not. They grow slowly, in large colonies of tiny individuals, die easily and retreat inside their hard coral quarters when they aren’t happy.

A better option, Pringle learned, was a sea anemone called Aiptasia. Aiptasia is a pest that drives aquarium hobbyists to distraction. It thrives in captivity, takes over aquaria, and is seemingly impossible to eradicate — in short, the perfect lab animal.

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Genetics, Microbiology, Neuroscience, Research, Science, Stanford News

Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Amyotrophic lateral sclerosis, or ALS, is a progressive, fatal neurodegenerative disease made famous by Lou Gehrig, who was diagnosed with the disorder in 1939. Although it can be inherited among families, ALS more often occurs sporadically. Researchers have tried for years to identify genetic mutations associated with the disease, as well as the molecular underpinnings of the loss of functioning neurons that gradually leaves sufferers unable to move, speak or even breathe.

We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions

Now Stanford geneticist Aaron Gitler, PhD, and postdoctoral scholar Ana Jovicic, PhD, have investigated how a recently identified mutation in a gene called C9orf72  may cause neurons to degenerate. In particular, a repeated sequence of six nucleotides in C9orf72 is associated with the development of ALS and another, similar disorder called frontotemporal dementia. They published their results today in Nature Neuroscience.

As Gitler explained in our release:

Healthy people have two to five repeats of this six-nucleotide pattern. But in some people, this region is expanded into hundreds or thousands of copies. This mutation is found in about 40 to 60 percent of ALS inherited within families and in about 10 percent of all ALS cases. This is by far the most common cause of ALS, so everyone has been trying to figure out how this expansion of the repeat contributes to the disease.

Gitler and Jovicic turned to a slightly unusual, but uncommonly useful, model organism to study the effect of this expanded repeat:

Previous research has shown that proteins made from the expanded section of nucleotides are toxic to fruit fly and mammalian cells and trigger neurodegeneration in animal models. However, it’s not been clear why. Gitler and Jovicic used a yeast-based system to understand what happens in these cells. Although yeast are a single-celled organism without nerves, Gitler has shown that, because they share many molecular pathways with more-complex organisms, they can be used to model some aspects of neuronal disease.

Using a variety of yeast-biology techniques, Jovicic was able to identify several genes that modulated the toxicity of the proteins. Many of those are known to be involved in some way in shepherding proteins in and out of a cell’s nucleus. They then created neurons from skin samples from people with and without the expanded repeat. Those with the expanded repeat, they found, often had a protein normally found in the nucleus hanging out instead in the cell’s cytoplasm.

Jovicic and Gitler’s findings are reinforced by those of two other research groups, who will publish their results in Nature tomorrow. Those groups used different model organisms, but came to the same conclusions, suggesting that the researchers may be close to cracking the molecular code for this devastating disease.

As Jovicic told me, “Neurodegenerative diseases are very complicated. They likely occur as a result of a defect or defects in basic biology, which is conserved among many distantly related species. We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions.”

Previously: Stanford researchers provide insights into how human neurons control muscle movement, Researchers pinpoint genetic suspects in ALS and In Stanford/Gladstone study, yeast genetics further ALS research

Genetics, In the News, NIH, Science, Technology

The quest to unravel complex DNA structures gets a boost from new technology and NIH funding

The quest to unravel complex DNA structures gets a boost from new technology and NIH funding

5232013153_7808b471a2_zIf you’ve ever tried folding a map, packing an overnight bag or coiling a string of holiday lights, you know that the way you arrange an object affects how much space it takes up and how easy it is to use in the future. This same principle is true of DNA.

As a recent article in Science News explains, the way a DNA double helix is folded, packed and coiled is known to have a big effect on how much space it requires and how easy it is to access the information stored within. But, until recently, researchers lacked the technology to fully explore these four-dimensional DNA structures.

Now, new technology and last year’s launch of the National Institutes of Health‘s five-year, $120 million, 4D Nucleome project is helping researchers reveal the complex architecture of DNA. William Greenleaf, PhD, assistant professor of genetics at Stanford, discusses the significance of a genome‘s arrangement in the Science News article:

Like the genetic text within it, the genome’s shape holds specific instructions. “The way it’s compacted forms this sort of physical memory of what the cell should be doing,” Greenleaf says.

Loops of DNA that aren’t needed by a particular cell are tucked away from the biological machinery that reads genetic blueprints, leaving only relevant genes accessible to produce proteins. Studies have shown that sections of the genome that are shoved toward the edges of a nucleus are often read less than centrally located DNA. Such specialized arrangements allow cells as diverse as brain cells, skin cells and immune cells to perform different jobs, even though each contains the same genome. “In different cell types, there are very large changes to the regions that are being used,” Greenleaf says.

Much more remains to be understood about how a genome’s shape directs its activity. Future maps might zero in on functionally interesting regions of the genome, Greenleaf says. But he cautions there is also a benefit to unbiased, general exploration. Focusing on one location in the nucleome might lead researchers to miss important structural information elsewhere, he says.

Previously: DNA origami: How our genomes foldPacked and ready to go: The link between DNA folding and disease and DNA architecture fascinates Stanford researcher – and dictates biological outcomes
Photo by: Kate Ter Haar

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