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Biomed Bites, Cancer, Genetics, Microbiology, Research, Videos

Packed and ready to go: The link between DNA folding and disease

Packed and ready to go: The link between DNA folding and disease

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

In cells, DNA doesn’t make a lovely, languid helix as popularly depicted. It’s scrunched up, bound with proteins that smoosh one meter of DNA into just one micrometer, a millionth of its size. DNA wound around proteins form a particle called a nucleosome.

Yahli Lorch, PhD, associate professor of structural biology, has studied nucleosomes since they were first discovered more than 20 years ago, as she mentions in the video above:

When I began working on the nucleosome, it was a largely neglected area since most people considered it just a packaging and nothing beyond that.

Since I discovered that it has a role and a very important role in the regulation of gene expression, the field has grown many fold and it’s one of the largest areas in biology now.

Many diseases have been linked to the packaging of DNA, including neurodegenerative diseases, autoimmune diseases and several types of cancer such as some pancreatic cancers. Enhancing the understanding of the basic biology of DNA folding is leading to new and improved treatments for these conditions, Lorch says.

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

Previously: DNA origami: How our genomes fold, DNA architecture fascinates Stanford researcher — and dictates biological outcomes and More than shiny: Stanford’s new sculpture by Alyson Shotz

Big data, BigDataMed15, Events, Medicine and Society, Research, Technology

On the move: Big Data in Biomedicine goes mobile with discussion on mHealth

On the move: Big Data in Biomedicine goes mobile with discussion on mHealth

17910585102_33293fefe7_zIda Sim, MD, PhD, would like to prescribe data as easily as she orders a blood test or a prescription for antibiotics. Sim, a professor of medicine at the University of California-San Francisco, told attendees of a Big Data in Biomedicine panel on mHealth yesterday afternoon that she doesn’t want access to data collected willy-nilly, with little regard for the patient’s health condition or needs.

Instead, she wants to tailor data collection to the individual patient. For example, there’s no need to collect activity data for a competitive marathoner, but it would be useful for a sedentary computer programmer.

And she doesn’t care how patients collect their data; they can “bring their own device,” Sim, who also co-directs of biomedical informatics at the UCSF Clinical and Translational Sciences Institute, said.

The design of those devices is integral to the quality of the data developed, pointed out panelist Ram Fish, vice president of digital health at Samsung. He said his team starts with “small data,” making sure devices such as their Simband watch accurately records biomarkers such as blood pressure or heart rate in a single individual, before expanding it to the population level.

He said he’s most keen on developing tools that make a real difference in health, such as the detection of abnormal heart rhythms, a project still in the works.

And speaking of new tools, Stanford’s Euan Ashley, MD, PhD, associate professor of medicine and of genetics, shared some early results from the cardiovascular app MyHeart Counts, which Stanford introduced in March to great acclaim.

Ashley reported that the study has yielded information about the link between sleep patterns and happiness (those who go to bed late and get up late are less happy than others) and about geographic patterns of produce consumption (South Dakota users out-eat Californians when it comes to fruits and veggies). The project’s team is just starting to delve into some of its other findings, which include correlations between the 6-minute timed walk and overall health.

“We’re in a really new era and one we don’t really understand,” Ashley said.

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Big data, BigDataMed15, Events, Genetics, Research, Technology

Big Data in Biomedicine panelists: Genomics’ future is bright, thanks to data-science tools

Big Data in Biomedicine panelists: Genomics' future is bright, thanks to data-science tools

Jill HagenkordStanford’s annual Big Data in Biomedicine began this morning with a “breathtaking set of talks,” as described by Russ Altman, MD, PhD, a Stanford professor of bioengineering, genetics and of medicine.

The first panel focused on genomics, with the speakers presenting a dizzying forecast of a future where biomedical data is standardized and easily accessible to researchers, yet carefully guarded to protect privacy.

“How do we build this in a way that allows you to spend time working on your science, and not spend your time to worry about reinventing the plumbing?,” asked David Glazer, director of engineering at Google and a speaker on the panel.

His team is hard at work ensuring the infrastructure of the Google Cloud Platform can withstand the rigorous demands of a slew of big data projects, including the Million Veteran Program and MSSNG, an effort to understand the genetics of autism.

For panelist Heidi Rehm, PhD, associate professor of pathology at Harvard Medical School and director of the Partners Laboratory for Molecular Medicine, a key hurdle is standardizing definitions and ensuring that supporting evidence is available for system users. For example, data developers should be able to demonstrate why a particular gene variant has been deemed benign, and what definition of “benign” they are using, she said.

Her team has developed a star system, which rates sources of data by their credibility, giving results submitted by expert panels more stars than data submitted by a single researcher.

Rehm also addressed the pros and cons of various models to share data. Rather than collecting it all centrally, she said she expects data will be shared through a small number of hubs, which each have the ability to connect with each other, similar to an airline trafficking model.

Individuals are not standing in the way of research advances, reported panelist Jill Hagenkord, MD, chief medical officer of the personal genetics company 23andMe. She said that of their 950,000 customers, nearly 80 percent have agreed to share their data for research. Participants are also eager to provide additional information when asked, Hagenkord said. It becomes almost a philanthropic effort, they feel grateful that someone is interested in their conditions, she said.

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Medical Education, Research, SMS Unplugged

Research in medical school: The need to align incentives with value (part 2)

Research in medical school: The need to align incentives with value (part 2)

SMS (“Stanford Medical School”) Unplugged is a forum for students to chronicle their experiences in medical school. The student-penned entries appear on Scope once a week; the entire blog series can be found in the SMS Unplugged category.

This is the second post in a three-part series on research in medical school. Part one is available here, and a third post will run on June 24.

5713991403_99bbdea4e1_zIn my last post, I discussed points brought up by Ezekiel Emanuel, MD, PhD, and John Ioannidis, MD, about research in medicine. The takeaway was that students are strongly incentivized to do research during their training, but those incentives don’t necessarily reward high-quality work. Furthermore, they don’t directly contribute to clinical skills and becoming an effective practitioner. As a result, students may be spending time and effort on projects that fail to maximize value for both themselves and for the medical system at large.

This inefficiency has several consequences. At the individual level, it means students spend more time in training (arguably 30-40 percent more), accrue more debt, and lack the opportunity to pursue other interests. At a societal level, it may contribute to the growing physician shortage and potentially limits the productivity of highly talented and well educated people.

The stakes are high when it comes to designing a system of medical education. After my last post, I spoke to several other medical students about the subject, and many of them felt that research requirements don’t align with their eventual goals. This got me thinking about how we can improve things, but before proposing any solutions, it’s important to understand the mentality that led to the status quo. So in this post, I want to delve deeper into why there are such strong incentives for research in medical training.

In reading and thinking more about the subject, I’ve identified four reasons. The most commonly cited one is that research is a means to a pedagogical end. It’s a way to teach students how to think critically about a problem, analyze available solutions, test those approaches, and then synthesize the resulting information. It’s the scientific method at work, and doctors have to use that method every day.

While true, this alone doesn’t justify medical training’s emphasis on research. It’s possible to develop those same skills through many intellectual pursuits, whether it’s working on a policy platform, developing a health education and outreach program, or even working in a corporate job, among other possibilities.

The second reason is that medical schools are typically part of a research university. As the name implies, one of their primary purposes is to do research – institutional prestige relies heavily on academic output. As members of this community, medical students are expected to participate.

But once again, this line of thinking doesn’t entirely explain why medical training should prioritize research to such a great extent. Consider two other professional schools at a university – business and law. Most students in these programs go on to become practitioners (just like most medical students go on to become practicing physicians). Students have the opportunity to conduct research, but the emphasis is on pursuing extracurricular activities relevant to their career plans.

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Big data, BigDataMed15, Events, Public Health, Research

Big Data in Biomedicine conference kicks off today

Big Data in Biomedicine conference kicks off today

14243103692_67ec6354f0_zThe third annual Big Data in Biomedicine conference kicks off today on the Stanford campus. The three-day event brings together thought leaders from academia, information technology companies, venture capital firms and public health institutions to explore opportunities for extracting knowledge from the rapidly growing reservoirs of health and medical information to transform how we diagnose, treat and prevent disease.

The year’s program will cover the intersection of disciplines as widespread as genomics, population health, neuroimaging and immunology; it will also touch on crowdsourcing, ethical and legal issues and “learning” health systems. Delivering the opening keynote will be Sharon Terry, president and CEO of Genetic Alliance. Other keynote speakers include Kathy Hudson, PhD, deputy director for science, outreach and policy at the National Institutes of Health; France Córdova, PhD, director of the National Science Foundation; Michael Levitt, PhD, professor of structural biology at Stanford and recipient of the 2013 Nobel Prize in Chemistry; and Lloyd Minor, MD, dean of Stanford’s School of Medicine.

Those unable to attend in person can tune in to the live webcast via the conference website. We’ll also be live tweeting the keynote talks and other proceedings from the conference; you can follow the coverage on the @StanfordMed feed or by using the hashtag #bigdatamed.

Previously: Countdown to Big Data in Biomedicine: Leveraging big data technology to advance genomics, Countdown to Big Data in Biomedicine: Mining medical records to identify patterns in public health and Harnessing mobile health technologies to transform human health
Photo from the 2014 Big Data in Biomedicine conference by Saul Bromberger

Big data, Genetics, Research, Technology, Videos

“An extremely interesting time to be a geneticist”: Using big data to identify rare diseases

"An extremely interesting time to be a geneticist": Using big data to identify rare diseases

With cheaper, faster genetic sequencing, researchers are able to pinpoint rare gene variants that may be contributing to disease.

But to find “the actual, causal rare variant contributing to the trait is like looking for a needle in a haystack,” says Stephen Montgomery, PhD, in the video above.

Montgomery and his team have plans to boost the efficacy of using genome sequencing to identify rare diseases by incorporating all of the information from genes that are actually turned on — using RNA in addition to its parent DNA to make that needle really stand out.

Eventually, Montgomery hopes to mix in even more information including details about individual lifestyles, environmental exposures and family histories to glean further insights into the origins of rare disease. His team received a 2014 Big Data for Human Health Seed Grant to support the work.

“We’re going to be able to answer very quickly questions about how the genome is influencing our lives and then we’re also going to be able to treat (these conditions),” Montgomery says. “This is an extremely interesting time to be a geneticist and these large data sets are just empowering a large number of discoveries.”

This effort is part of Stanford Medicine’s Biomedical Data Science Initiative (BDSI), which strives to make powerful transformations in human health and scientific discovery by fostering innovative collaborations among medical researchers, computer scientists, statisticians and physicians. Work being done in this area is the focus of Stanford’s Big Data in Biomedicine conference, which kicks off tomorrow morning.

Previously: Collecting buried biomedical treasure – using big data, All data – big and small – informs large-scale neuroscience project, Registration for Big Data in Biomedicine conference now open, Parent details practical ways to get care and support for your child’s rare disease, New search engine designed to help physicians and the public in diagnosing rare diseases and Big data used to help identify patients at risk of deadly high-cholesterol disorder

Autoimmune Disease, Bioengineering, Immunology, Research, Stanford News

Adult humans harbor lots of risky autoreactive immune cells, study finds

Adult humans harbor lots of risky autoreactive immune cells, study finds

dangerIf a new study published in Immunity is on the mark, the question immunologists may start asking themselves will be not “Why do some people get autoimmune disease?” but “Why doesn’t everybody get it?”

The study, by pioneering Stanford immunologist Mark Davis, PhD, and colleagues, found that vast numbers of self-reactive immune cells remain in circulation well into adulthood, upending a long-established consensus among immunologist that these self-reactive immune cells are weeded out early in life in an organ called the thymus.

A particular type of immune cell, called “killer T cells,” is particularly adept at attacking cells showing signs of harboring viruses or of becoming cancerous. As I wrote in my news release about Davis’s study:

[The human immune system generates] a formidable repertoire of such cells, collectively capable of recognizing and distinguishing between a vast array of different antigens – the biochemical bits that mark pathogens or cancerous cells (as well as healthy cells) for immune detection. For this reason, pathogenic invaders and cancerous cells seldom get away with their nefarious plans.

Trouble is, I wrote:

[This repertoire includes] not only immune cells that can become appropriately aroused by any of the billions of different antigens characteristic of pathogens or tumors, but also immune cells whose activation could be triggered by myriad antigens in the body’s healthy tissues. This does happen on occasion, giving rise to autoimmune disease. But it happens among few enough people and, mostly, late enough in life that it seems obvious that something is keeping it from happening to the rest of us from day one.

It’s been previously thought that the human body solves this problem by eliminating all the self-reactive T cells during our early years via a mysterious select-and-delete operation performed in a mysterious gland called the thymus that’s nestled between your heart and your breastbone. Sometime in or near your early teens, the thymus mysteriously begins to shrink, eventually withering and largely turning to useless fat. (Is that mysterious enough for you? It sure creeps me out.)

But Davis and his team used some sophisticated technology – some of it originally invented by Davis, some of it by Stanford bioengineering professor and fellow study co-author Stephen Quake, PhD – to show that, contrary to prevailing dogma, tons of self-reactive killer T-cells remain in circulation well into adulthood. Then the scientists proceeded to explore possible reasons why the immune system keeps these risky cells around (it boils down to: just in case a pathogen from Mars comes along and we need to throw the kitchen sink at it) and why (at least most of the time) they leave our healthy tissues alone: A still-to-be-fully-elucidated set of molecular mechanisms keeps these self-reactive cells locked in the biochemical equivalent of parking gear, shifting out of which requires unambiguous signs of an actual pathogen’s presence: bits of debris from a bacterial cell wall, or stretches of characteristically viral DNA.

That’s our immune system, folks. Complicated, mysterious, and yet somehow incredibly efficient. You really don’t want to leave home – or even the womb – without it.

Previously: In human defenses against disease, environment beats heredity, study of twins shows, Knight in lab: In days of yore, postdoc armed with quaint research tools found immunology’s Holy Grail, In men, a high testosterone count can mean a low immune response and Deja vu: Adults’ immune systems “remember” microscopic monsters they’ve never seen before
Photo by Frederic Bisson

Pediatrics, Research, Stanford News, Stem Cells

Near approval: A stem cell gene therapy developed by Stanford researcher

Near approval: A stem cell gene therapy developed by Stanford researcher

It has been a momentous month for Stanford researcher Maria Grazia Roncarolo, MD. Following decades of research in Roncarolo’s lab and the clinic, pharmaceutical company Glaxo SmithKline has applied for final approval by European Medicines Agency (EMA) of a treatment she developed to cure a deadly childhood immune disorder. If approved by the EMA, which is Europe’s equivalent of the U.S. Food and Drug Administration (FDA), the treatment would be the first gene stem cell therapy to be granted approval by a major medical regulatory agency.

The therapy cures a disease called severe combined immune deficiency (SCID), sometimes called the “bubble boy disease,” by inserting a gene into blood stem cells and transplanting the stem cells into the patient’s body. The treatment is still being evaluated by the FDA.

My greatest satisfaction is that kids who were once incurable now have options

If approved, the treatment will no longer be considered an experimental therapy in Europe, and “people will be able to get this treatment as they would any other, and will be able to get their insurance company to pay for it,” Roncarolo told me. The final regulatory review marks the beginning of a new era in which genetically modified stem cells might be used to treat or cure a wide variety of human diseases, she also noted.

Roncarolo developed the treatment while she was scientific director at the San Raffaele Scientific Institute in Milan, Italy. There, she treated kids who were born with an inability to make the enzyme adenosine deaminase (ADA), which leaves them unable to make certain immune cells that protect them from infection. For that reason, children with ADA-SCID are forced to spend their lives in a sterile environment that protects them from infections that most people would easily fight off but are deadly for them.

Roncarolo and her team inserted the gene for ADA into blood stem cells which were transplanted into 18 children with the disease. Once the modified blood stem cells could produce the enzyme, they were able to form the necessary immune cells and the children were able to leave their sterile environment. “Those children have been effectively cured,” Roncarolo said.

Other gene therapies have been developed before, but those therapies modified more mature cells that cannot reproduce themselves. Only stem cells can both make more copies of themselves and also produce more specialized cells. If gene therapy is used to modify cells that are not stem cells, the treatment will only last as long as the cells last. Eventually, mature cells age and die, and the disorder returns.

Last year, Roncarolo was recruited to Stanford to continue her work while serving as co-director of the Institute for Stem Cell Biology and Regenerative Medicine. She is busy researching cures for other congenital immune disorders and developing methods that could lead to stem cell treatments for a wide variety of other diseases.

“My greatest satisfaction is that kids who were once incurable now have options,” Roncarolo said.

Previously: Countdown to Childx: Stanford expert highlights future of stem cell and gene therapies

Patient Care, Pediatrics, Research, Stanford News, Technology

A new tool for tracking harm in hospitalized children

A new tool for tracking harm in hospitalized children

Medical-chartsIn the 15 years since the Institute of Medicine issued its groundbreaking report showing frequent harm caused by medical care, researchers have worked to devise efficient, reliable ways to detect harm to patients. Finding out what aspects of care most often hurt patients is a key step in reducing these harms, but voluntary reports, in which caregivers are asked to document harm they cause, only identify a small percentage of total harms.

New research published today in Pediatrics describes a better approach for tracking harm to kids in hospitals. Using the system on 600 medical charts from six U.S. children’s hospitals, the researchers found that almost 25 percent of patients included in the chart review had experienced at least one harm, and that 45 percent of these harms were probably preventable. The approach, called a “trigger tool,” was based on a similar harm-tracking method designed for hospitalized adult patients. Researchers look at each medical chart for “triggers” – events or lab measurements often associated with harm – and when they find a trigger, explore the medical chart in detail around the time of the trigger to see if harm occurred.

“This tool will allow us to better understand the epidemiology of harm in hospitalized children, as well as give us the capacity to track harms over time to determine if our interventions are making an improvement,” said senior study author Paul Sharek, MD, an associate professor of pediatrics and chief clinical patient safety officer at Lucile Packard Children’s Hospital Stanford and Stanford Children’s Health. He collaborated with scientists from several other institutions on the research.

I talked with Sharek last week about the study’s findings and implications. To start, I asked him to give me an example that would help me understand the difference between preventable and non-preventable harm. A child who receives a medication that provokes an allergic reaction has experienced a non-preventable harm if it’s the first time the child ever got the drug, and there were no clues beforehand that she had the allergy, he told me. But if the drug allergy was already known and the patient got the drug anyway and had an allergic reaction, that is a preventable harm.

The high rate of preventable harms shows that there is a lot of room to make all hospitals safer for kids, Sharek said. One surprise in the data was that nine common healthcare-acquired conditions that have been targeted by national safety efforts – including central line-associated bloodstream infections, ventilator-associated pneumonia and surgical site infections – together accounted for only 4 percent of all harms identified in this study. “If we were able to eliminate every one of these, according to these data, we’d still be left with 96 percent of the harms we identified,” Sharek said.

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Cancer, Neuroscience, Pediatrics, Research, Stanford News, Videos

How one family’s generosity helped advance research on the deadliest childhood brain tumor

How one family’s generosity helped advance research on the deadliest childhood brain tumor

Back in February 2014, Libby and Tony Kranz found themselves at the center of every parent’s worst nightmare. Their six-year-old daughter Jennifer died just four months after being diagnosed with diffused intrinsic pontine glioma (DIPG), an incurable and fatal brain tumor. At the time, the Kranzes decided to generously donate their daughter’s brain to research in hopes that scientists could hopefully develop more effective treatments for DIPG, which affects 200-400 school-aged children in the United States annually and has a five-year survival rate of less than 1 percent.

As reported in the above Bay Area Proud segment, Michelle Monje, MD, PhD, an assistant professor of neurology and neurological sciences who sees patients at Lucile Packard Children’s Hospital Stanford, and colleagues harvested Jennifer’s tumor and successfully created a line of DIPG stem cells, one of only 16 in existence in the world. More from the story:

Using Jennifer’s stem cell lines and others, Monje and her team tested dozens of existing chemotherapy drugs to see if any were effective against DIPG. One appears to be working.

The drug was able to slow the growth of a DIPG tumor in a laboratory setting. Monje’s hope is that this treatment one day could extend the life of children diagnosed with DIPG by as many as six months.

That would have more than doubled Jennifer’s life expectancy.

“It’s a step in the right direction if we can effectively prolong life and prolong quality of life,” Monje said.

Libby Kranz says that for their family, donating their daughter’s tumor to researchers “just felt right.” She and Tony hope that by aiding the research efforts, parents and families will have more, and better quality time with their sick children.

“It’s incredible and it’s humbling,” she said, “to know my daughter is part of it, and that we’re part of it too.”

Previously: Existing drug shows early promise against deadly childhood brain tumor, Stanford brain tumor research featured on “Bay Area Proud,Emmy nod for film about Stanford brain tumor research – and the little boy who made it possible and Finding hope for rare pediatric brain tumor

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