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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, 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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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

Big data, Emergency Medicine, Genetics, Infectious Disease, Research, Stanford News

Study means an early, accurate, life-saving sepsis diagnosis could be coming soon

Study means an early, accurate, life-saving sepsis diagnosis could be coming soon

image.img.320.highA blood test for quickly and accurately detecting sepsis, a deadly immune-system panic attack set off when our body wildly overreacts to the presence of infectious pathogens, may soon be at hand.

Sepsis is the leading cause of hospital deaths in the United States and is tied to the early deaths of at least 750,000 Americans each year. Usually caused by bacterial rather than viral infections, this intense, dangerous and rapidly progressing whole-body inflammatory syndrome is best treated with antibiotics.

The trouble is, sepsis is exceedingly difficult to distinguish from its non-infectious doppelganger: an outwardly similar but pathogen-free systemic syndrome called sterile inflammation, which can arise in response to traumatic injuries, surgery, blood clots or other noninfectious causes.

In a recent news release, I wrote:

[H]ospital clinicians are pressured to treat anybody showing signs of systemic inflammation with antibiotics. That can encourage bacterial drug resistance and, by killing off harmless bacteria in the gut, lead to colonization by pathogenic bacteria, such as Clostridium difficile.

Not ideal. When a patient has a sterile inflammation, antibiotics not only don’t help but are counterproductive. However, the occasion for my news release was the identification, by Stanford biomedical informatics wizard Purvesh Khatri, PhD, and his colleagues, of a tiny set of genes that act differently under the onslaught of sepsis from they way they behave when a patient is undergoing sterile inflammation instead.

In a study published in Science Translational Medicine, Khatri’s team pulled a needle out of a haystack – activity levels of more than 80 percent of all of a person’s genes change markedly, and in a chaotically fluctuating manner over time, in response to both sepsis and sterile inflammation. To cut through the chaos, the investigators applied some clever analytical logic to a “big data” search of gene-activity results on more than 2,900 blood samples from nearly 1,600 patients in 27 different data sets containing medical information on diverse patient groups: men and women, young and old, some suffering from sterile inflammation and other experiencing sepsis,  and (as a control) healthy people.

The needle that emerged from that 20,000-gene-strong haystack of haywire fluctuations in gene activity consisted of an 11-gene “signature” that, Khatri thinks, could serve up a speedy, sensitive, and specific diagnosis of sepsis in the form of a simple blood test.

The 11-gene blood test still has to be validated by independent researchers, licensed to manufacturers, and approved by the FDA. Let’s hope for smooth sailing. Every hour saved in figuring out a possible sepsis sufferer’s actual condition represents, potentially, thousands of lives saved annually in the United States alone, not to mention billions of dollars in savings to the U.S. health-care system.

Previously: Extracting signal from noise to combat organ rejection and Can battling sepsis in a game improve the odds for material world wins?
Photo by Lightspring/Shutterstock

Chronic Disease, Genetics, Patient Care

Navigating a rare genetic disorder with a positive attitude

Navigating a rare genetic disorder with a positive attitude

We’ve partnered with Inspire, a company that builds and manages online support communities for patients and caregivers, to launch a patient-focused series here on Scope. Once a month, patients affected by serious and often rare diseases share their unique stories; this month’s column comes from Carla Charter.

roam-1024x1024Seven years ago, when my youngest child was diagnosed with chromosome 12q duplication syndrome, I learned that I too had the syndrome. It’s a rare condition caused by the abnormal duplication of the long arm of chromosome 12, leaving three copies rather two.

At that point the 12q was more of a footnote to my hectic life. Syndrome or not, life went on. There was work and the children and hundreds of other things to think about, none of which the 12q really affected.

The syndrome that hadn’t affected my life too much reared its ugly head two years ago while I was driving home one night. In an instant, a highway exit disappeared from view and came back, giving me an extreme “What the heck was that?” moment. Little did I know that this episode was about to usher me into the world of visual impairments. I now have forearm crutches to help me walk. My visual distance impairment changes are frequent, and I have slight hearing loss.

Because I’m an advocate for people with disabilities, some praise me as inspirational. But I am not inspirational. I am human. There are days when I feel frustrated, overwhelmed with the changes in my life, and even a little cranky. It’s OK to admit it, because I’ve got a family who loves me through all of it. If I seem a little quiet or snappy, you may be meeting me on an off day. We all have off days — disability or not.

Those of us with disabilities also have our own way of coping with them. For me, it’s humor. It’s the reason I had a bright pink cane for a time. If I was going to have to deal with using a cane because of the 12q, I was going to find the brightest prettiest cane I could find and rock the heck out of the 12q.

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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

Big data, Ethics, Genetics, Science Policy, Stanford News

Stanford panel: Big issues will loom when everyone has their genomic sequence on a thumb drive

Stanford panel: Big issues will loom when everyone has their genomic sequence on a thumb drive

When I was a biology grad student in the early 1980s, we used to joke about people who were getting their PhDs by spending six long years sequencing a single gene. They worked around the clock seven days a week – and seven nights, too, sleeping on their lab benches when they slept at all.

A few years later the Human Genome Project came along and sped things up quite a bit. But it still took 13 years and a billion dollars to fully sequence a single human genome.

It’s a different story now. With a one-day, $1,000 genome sequence in sight, a 20-minute, $100 sequence can’t be far off. It appears that within 15 years or so, the average individual’s genomic sequence will be just another lengthy, standard supplemental addition to that person’s electronic medical record.

That raises a lot of questions. Last Saturday, I had the great privilege of asking a few of them to a panel of three tier-one Stanford experts: Mildred Cho, PhD, associate director of the Stanford Center for Biomedical Ethics; Hank Greely, JD, director of the Center for Law and the Biosciences, and Mike Snyder, MD, PhD, chair of Stanford’s genetics department and director of the Center for Genomics and Personalized Medicine. (I was the moderator.)

The panel, titled “Genetic Privacy: The Right (Not) to Know,” was a lively one, part of a day-long Alumni Day event sponsored by the Stanford Medical Center Alumni Association. (Here’s a link to the video above). Cho, Greely and Snyder have their own well-developed perspectives and policy preferences on the utility of mass genomic-sequence availability, and they articulated those views with passion and aplomb.

The 300 people in the audience, most of them doctors, had plenty of questions of their own. Several were ones I’d hoped to ask but hadn’t had time.

By the time I walked away from this consciousness-raising clash of perspectives, newly aware of just how fast the future is coming at us, I had another question: Once everyone has the equivalent of a thumb drive with their complete genome on it, can you imagine a kind of online matchmaking service in which you upload your genome to a server, which then picks out a date or a mate for you? The selection is guided by what you say you’re looking for: short-term mutual attraction, an enduring monogamous relationship, robust offspring … Is that now thinkable?

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Autism, Ethics, Genetics, Medicine and Society, Patient Care

Genetic testing, autism, and “fixing” the pathological body

Genetic testing, autism, and "fixing" the pathological body

2678541254_029f25704b_zHow do we know what is pathological, versus what is normal? It seems obvious until you start thinking philosophically, which was the goal of a panel hosted last week by the Science and Justice Working Group at University of California, Santa Cruz. The event was titled “‘Fixing’ the Pathological Body,” a pun on how fixing can mean both repairing and immobilizing.

An anthropologist, a philosopher, and a geneticist discussed how simple, everyday practices like using particular words or certain tests define a line between pathology and normalcy. That line has a huge impact on our experience as humans.

Matthew Wolfmeyer, PhD, professor of anthropology at UCSC, used the term “multibiologism” to indicate that pathology can be seen as a form of human variation. There are three kinds of bodies, he says: those that need no intervention of social, legal, or medical support to enable a livable life, those that do need such intervention (such as a quadriplegic or someone with severe Alzheimer’s), and those that could have such intervention (anyone from hyperactive kids or insomniacs to those with PTSD or arthritis). American society currently divides this spectrum such that the “no intervention” category is becoming empty and the “could have intervention” category is growing by leaps and bounds. Despite what he calls our “cure ideology” from our Judeo-Christian heritage, the pathologies we recognize are increasingly incurable, whether it be gluten sensitivity or chronic cancer, and must be treated with ongoing therapies.

Kelly Ormond, MS, professor of genetics at Stanford, provides genetic counseling and helps people think about these issues every day. She helps expectant parents face the grueling task of deciding what it means to have a baby who might be labeled disabled, pathological, or normal — how would such a child fit into their life, and are they able and willing to accommodate that? Do they even want the information that genetic tests can offer? When counseling parents, Ormond tries to emphasize the lived experience of a condition instead of its medical aspects. Medical information tends to categorize and stir up preconceived notions, but in everyday life the significance of such designations is more fluid, she said.

Janette Dinishak, PhD, professor of philosophy at UCSC, studies autism. She wants to reframe society’s understanding of people with autism such that those without autism are the ones who are limited.

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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

Cancer, Genetics, Patient Care, Research, Science, Stanford News

Identifying relapse in lymphoma patients with circulating tumor DNA

Identifying relapse in lymphoma patients with circulating tumor DNA

3505577004_6fc17ba8c2_zCancer patients in remission often live on a knife’s edge, wondering if their disease will recur. This possibility is more likely in some types of cancers than in others. One of these is diffuse large B-cell lymphoma, which is the most common blood cancer in this country. It’s often successfully treated, but a significant minority of patients will relapse. Detecting these relapses early is critical, but difficult.

Hematologist and oncologists Ash Alizadeh, MD, PhD, and David Kurtz, MD, and former postdoctoral scholar Michael Green, PhD, wanted to find a better way to track disease progression in these patients. They’ve developed a new technique, published Friday in the journal Blood, that is more accurate and can detect relapses earlier than conventional methods.

“As a clinician, I care for many of these patients,” Alizadeh explained to me. “Detecting relapse can be very difficult. It would be a major step forward to develop a way to identify these patients before they become sick again.”

Detecting relapse can be very difficult. It would be a major step forward to develop a way to identify these patients before they become sick again.

The researchers turned to what’s known as circulating tumor DNA in the blood. The approach, which was pioneered by Stanford bioengineer Stephen Quake, PhD, relies on the idea that when the cells in our body die, they rupture and release their contents, including their DNA, into our bloodstream. Tracking the rise and fall of the levels of these tiny snippets of genetic information can give insight into what is happening throughout the body.

When a B cell becomes cancerous, it begins to divide uncontrollably. Each of these cancer cells shares the DNA sequence of the original cell; as the cells multiply, so does the overall amount of that DNA sequence in the body. Alizadeh and his colleagues wondered whether tracking the levels of cancer-specific DNA in a patient’s blood could help them identify those patients in the early stages of relapse.

Currently patients in remission are monitored for relapse with regular physical exams and blood tests. Imaging techniques such as PET or CT scans can be used to look for residual disease, but they don’t detect every case, and often deliver false positive results. They are also costly and expose the patient to DNA-damaging radiation that could potentially cause secondary cancers years later.

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