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Bioengineering, Research, Stanford News, Technology

Proteins from pond scum revolutionize neuroscience

Proteins from pond scum revolutionize neuroscience

pond scum smallI wrote a story recently about a cool technique called optogenetics, developed by bioengineering professor Karl Deisseroth, MD, PhD. He won the Keio Prize in Medicine, and I thought it might be interesting to talk with some other neuroscientists at Stanford to get their take on the importance of the technology. You know something is truly groundbreaking when each and every person you interview uses the word “revolutionary” to describe it.

Optogenetics is a technique that allows scientists to use light to turn particular nerves on or off. In the process, they’re learning new things about how the brain works and about diseases and mental health conditions like Parkinson’s disease, addiction and depression.

In describing the award, the Keio Prize committee wrote:

By making optogenetics a reality and leading this new field, Dr. Deisseroth has made enormous contributions towards the fundamental understanding of brain functions in health and disease.

One of the things I found most interesting when writing the story came from a piece Deisseroth wrote several years ago in Scientific American in which he stressed the importance of basic research. Optogenetics would not have been a reality without discoveries made in the lowly algae that makes up pond scum.

“The more directed and targeted research becomes, the more likely we are to slow our progress, and the more certain it is that the distant and untraveled realms, where truly disruptive ideas can arise, will be utterly cut off from our common scientific journey,” Deisseroth wrote.

Deisseroth told me that we need to be funding basic, curiosity-driven research along with efforts to make those discoveries relevant. He said that kind of translation is part of the value of  programs like Stanford Bio-X – an interdisciplinary institute founded in 1998 – which puts diverse faculty members side by side to enable that translation from basic science to medical discovery.

Previously: They said “Yes”: The attitude that defines Stanford Bio-X, New York Times profiles Stanford’s Karl Deisseroth and his work in optogenetics, An in-depth look at the career of Stanford’s Karl Deisseroth, “a major name in science”, Lightning strikes twice: Optogenetics pioneer Karl Deisseroth’s newest technique renders tissues transparent, yet structurally intact, The “rock star” work of Stanford’s Karl Deisseroth and Nature Methods names optogenetics its “Method of the Year
Photo by Tim Elliott, Shutterstock photos

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

Emergency Medicine, Health Policy, In the News, Patient Care, Research, Stanford News

Exploring how the Affordable Care Act has affected number of young adults visiting the ER

Exploring how the Affordable Care Act has affected number of young adults visiting the ER

ER sign - 560

One of the earliest – and most popular – parts of the Affordable Care Act allowed young adults to stay on their parents insurance until their 26th birthday. This week, Stanford researchers led by Tina Hernandez-Boussard, PhD, published a paper in the journal Health Affairs that tracked emergency room visits in California, New York and Florida for two age groups: 19 to 25 year olds – the group affected by the new requirement -  and 26 to 31 year olds for comparison. The researchers examined ER visits for the two years prior to the ACA requirement (2009 and 2010) and one year after the requirement went into effect (2011). Their findings showed that in 2011, 19- to 25-year-olds had slightly fewer ER visits – 2.7 per 1,000 people -compared to the older group.

The researchers calculated that the drop in ER use means more than 60,000 fewer visits for 19- to 26-year-olds across the three states  in 2011. They also found that the  largest relative decreases in ER use were among women and blacks.

post on Washington Post‘s Wonkblog covered the study and discussed further findings:

The researchers had another finding that seems just as important. While the total number of ER visits among the under-26 group was down, about the same number of people still went to the ER. The distinction here is that young adults with chronic conditions, who have greater care needs, probably now had better access to non-ER care settings, so their number of visits to the ER decreased. But the finding also suggests that healthy young adults, who might have shunned health insurance before, still continued to see the ER as a place for seeking out routine care, according to the study. Further, insurance likely makes those ER visits cheaper, which could actually increase how much people use the ER, the researchers wrote.

Hernandez-Boussard and her colleagues concluded in their paper, “As EDs face capacity challenges, it is important to consider how to meet the broad underlying needs of young adults through other channels and ensure the needed availability of these alternative health services.”

Previously: Abraham Verghese on health-law battle: “We’ve worried so much about the process, not the patient”
Photo by Eric Staszczak/KOMU

Mental Health, Research, Stanford News

Study shows benefits of breathing meditation among veterans with PTSD

Study shows benefits of breathing meditation among veterans with PTSD

man meditating - smallEarlier this year, Emma Seppala, PhD, associate director of Stanford’s Center for Compassion and Altruism Research and Education and a research psychologist at the the medical school, wrote on Scope about her work using breathing meditation to help veterans with PTSD. One of her studies, involving 21 male veterans of the Afghanistan and Iraq wars who were taught a set of breathing techniques from the Sudarshan Kriya Yoga practice, has now been published.

A recent Stanford Report article provides more details on the research, which found that the breathing techniques “resulted in reduced PTSD symptoms, anxiety and respiration rate” among study participants. The piece also highlights Seppala’s surprise that the meditation appeared to have a lasting effect:

“It is unusual to find the benefits of a very short intervention – one-week, 21 hours total – lasting one year later,” she said. One year after the study, the participants’ PTSD scores still remained low, suggesting that there had been long-lasting improvement.

When the scientists asked the veterans whether they had continued practicing at home, a few had but most had not. The data showed that whether or not they had practiced at home, it did not hinder meditation’s long-term benefits.

One reason, Seppala suggested, is that Sudarshan Kriya yoga retrained the veterans’ memories.

Before the breathing meditation training, participants reported re-experiencing traumatic memories frequently and intensely, Seppala said. Afterward, they reported that the traumatic memories no longer affected them as strongly or frequently.

The study appears in the in the Journal of Traumatic Stress.

Previously: The remarkable impact of yoga breathing for trauma, The promise of yoga-based treatments to help veterans with PTSD, Using mindfulness therapies to treat veterans’ PTSD, As soldiers return home, demand for psychologists with military experience grows, Stanford and other medical schools to increase training and research for PTSD, combat injuries and Can training soldiers to meditate combat PTSD?
Photo by Sebastien Wiertz

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

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

Applied Biotechnology, Cancer, Genetics, Pediatrics, Research

Gene-sequencing rare tumors – and what it means for cancer research and treatment

Gene-sequencing rare tumors - and what it means for cancer research and treatment

Sequencing the genes of cancer patients’ tumors has the potential to surmount frustrating problems for those who work with rare cancers. Doctors who see patients with rare tumors are often unsure of which treatments will work. And, with few patients available, researchers are unable to assemble enough subjects to compare different therapies in gold-standard randomized clinical trials. But thanks to gene sequencing, that is about to change.

Though this specific research was not intended to shape the child’s treatment, similar sequencing could soon help doctors decide how to treat rare cancers in real time

That’s the take-away from a fascinating conversation about the implications of personalized tumor-gene sequencing that I had recently with two Stanford cancer experts. Cancer researcher Julien Sage, PhD, is the senior author of a recent scientific paper describing sequencing of a pediatric tumor that affects only one in every 5 million people. Alejandro Sweet-Cordero, MD, an oncologist who treats children with cancer at Lucile Packard Children’s Hospital Stanford, is leading one of Stanford’s several efforts to develop an efficient system for sequencing individual patients’ tumors.

In their paper, Sage’s team (led by medical student Lei Xu) analyzed the DNA and RNA of one child’s unusual liver tumor, a fibrolamellar hepatocellular carcinoma. The cause of this form of cancer has never been found. Curious about what genes drove the tumor’s proliferation, the scientists identified two genes that were likely culprits, both of which promoted cancer in petri dishes of cultured cells. One of the genes, encoding the enzyme protein kinase A, is a possible target for future cancer therapies.

Though this specific research was not intended to shape the child’s treatment, similar sequencing could soon help doctors decide how to treat rare cancers in real time. Sweet-Cordero is working to develop an efficient system for getting both the mechanics of sequencing and the labor-intensive analysis of the resulting genetic data completed in a few weeks, instead of the two to three months now required. “We’re trying to use this kind of technology  to really help patients,” Sage said. “If you’re dealing with a disease that may kill the patient very fast, you want to act on it as soon as possible.”

In addition to giving doctors clues about which chemotherapy drugs to try, gene sequencing gives them a new way to study tumors.

“What’s really important is that, instead of categorizing tumors based on how they look under a microscope, we’ll be able to categorize them based on their gene-mutation profile,” Sweet-Cordero said. Rather than setting up clinical trials based on a tumor’s histology, as doctors have done in the past, scientists will group patients for treatment trials on the basis of similar mutations in their tumors. “In my mind, as a clinical oncologist, this is the most transformative aspect of this technology,” he said. This is especially true for patients with rare tumors who might not otherwise benefit from clinical trials at all.

And for childhood cancers, knowing a tumor’s gene mutations could also help doctors avoid giving higher doses of toxic chemotherapy drugs than are truly needed.

“The way we’ve been successful in pediatric oncology is by being extremely aggressive,” Sweet-Cordero said. Oncologists take advantage of children’s natural resilience by giving extremely strong chemotherapy regimens, which beat back cancer but can also have damaging long-term side effects. “We end up over-treating significant groups of patients who could survive with less aggressive therapy,” Sweet-Cordero said. “If we can use genetic information to back off on really toxic therapies, we’ll have fewer pediatric cancer survivors with significant impairments.”

Meanwhile, Stanford cancer researchers are also tackling a related problem: the fact that not all malignant cells within a tumor may have the same genetic mutations, and they may not all be vulnerable to the same cancer drugs. Next month, the Stanford Cancer Institute is sponsoring a scientific symposium on the concept, known as tumor heterogeneity, and how it will affect the future of personalized cancer treatments.

Sage’s research was supported by the Lucile Packard Foundation for Children’s Health, Stanford NIH-NCATS-CTSA UL1 TR001085 and Child Health Research Institute of Stanford University. Sage and Sweet-Cordero are both members of the Stanford Cancer Institute, and the National Cancer Institute-designated Cancer Center.

Previously: Smoking gun or hit-and-run? How oncogenes make good cells go bad, Stanford researchers identify genes that cause disfiguring jaw tumor and Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers

Neuroscience, Research, Stanford News

Brain’s wiring more dynamic than originally thought

Brain's wiring more dynamic than originally thought

brain branches

I write a lot about news developments in which scientists learn new things about the body – how diseases develop or can be treated, how genes and proteins in our bodies make us who we are, how different areas of the brain work together to help us learn, remember and interact with our environment.

Yesterday I wrote a story in which the scientists learned that they have more work to do.

It all started when Joanna Mattis was looking for a PhD project. She had been working  in the lab of bioengineer Karl Deisseroth, MD, PhD, helping to develop optogenetics. At the time, that was an entirely new tool that scientists could use to turn parts of the brain on and off to see what happens. Mattis wanted to use optogenetics to map the wiring of two regions of the brain that were known to work together to help develop a spatial map of the environment. Those two regions are known as the hippocampus and the septum.

Some of the expertise needed to do this project didn’t exist in the Deisseroth lab. Mattis got a fellowship through Stanford Bio-X that specifically allows students to work with multiple mentors  – Mattis added neuroscientist John Huguenard, PhD, – bringing interdisciplinary expertise together to solve problems. In this case, those combined expertise didn’t so much solve a problem as create a new one.

What they found is that nerves in the hippocampus create one reaction in the septum if they fire slowly and a completely different reaction of they fire quickly. It was like learning that the wiring diagram of the brain shifts depending on how the brain sends signals.

Mattis told me, “There’s a lot of excitement about being able to make a map of the brain with the idea that if we could figure out how it is all connected we could understand how it works. It turns out it’s so much more dynamic than that.”

She said that next steps will include learning how widespread this type of wiring is throughout the brain, and understanding how it ties back to learning and memory.

Previously: Optogenetics: Offering new insights into brain disorders
Photo by nednapa/Shutterstock

Health Costs, Research, Women's Health

Menopausal symptoms tied to lost work productivity, higher health-care costs

Menopausal symptoms tied to lost work productivity, higher health-care costs

Previous studies have shown that hormone therapy, a common treatment for menopausal symptoms such as hot flashes, can lead to a higher risk of breast cancer, heart disease, stroke and blood clots in some women. For that reason, many women no longer use the treatment for their symptoms.

Now, a study from Yale School of Medicine researchers has highlighted the economic consequences of this aspect of menopause, with hot flashes being tied to lost productivity at work and to increased health-care costs. Medical News Today reports on the findings (subscription required), which appear in the journal Menopause:

[The research team] used data on health insurance claims to compare over 500,000 women, half with and half without hot flashes. The team calculated the costs of health care and work loss over a 12-month period. Participants were all insured by Fortune 500 companies.

The team found that women who experienced hot flashes had 1.5 million more health care visits than women without hot flashes. Costs for the additional health care was $339,559,458. The cost of work lost was another $27,668,410 during the 12-month study period.”

“Not treating these common symptoms causes many women to drop out of the labor force at a time when their careers are on the upswing,” Philip Sarrel, MD, said in the piece, later adding that there are options for those suffering: “The symptoms can be easily treated in a variety of ways, such as with low-dose hormone patches, non-hormonal medications, and simple environmental adjustments such as cooling the workplace.”

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: Studying the link between post-menopausual hormones, cognition and moodAnxiety, poor sleep, and time can affect accuracy of women’s self-reports of menopause symptoms  and Most physicians not prescribing low-dose hormone therapy 

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