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Autoimmune Disease, Genetics, NIH, Research, Science

Tiny hitchhikers, big health impact: Studying the microbiome to learn about disease

Tiny hitchhikers, big health impact: Studying the microbiome to learn about disease

I don’t know about you, but I’m fascinated with the idea of the “microbiome.” If you’re unfamiliar with the term, it describes the millions upon millions of tiny, non-human hitchhikers that live on and in you (think bacteria, viruses, fungi and other microscopic life). Although the exact composition of these molecular roommates can vary from person to person, they aren’t freeloaders. Many are vitally important to your metabolism and health.

We’ve reported here on the Human Microbiome Project, launched in 2007 and supported by the National Institutes of Health’s Common Fund. Phase 2 of the project started last fall, with grants to three groups around the country to study how the composition of a person’s microbiome might affect the onset of diseases such as type 2 diabetes and inflammatory bowel disease, as well as its role in pregnancy and preterm birth. Now the researchers, which include Stanford geneticist Michael Snyder, PhD, have published an article in Cell Host & Microbe detailing what data will be gathered and how it will be shared.

As explained in a release by the National Human Genome Research Institute:

“We’re producing an incredibly rich array of data for the community from the microbiomes and hosts in these cohorts, so that scientists can evaluate for themselves with these freely available data which properties are the most relevant for understanding the role of the microbiome in the human host,” said Lita M. Proctor, Ph.D., program director of the Human Microbiome Project at NIH’s National Human Genome Research Institute (NHGRI).

“The members of the Consortium can take advantage of each other’s expertise in dealing with some very complex science in these projects,” she said. “We’re generating these data as a community resource and we want to describe this resource in enough detail so people can anticipate the data that will be produced, where they can find it and the analyses that will come out of the Consortium’s efforts.”

As I’ve recently blogged, data-sharing among researchers and groups is particularly important for research efficiency and reproducibility. And I’m excited to hear what the project will discover. More from the release:

For years the number of microbial cells on or in each human was thought to outnumber human cells by 10 to 1. This now seems a huge understatement. Dr. Proctor noted that the 10-to-1 estimate was based only on bacterial cells, but the microbiome also includes viruses, protozoa, fungi and other forms of microscopic life. “So if you really look at the entire microbial community, you’re probably looking at more like a 100-to-1 ratio,” she said.

Although thousands of bacterial species may make their homes with human beings, each individual person is host to only about 1,000 species at a time, according to the findings of the Human Microbiome Project’s first phase in 2012.

In addition, judging from the array of common functions of bacterial genes, if the bacteria are healthy, each individual’s particular suite of species appear to come together to perform roughly the same biological functions as another healthy individual. In fact, researchers found that certain bacterial metabolic pathways were always present in healthy people, and that many of those pathways were often lost or altered in people who were ill.

Stanford’s Snyder will join forces with researchers in the laboratory of George Weinstock, PhD, of the Jackson Laboratory for Genomic Medicine in Connecticut to investigate the effect of the microbiome on  the onset of Type 2 diabetes. Snyder may be uniquely positioned to investigate the causes of the condition. In 2012, he made headlines when he performed the first ever ‘omics’ profile of himself (an analysis that involves whole genome DNA sequencing with repeated measurements of the levels of RNA, proteins and metabolites in a person’s blood over time). During the process, he learned that he was on the cusp of developing type 2 diabetes. He was able to halt the progression of the disease with changes in exercise and diet.

Previously: Stanford team awarded NIH Human Microbiome Project grantElite rugby players may have more diverse gut microbiota, study shows and Could gut bacteria play a role in mental health?

Science, Stanford News, Videos

Science is like an ongoing mystery novel, says Stanford neurobiologist Carla Shatz

Carla Shatz

We all know that Carla Shatz, PhD, director of the interdisciplinary institute Stanford Bio-X, is a pioneering scientist — her work in early brain development and in Alzheimer’s disease has earned her many accolades. Now she’s being featured in a videos series celebrating women pioneers in science.

I want to say first that it always rankles a bit when people are celebrated as being “pioneering women in XXX”. That makes it seem like if they weren’t women they wouldn’t have made the pioneer cut. Carla is a pioneer period. And also a woman. And gave a great interview.

One interesting point she made had to do with what she wished she’d known before starting a career in science. She said, “If you really like science and you like research, that is the joy and the easy part. The hard part is managing the teams and the research itself – the people.”

She went on to talk about the people who influenced her (her dad) and her first scientific experiment (it had to do with Siamese cats, and initially didn’t work).

When it comes to women in science, her answer was straightforward. She said we need talented people working on critical problems, and women are half the population. Without them, there are fewer people working on these important questions. She also said that she worries about the diminished funding for science driving the best minds (male and female) into other fields.

Her answer to what gets her up in the morning should help lure at least a few of those potential best minds into a scientific career, even with weak funding. She said:

Every day when I come to work I am so excited to be here and go to my lab and do experiments and be with my students. It’s part of an ongoing mystery. I can hardly wait to see the next part of the mystery that is going to be solved.

The series is sponsored by Scientista, which supports women in math and science, The Scientist magazine, Lab Manager and Mettler Toledo.

Previously: They said “Yes”: The attitude that defines Stanford Bio-X and Pioneers in science
Photo be Steve Fisch

Biomed Bites, Research, Science, Stanford News, Videos

Studying the drivers of metastasis to combat cancer

Studying the drivers of metastasis to combat cancer

Today we’re launching Biomed Bites, a weekly series created to highlight some of Stanford Medicine’s most compelling research and introduce readers to promising scientists from across the basic and clinical sciences.

One might not think there’s much of a connection between grapes and cancer cells, but Amato Giaccia, PhD, has found some similarities. “The tumor microenvironment is very analogous to the microenvironment you would have in Napa Valley, where different types of grapes grow in different areas depending on the richness of the soil and the different climate and weather that exist,” explains the Stanford radiation oncologist and cancer biologist in the video above. “In a similar matter, tumors require different environments for them to be able to grow and… metastasize.”

Giaccia and his colleagues study the genetic and epigenetic regulators of metastasis, and their work could lead to the development of therapeutics that inhibit or eradicate the process, which contributes to 90 percent of cancer-related deaths. “Understanding the drivers of metastasis and how to best target them is going to have a major impact on cancer survival and mortality in the future,” Giaccia says.

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

Previously: Cellular culprit identified for invasive bladder cancer, according to Stanford study, Potential anti-cancer therapy starves cancer cells of glucose and Nomadic cells may hold clues to cancer’s spread
Photo in featured entry box by Lee Coursey/Flickr

Cardiovascular Medicine, Research, Science, Stanford News

Scientists preferentially cite successful studies, new research shows

Scientists preferentially cite successful studies, new research shows

Say you’re a medical researcher. You slave over a project for months, even years, and you’re thrilled when a stellar journal agrees to publish it. That’s it, right? Well, no. Now, you need others to spot your work – and cite it in their studies. You can court citations just as you court Twitter followers: by producing high-quality content worthy of a bigger audience.

That said, sometimes bias creeps in. For example, studies by superstar scientists are cited more often than those by their junior colleagues — no surprise there. But now, Stanford medical resident Alex Perino, MD; cardiologist Mintu Turakhia, MD, MAS; and colleagues have shown that studies documenting higher success rates of a certain procedure are more likely to be cited than studies of the same procedure with lower success rates.

“This is an indication that we as clinicians and investigators need to be mindful of how we present the data,” Turakhia told me.

In a study released yesterday in Circulation: Cardiovascular Quality and Outcomes, Perino, Turakhia and other colleagues examined research papers on catheter ablation for atrial fibrillation, a treatment with widely varying success rates. For example, among the examined studies, the success of a single treatment varied between 10 and 92 percent. The variation is perfectly understandable, Turakhia said. Atrial fibrillation, an irregular heart rhythm, can be caused by a variety of underlying conditions and can vary in severity, he explained. The procedure itself, which uses energy to destroy tissue in key areas of the left atrium, can also vary, Turakhia said.

That’s why ablation for atrial fibrillation was an apt treatment to examine. The team included 174 studies with 36,289 patients published since 1990. They found that for every 10 point increase in reported success rate, there was an 18 percent increase in the mean citation count. The citation bias remained significant even when accounting for time since publication, the journal’s impact rating, sample size and study design.

The bias is important when considering the efficacy of new and evolving treatments, Turakhia said: “We just wanted to make sure the totality of evidence is being presented fairly and completely to readers of the medical literature, which may be clinicians, scientists, insurance companies and policy makers. However, in this case, we found that ablation could be perceived to be more effective than the totality of evidence would suggest.”

Turakhia said he hopes this study prompts other researchers to examine bias in other treatments and specialties.

Previously: Re-analyses of clinical trial results rare, but necessary, say Stanford researchers, John Ioannidis discusses the popularity of his paper examining the reliability of scientific research, A discussion on the reliability of scientific research, U.S. effect leads to publication of biased research, says Stanford’s John Ioannidis

Clinical Trials, Patient Care, Research, Science, Stanford News

Re-analyses of clinical trial results rare, but necessary, say Stanford researchers

Re-analyses of clinical trial results rare, but necessary, say Stanford researchers

The results of large clinical trials are used to make important clinical decisions. But the raw data on which these results are based are rarely made available to other researchers, perhaps due to concerns about intellectual property or giving a leg up to competitors in the field. But a new study by Stanford’s John Ioannidis, MD, DSci, shows that the re-analysis of such data by independent research is critical: About one third of the time it leads to conclusions that differ from those of the original study.

The research was published today in the Journal of the American Medical Association.

Clearly, data sharing is an important step in making sure research is conducted efficiently and renders reproducible results

For the study, Ioannidis and his co-authors surveyed about three decades of research cataloged in the National Library of Medicine’s PubMed database looking for re-analyses of previously published clinical-trial data. They found fewer than 40 studies that met their criteria (reanalyses using the original data to investigate a new hypothesis, or meta-analyses of several studies were not included) and, as I wrote in a release:

Thirteen of the re-analyses (35 percent of the total) came to conclusions that differed from those of the original trial with regard to who could benefit from the tested medication or intervention: Three concluded that the patient population to treat should be different than the one recommended by the original study; one concluded that fewer patients should be treated; and the remaining nine indicated that more patients should be treated.

The differences between the original trial studies and the re-analyses often occurred because the researchers conducting the re-analyses used different statistical or analytical methods, ways of defining outcomes or ways of handling missing data. Some re-analyses also identified errors in the original trial publication, such as the inclusion of patients who should have been excluded from the study.

Clearly, data sharing is an important step in making sure research is conducted efficiently and renders reproducible results – goals shared by the recently launched Meta-Research Innovation Center at Stanford (or METRICS), which Ioannidis co-directs. More from our release:

The fact that researchers conducting re-analyses often came to different conclusions doesn’t indicate the original studies were necessarily biased or deliberately falsified, Ioannidis added. Instead, it emphasizes the importance of making the original data freely available to other researchers to encourage dialogue and consensus, and to discourage a culture of scientific research that rewards scientists only for novel or unexpected results.

“I am very much in favor of data sharing, and believe there should be incentives for independent researchers to conduct these kinds of re-analyses,” said Ioannidis. “They can be extremely insightful.”

Previously: John Ioannidis discusses the popularity of his paper examining the reliability of scientific research, New Stanford center aims to promote research excellence and “U.S. effect” leads to publication of biased research, says Stanford’s John Ioannidis

Podcasts, Public Safety, Science, Science Policy, Stanford News

The risks of tinkering with dangerous pathogens

The risks of tinkering with dangerous pathogens

In an effort to understand new and rare infectious diseases, researchers often use recombinant DNA technology to create novel strains in the lab. In 2012, researchers did just that, creating strains of the H5N1 influenza virus that were transmissible between mammals, setting off a debate about the ethics of creating viruses that were potentially more dangerous than those that occurred naturally.

Earlier this year, in July, a group called the Cambridge Working Group convened to continue discussing these questions. David Relman, MD, a biosecurity expert at Stanford, is a member of the group and spoke to Paul Costello about the risks and benefits of lab-created pathogens. Highlights of their conversation are in a piece in the most recent issue of Inside Stanford Medicine, where Relman notes:

My greatest fear is that someone will create a highly contagious and highly pathogenic infectious agent that does not currently exist in nature, publish its genetic blueprint, allow it to escape the laboratory by accident, or else enable a malevolent person or persons to synthesize the agent with the intention of releasing it in a deliberate manner. Although these may be unlikely scenarios, they could have catastrophic consequences, which is why I and others feel that we need to sensitize everyone to these possibilities and decide how to manage these risks ahead of time. I want to be clear: I am not opposed to laboratory work on dangerous pathogens, especially if they are known to exist in nature. Rather, I am opposed to high-risk experiments and, in particular, those that seek to create novel, dangerous pathogens that cannot be justified by well-founded expectations of near-term, critical benefits for public health — benefits that clearly outweigh the risks, and benefits that cannot be achieved through other means.

But not all researchers advocate the same level of caution. A few weeks after the Cambridge Working Group formed, another group called Scientists for Science to advocate in favor of using recombinant versions of pathogens in order to understand them better. Relman says that the two groups are probably not as far apart as they appear. He says he fully supports studying disease-causing bacteria, but:

The place where we may disagree is on whether we are willing to acknowledge that there may be experiments — probably few and far between — that perhaps ought not to be undertaken because of an unusual degree of risk. Just because a scientist can think up an experiment doesn’t mean it should be performed.

Relman elaborates on these topics in the 1:2:1 podcast with Costello above.

Previously:  How-to manual for making bioweapons found on captured Islamic State computer, Microbial mushroom cloud: How real is the threat of bioterrorism? (Very) and Stanford bioterrorism expert comments on new review of anthrax case

Cancer, Dermatology, Research, Science, Stanford News

Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers

Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers

sunbathingA link between the UV rays in sunshine and the development of skin cancer is nothing new. We’ve all (hopefully) known about the damage sun exposure can wreak on the DNA of unprotected cells. But it’s not been known exactly how it causes cancers like squamous cell carcinoma or melanoma. Now, Stanford dermatologists Paul Khavari, MD, PhD and Carolyn Lee, MD, PhD have identified a UV-induced mutation in a protein active during cell division as the likely driver in tens of thousands of cases of skin cancer. Although the protein hasn’t been previously associated with cancer, the work of Khavari and Lee suggests it may actually be the most-commonly mutated oncogene in humans.

Their work was published yesterday in Nature Genetics. As we describe in our release:

Lee and Khavari made the discovery while investigating the genetic causes of cutaneous squamous cell carcinoma. They compared the DNA sequences of genes from the tumor cells with those of normal skin and looked for mutations that occurred only in the tumors. They found 336 candidate genes for further study, including some familiar culprits. The top two most commonly mutated genes were CDKN2A and TP53, which were already known to be associated with squamous cell carcinoma.

The third most commonly mutated gene, KNSTRN, was a surprise. It encodes a protein that helps to form the kinetochore — a structure that serves as a kind of handle used to pull pairs of newly replicated chromosomes to either end of the cell during cell division. Sequestering the DNA at either end of the cell allows the cell to split along the middle to form two daughter cells, each with the proper complement of chromosomes.

If the chromosomes don’t separate correctly, the daughter cells will have abnormal amounts of DNA. These cells with extra or missing chromosomes are known as aneuploid, and they are often severely dysfunctional. They tend to misread cellular cues and to behave erratically. Aneuploidy is a critical early step toward the development of many types of cancer.

The mutation in KNSTRN is a type known to be specifically associated with exposure to UV light. Khavari and Lee found the mutation in pre-cancerous skin samples from patients, but not in any samples of normal skin. This suggests the mutation occurs early, and may be the driving force, in the development of skin cancers. As Khavari, chair of the Department of Dermatology and dermatology service chief at the Veterans Affairs Palo Alto Health Care System, explained in the release:

Mutations at this UV hotspot are not found in any of the other cancers we investigated. They occur only in skin cancers… Essentially, one ultraviolet-mediated mutation in this region promotes aneuploidy and subsequent tumorigenesis. It is critical to protect the skin from the sun.

Previously: Master regulator for skin development identified by Stanford researchers and My pet tumor – Stanford researchers grow 3D tumor in lab from normal cells
Photo by Michael Coghlin

Big data, Evolution, Genetics, In the News, Research, Science, Stanford News

Flies, worms and humans – and the modENCODE Project

Flies, worms and humans - and the modENCODE Project

It’s a big day in comparative biology. Researchers around the country, including Stanford geneticist Michael Snyder, PhD, are publishing the results of a massive collaboration meant to suss out the genomic similarities (and differences) among model organisms like the fruit fly and the laboratory roundworm. A package of four papers, which describe how these organisms control how, when and where they express certain genes to generate the cell types necessary for complex life, appears today in Nature.

From our release:

The research is an extension of the ENCODE, or Encyclopedia of DNA Elements, project that was initiated in 2003. As part of the large collaborative project, which was sponsored by the National Human Genome Research Institute, researchers published more than 4 million regulatory elements found within the human genome in 2012. Known as binding sites, these regions of DNA serve as landing pads for proteins and other molecules known as regulatory factors that control when and how genes are used to make proteins.

The new effort, known as modENCODE, brings a similar analysis to key model organisms like the fly and the worm. Snyder is the senior author of two of the papers published today describing some aspects of the modENCODE project, which has led to the publication, or upcoming publication, of more than 20 papers in a variety of journals. The Nature papers, and the modENCODE project, are summarized in a News and Views article in the journal (subscription required to access all papers).

As Snyder said in our release, “We’re trying to understand the basic principles that govern how genes are turned on and off. The worm and the fly have been the premier model organisms in biology for decades, and have provided the foundation for much of what we’ve learned about human biology. If we can learn how the rules of gene expression evolved over time, we can apply that knowledge to better understand human biology and disease.”

The researchers found that, although the broad strokes of gene regulation are shared among species, there are also significant differences. These differences may help explain why humans walk, flies fly and worms slither, for example:

The wealth of data from the modENCODE project will fuel research projects for decades to come, according to Snyder.

“We now have one of the most complete pictures ever generated of the regulatory regions and factors in several genomes,” said Snyder. “This knowledge will be invaluable to researchers in the field.”

Previously: Scientists announce the completion of the ENCODE project, a massive genome encyclopedia

Genetics, Medicine and Society, Pain, Research, Science, Stanford News

From plant to pill: Bioengineers aim to produce opium-based medicines without using poppies

From plant to pill: Bioengineers aim to produce opium-based medicines without using poppies

Basic RGBStanford bioengineer Christina Smolke, PhD, and her team have been on a decade-long mission to replicate how nature produces opium in poppies by genetically engineering the DNA of yeast and then further refining the process to manufacture modern day opioid drugs such as morphine, codeine and the well-known painkiller Vicodin.

Smolke outlined the methods in a report  (subscription required) published in this week’s edition of Nature Chemical Biology, which details the latest stages in the process of manufacturing opium-based medicines, from start to finish, in fermentation vats, similar to the process for brewing beer.

An article published today in the Stanford Report offers more details:

It takes about 17 separate chemical steps to make the opioid compounds used in pills. Some of these steps occur naturally in poppies and the remaining via synthetic chemical processes in factories. Smolke’s team wanted all the steps to happen inside yeast cells within a single vat, including using yeast to carry out chemical processes that poppies never evolved to perform – such as refining opiates like thebaine into more valuable semi-synthetic opioids like oxycodone.

So Smolke programmed her bioengineered yeast to perform these final industrial steps as well. To do this she endowed the yeast with genes from a bacterium that feeds on dead poppy stalks. Since she wanted to produce several different opioids, her team hacked the yeast genome in slightly different ways to produce each of the slightly different opioid formulations, such as oxycodone or hydrocodone.

“We are now very close to replicating the entire opioid production process in a way that eliminates the need to grow poppies, allowing us to reliably manufacture essential medicines while mitigating the potential for diversion to illegal use,” Smolke added.

While it could take several more years to refine these last steps in the lab, bioengineering opioids would eventually lead to less dependence on legal poppy farming, which has numerous restrictions and international dependencies from other countries. It would also provide a reliable supply and secure process for manufacturing important pain killing drugs.

Jen Baxter is a freelance writer and photographer. After spending eight years working for Kaiser Permanente Health plan she took a self-imposed sabbatical to travel around South East Asia and become a blogger. She enjoys writing about nutrition, meditation, and mental health, and finding personal stories that inspire people to take responsibility for their own well-being. Her website and blog can be found at www.jenbaxter.com.

Previously: Blocking addiction risks of morphine without reducing its pain-killing effects, Do opium and opioids increase mortality risk? and Patients’ genetics may play a role in determining side effects of commonly prescribed painkillers 
Photo by Kate Thodey and Stephanie Galanie

Genetics, Humor, Medicine and Society, Science, Stanford News

Using epigenetics to explain how Captain America and the Incredible Hulk gained their superpowers

Using epigenetics to explain how Captain America and the Incredible Hulk gained their superpowers

When I was kid I used to watch the Incredible Hulk on TV and wait for Bruce Banner to fly into a rage, his muscles inflating like balloons, pants torn to shreds while his entire body turns green as he transforms into the Hulk. As I grew up, and learned more about the advances in genetics, it never occurred to me that cutting-edge genome-editing techniques could explain the scientific principles behind the Hulk’s metamorphosis or his fellow Marvel Comics star-spangled hero Captain America. In a recent Stanford Report story,  Sebastian Alvarado, a postdoctoral research fellow in biology, creatively applies the concepts of epigenetics to illuminate the process by which average Joes become superheroes.

As Alvarado notes in the piece and above video,  over the past  70 years scientists have developed tools for selectively activating and deactivating individual genes through chemical reactions, a process termed epigenetics. Similar to flipping on a light, switch gene expression can be “turned on” or “turned off. “We have a lot of genome-editing tools – like zinc finger nucleases, or CRISPR/Cas9 systems – that could theoretically allow you to epigenetically seek out and turn on genes that make your muscles physically large, make you strategically minded, incredibly fast, or increase your stamina,” he said.

In the case of Captain America, the process of deliberately switching on and off genes could offer a real-world explanation as to how scrawny Steve Rodgers gained extraordinary, strength, stamina and intelligence after being injected with “Super Solider Serum” and then blasted with  “Vita-Rays.” When it comes to Bruce Banner, a little more creative license is required. Alvarado’s theory is:

First, when gamma radiation hits DNA, it breaks the molecule’s double-stranded, ladder-like helix, a process known as chromothripsis. Your body can repair a few breaks without significant loss of function.

If many breaks occur – say, if you were caught in a giant gamma explosion – the repairs can become sloppy, and new instructions can be keyed into the genetic code. Alvarado suggested that it’s possible that when Banner’s DNA reassembled after the initial blast, it now included a handful of epigenetic switches. Instead of the switches being activated by light, however, the hormones produced when Banner is angry might flip the genetic switches to reconfigure his DNA to transform him into the big, green Hulk.

As for the Hulk’s skin turning green, anyone who has suffered a nasty bruise has firsthand knowledge of the process that might be behind this transformation. When you bruise, red blood cells at the point of injury die and the oxygen-carrying molecule on their surface, hemoglobin, begins to break up. One of hemoglobin’s metabolites, Alvarado said, is a molecule called biliverdin, which can make the blood appear green and is responsible for the avocado hue at the edge of a bruise.

Giant gamma explosion and epigenetics aside, there’s one question that has scientifically stumped Alvarado: How do the Hulk’s pants stay on after every transformation?

Jen Baxter is a freelance writer and photographer. After spending eight years working for Kaiser Permanente Health plan she took a self-imposed sabbatical to travel around South East Asia and become a blogger. She enjoys writing about nutrition, meditation, and mental health, and finding personal stories that inspire people to take responsibility for their own well-being. Her website and blog can be found at www.jenbaxter.com.

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