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Research, Science, Stanford News, Stem Cells

Bridging the stem-cell gap: Stanford researchers identify unique transition state

Bridging the stem-cell gap: Stanford researchers identify unique transition state

474026463_87cca6b272_zIn 2006, Shinya Yamanaka, MD, PhD, turned the stem-cell world upside down when he showed it was possible to take mature, specialized cells such as those found in skin and convert them to a pluripotent state simply by exposing them to a few key proteins. The discovery earned Yamanaka the Nobel Prize in Physiology or Medicine in 2012 and sparked an explosion of stem-cell science.

Although the exact steps of the reprogramming process are unknown, scientists have thought it proceeded mostly as a two-step pathway that essentially rewinds the march to specialization that normally occurs during development. Now Marius Wernig, MD, and his colleagues at the Stanford Institute for Stem Cell Biology and Regenerative Medicine have uncovered an intermediary state through which the cells must pass to successfully acquire pluripotency (a term that describes a cell’s ability to become nearly any cell type in the body). The researchers published their findings in today’s  Nature.

As Wernig described in my article on the research:

This [finding] was completely unexpected. It’s always been assumed that reprogramming is simply a matter of pushing mature cells backward along the developmental pathway. These cells would undergo two major changes: they’d turn off genes corresponding to their original identity, and begin to express pluripotency genes. Now we know there’s an intermediary state we’d never imagined before.

Cells in this “bridge” state express cell surface markers that are distinct from those found on fibroblasts (the starting cell type) and on successfully reprogrammed iPS cells. They also express specific transcription factors that likely contribute to the cells’ progression through the reprogramming process.

The researchers believe it may be possible to increase the efficiency of reprogramming in cells that typically resist the process (these cell types include highly specialized cells or cancer cells). But they’re more excited about peeking into the inner workings of a transformation that’s been both revolutionary and mysterious.

“We’re learning more and more about how cells accomplish this really unbelievable task of reverting to pluripotency,” Wernig told me. “Now we know that the cell biology of this process is novel, and this intermediary state is unique.”

Previously: Congratulations to Marius Wernig, named Outstanding Young Investigator by stem cell society, The end of iPS? Stanford scientists directly convert mouse skin cells to neural precursors and Human neurons from skin cells without pluripotency?
Photo by Alexis R

Emergency Medicine, Health Costs, In the News, Research, Stanford News

Thinking twice before doing blood transfusions improves outcomes, reduces costs

Thinking twice before doing blood transfusions improves outcomes, reduces costs

7413610060_317879301e_zStanford Hospital has figured out that doing fewer blood transfusions saves lives – and millions of dollars annually. In two studies headed by Stanford’s Lawrence Goodnough, MD, professor of pathology and hematology, doctors were gently nudged by a computer program to think twice before performing a blood transfusion. The impressive results were discussed in a Nature news feature published Tuesday:

The number of red-blood-cell transfusions dropped by 24% between 2009 and 2013, representing an annual savings of $1.6 million in purchasing costs alone. And as transfusion rates fell, so did mortality, average length of stay and the number patients who needed to be readmitted within 30 days of a transfusion. By simply asking doctors to think twice about transfusions, the hospital had not only reduced costs, but also improved patient outcomes.

Transfusions are common procedures in industrialized countries, but scientists are finding that they’re overused. More research needs to be done to determine when, exactly, transfusions cross the line between helpful and harmful. They do save lives, but probably only for the most critically ill patients.

Decades of established practice and protocol are hard to change, though. Clinicians acting in the moment refer to their experience, not to guidelines. That’s one reason Stanford’s simple computer innovation is so important. Goodnough, quoted in Nature, speculates about why it succeeded: Not only did alerts remind doctors about the guidelines and provide links to the relevant literature, they forced them to slow down and think instead of running with the default. The alerts may have provided an opening for more individualized discussion among caregivers:

‘Maybe the intern, who was ordering the blood because they were told to, goes back to the team and says, “I have to give a reason”, and then they discuss it,’ Goodnough says. The clinicians might decide to order the blood anyway, of course. Or they might stop, consider the evidence, and come to agree with what Goodnough believes is its clear message. ‘The safest blood transfusion,’ he says, ‘is the one not given.’

Check out the article for more on the history of blood transfusions, other research into their optimal use, and new practices being pioneered around the world.

Previously: Fewer transfusions means better patient outcomes, lower mortality, Stanford Hospital trims use of blood supplies, Stanford test a landmark in the blood banking industry and Should the US create a national blood transfusion reporting system?
Related: Against the flow: What’s behind the decline in blood transfusions?
Photo by Banc de Sang i Teixits

Aging, Global Health, Medical Education, Patient Care, SMS Unplugged

After the rain: Experiencing illness as a medical student and granddaughter

After the rain: Experiencing illness as a medical student and granddaughter

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.

rainy groundIn India, when the first heavy droplets of rain meet dry earth it releases a particular kind of smell: a dampness arising from sizzling soil that in Bengal we call shnoda gondho. It is raining on the second day we go to visit my grandfather in the hospital.

He has been readmitted to the hospital, after spending a week recovering at home from a hospitalization for rib fractures and bleeding into his lungs. The irony of his hospitalization is not lost on his family: that a renowned doctor, one of the first cancer surgeons in the city of Kolkata and one who spearheaded oncological care in this region, is now gowned and sitting in a hospital bed. This happens frequently, of course, for doctors are not immune to being patients, even if we would like to think so. The problem is that we are little prepared for the unstructured, unscripted nature of experiencing illness rather than treating it.

Certainly for my grandfather, a man who even recently traveled to multiple hospitals each day to supervise surgeries and see patients in clinic, being confined to bed for respiratory treatments and being unable to walk without support feels equivalent to being bound up, tied down, and chained to the hospital. This is the way illness imprisons. For his family, used to seeking his wise medical advice on various things from pesky coughs to unremitting cancers, we are unprepared to now help make decisions for him.

We never stop being medical students, and later we never stop being doctors, whether in relationships with family members, friends, acquaintances, or strangers in emergency situations

Perhaps this reflection is too personal for a forum created for sharing medical school experiences. But I suppose my realization is that medical school is not a place but rather a privilege we hold. We never stop being medical students, and later we never stop being doctors, whether in relationships with family members, friends, acquaintances while traveling, or strangers in emergency situations.

But, as I spend these three weeks with my grandfather and my family in Kolkata, I find that it is important to play both roles: that of medical student, the one who can help translate the staccato of medical jargon into fluid lines, and that of loved one, the one who listens not via an earpiece through the taut drum of a stethoscope but through bare ears and naked eyes, the one who listens for and is moved by the cries of pain, or suffering, or confusion, or desperation, of the ones they love.

In many ways the loved one is the harder role to play, for it is the role with no lines. No chest x-rays to evaluate in the morning. No medications to re-dose for a rising creatinine. No growing charts of oxygen saturation, or heart rate, or urine output. As someone who has recently grown used to doing these things on the medicine wards of Stanford Hospital, I now acculturate to a more improvisational kind of care. Placing a soothing hand on an aching back. Sitting at someone’s bedside while he nods in and out of sleep. Holding down an arm so that it doesn’t tremble like the string on a harp. In Indian hospitals, the family must often arrange to bring the medications that the doctors have prescribed and may often visit the hospital multiple times a day to bring food. We mix rice with soft, curried vegetables or boiled eggs and offer them to our loved ones, hoping to find through these labors some connection, some solace.

As family members we grasp for metaphors. In India, these metaphors of illness are often built around ideas of hot or cold, of water or wind. Perhaps that is why I find it so poignant that it rained today, the dense, gray clouds releasing their water just as the water from the pleural effusion in my dadu’s lungs was drained.

I hope that one day soon, when this rain had cleared, my grandfather will write his own words as he has planned to do. And then he can tell you his story, not I.

Amrapali Maitra is a fifth-year MD/PhD student working towards a PhD in Anthropology. She is interested in the illness experience, the cultural and social basis of health, and practices of care.   Amrapali grew up in New Zealand and Texas, and she studied history and literature as an undergraduate at Harvard. She is a 2013 Paul and Daisy Soros Fellow.  

Photo by Jason Devaun

Grand Roundup

Grand Roundup: Top posts of March

Grand Roundup: Top posts of March

The five most-read stories this month on Scope were:

Stanford neurosurgeon/cancer patient Paul Kalanithi: “I can’t go on. I will go on.”: Paul Kalanithi, MD, who wrote eloquently and movingly about being diagnosed with lung cancer, died of the disease earlier this month. In a 1:2:1 podcast recorded last November, the 37-year-old first-time father reflected on his struggle with mortality, his changing perception of time and the meaning he continued to experience despite his illness.

For this doctor couple, the Super Bowl was about way more than football: Paul Kalanithi and his wife, Lucy, won a trip to the Super Bowl by raising money for lung-cancer research and winning the Lung Cancer Survivors Super Bowl Challenge, sponsored by the Chris Draft Family Foundation.

Patients with “invisible illnesses” speak out about challenges in their communities and workplaces: This post links to a recent NPR story during which Carly Medosch, a former ePatient scholar at Stanford’s Medicine X, speaks about discrimination in the workplace for those whose health challenges are not immediately obvious.

It’s Match Day: Good luck, medical students!: Small envelopes containing big news were handed out to medical students at Stanford, and those at 155 medical schools across the country, on March 20. A story on the day’s happenings can also be found here.

Stanford neurosurgeon Paul Kalanithi, who touched countless lives with his writing, dies at 37: This post shares the obituary of Paul Kalanithi, who died on March 9.

Our most-shared story of the month: Stanford neurosurgeon/cancer patient Paul Kalanithi: “I can’t go on. I will go on.”

And still going strong – the most popular post from the past:

Stop skipping dessert:” A Stanford neurosurgeon and cancer patient discusses facing terminal illness: In this 2014 Q&A, Paul Kalanithi talked about his experience with cancer and about the importance of end-of-life decisions.

Cardiovascular Medicine, Patient Care, Pediatrics, Stanford News, Surgery

Complex procedure helps teen with rare congenital heart defect

Complex procedure helps teen with rare congenital heart defect

broken heartPeople don’t usually associate teenagers with heart problems, but congenital heart defects are more common than you might think.

A recent Healthier, Happy Lives Blog post tells the story of Ray Santa Cruz, a high-school senior from Salinas, Calif. who began to suffer from a mysterious and severe chest pain when he exerted himself. It had gotten so bad he had trouble breathing and sleeping.

It turns out that Cruz had an anomalous aortic origin of a coronary artery, meaning that his arteries didn’t attach in the right places. Until very recently, most people with this condition went undiagnosed until a post-heart-attack autopsy. Even with a more timely diagnosis, many surgeons would try to operate in the same way they would on a 70-year old, which is “absolutely the wrong thing to do,” according to Frank Hanley, MD, the surgeon who ultimately fixed Cruz’s heart. A standard bypass operation is “what you do for Grandpa” but not young patients like Cruz.

Stanford physicians developed surgical techniques to fix the defect fifteen years ago, and since then, Lucile Packard Children’s Hospital has treated about 90 young patients, more than any other institution. Cruz had a very specific variation of the condition, for which neither of the standard procedures would have worked; Hanley tried something entirely new, and so far the complex procedure has been a success.

Check out the story to read more.

Previously: Baby with rare heart defect saved by innovative surgery, A nurse puts heart into her work at Adult Congenital Heart Program, Patient is “living to live instead of living to survive,” thanks to heart repair surgery and Should high school and college athletes be routinely screened for heart conditions?
Photo by Nicolas Raymond

Aging, Chronic Disease, Events, Health Policy, Neuroscience, Public Health, Women's Health

Alzheimer’s forum with Rep. Jackie Speier spurs conversation, activism

Alzheimer's forum with Rep. Jackie Speier spurs conversation, activism

10776927963_3dd8d244da_zWhat happens when you bring together a woman with Alzheimer’s, a congresswoman, a policy expert and two doctors? No, this isn’t a joke – but an intro to an informative and wide-ranging discussion on Alzheimer’s disease and its effects on women.

“I was pretty ignorant until fairly recently,” said Rep. Jackie Speier (D-CA), who organized the forum Alzheimer’s: A women’s health issue held in San Mateo, Calif. yesterday. She also penned an opinion piece published recently in the San Francisco Chronicle. “I had no idea that two out of three people diagnosed with Alzheimer’s are women.”

Although it’s the fifth leading cause of death in California, Alzheimer’s receives much less federal money than many other major diseases, she said.

To spur conversation and provide information, Speier invited Cynthia Ortiz Guzman, a former nurse who suffers from Alzheimer’s; Ruth Gay, director of public policy and advocacy for the Alzheimer’s Association; Elizabeth Landsverk, MD, medical director of ElderConsult, and Stanford’s Michael Greicius, MD, MPH, an associate professor of neurology and neurology and medical director of the Stanford Center for Memory Disorders. Greicius has done research on women’s risk of the disease.

Nearly all of the 150-plus people who attended the forum had a loved one who suffered from Alzheimer’s. “We still have a good life, but there is so much that needs to be done,” Guzman told them.

Greicius and Landsverk fielded questions about how to diagnose and treat Alzheimer’s as well as promising directions of research.

At Stanford, Greicius said a person with memory impairment would meet with a neurologist, take a several hour neuropsychological exam, have bloods tests and a brain scan, and meet with social workers and nurses. He emphasized that this is far above the level of care available in more community medical centers. Sometimes physicians are able to find biomarkers that signal Alzheimer’s presence more than a decade before symptoms appear he said.

Greicius urged attendees to find out if they’re eligible for a neurological research trial at Stanford and to consider donating their brains and the brains of their loved ones to use for research. He also thanked Speier for focusing attention on Alzheimer’s.

“We’ve got to get the attention of policymakers to address this issue,” Speier said, adding that she might try to secure federal funds as part of the defense budget.

Gay, who recently traveled to Washington, D.C. to advocate for the disease, agreed. “We know that today we need a game changer – we need people to step forward and speak out about this disease,” she said.

Previously: Science Friday explores women’s heightened risk for Alzheimer’s, The state of Alzheimer’s research: A conversation with Stanford neurologist Michael Greicius and The toll of Alzheimer’s on caretakers 
Photo by Marjan Lazarevski

Science, Stanford News

Using ants to teach high-schoolers about science

Using ants to teach high-schoolers about science

ants

Now this is fun: Stanford biologist Deborah M. Gordon, PhD, has developed a “citizen science” lesson plan that gets high-school students to study ants. Yes, ants. Gordon, who studies group behavior and is also a member of the Stanford Neurosciences Institute, sent hundreds of the picnic pests to the orbiting International Space Station last year, and this collaborative work is a continuation of that research.

From a Stanford News piece:

The lesson plan guides students as they investigate new collective search algorithms in species of ants that haven’t been studied – and there are more than 14,000 species to learn about. Ants may not encounter microgravity on Earth, but they search in every other kind of environment. The results might offer suggestions on how to program robots for rescue and exploration. Collective search algorithms are used to program rescue robots to search efficiently. When robots search dangerous territory for humans, it may be most effective, and cheapest, to mimic ants and not require the robots to report back to a central controller.

“Deborah Gordon is a scientist who wants to reach out to classroom teachers who are preparing our future scientists and citizens,” [Tammy Moriarty, PhD, a professional development associate at Stanford’s Center to Support Excellence in Teaching] says. The lesson plan engages students with a scientific inquiry that does not have a predictable answer. As a result, the students are actually doing science, including collecting and observing wild ants and looking for patterns in their behavior.

Students will use technology, such as cell phone photography or video, to record ant behavior and see how ants go about searching a new area thoroughly. Using affordable and commonly available materials, the students will build an enclosure that allows them to observe ant behavior as the ants explore a new area. Then they will measure the ants’ movements, to see how the ants coordinate their search and how well they cover the area. When student researchers record their results in an online database, the data will be available to other students and scientists.

It’s true that the work of these young scientists is unlikely to have direct applications to human health. But anything that interests kids in the science, technology, engineering and math (STEM) subjects, as this lesson plan does, is a good thing in my book – and could potentially steer them towards a career in medicine or biomedical research.

Previously: Internships expose local high-schoolers to STEM careers and academic life, Free DIY microscope kits to citizen scientists with inspiring project ideas and Fruit flies headed to the International Space Station to study the effects of weightlessness on the heart
Photo by Troup Dresser

Cancer, In the News

“Cancer will always be in our midst:” A conversation with physician-writer Siddhartha Mukherjee

"Cancer will always be in our midst:" A conversation with physician-writer Siddhartha Mukherjee

MukherjeeTonight PBS television airs its new documentary Cancer: The Emperor of All Maladies. The six-hour feature (shown over three nights) is an in-depth look at the past, present and future of cancer, told primarily through the eyes of those dedicated to understanding and treating it.

The video preview promises the kind of data-rich and intensely dramatic storytelling we expect from acclaimed filmmaker Ken Burns, especially when he describes his acute awareness in early childhood that “something was desperately wrong with my mother.” That something was cancer, and his mother died before Burns was 12 years old.

As its title implies, the film is based on the Pulitzer Prize-winning work The Emperor of All Maladies: A Biography of Cancer by Siddhartha Mukherjee, MD, PhD. Now an assistant professor of oncology at Columbia, Mukherjee earned his undergraduate degree from Stanford, and last year he returned for a guest lecture. During his visit he sat for an interview with the Stanford Cancer Institute. Here is an excerpt:

What motivated you to pursue medicine?

I became interested in natural biology while here at Stanford. I took my first biology class as an undergraduate and became fascinated by the natural world. Over time I began to understand that medicine is actually applied biology, in that there is a direct connection between understanding human physiology and translating that understanding to people who are ill.

Why cancer?

I started as a cell biologist working on immunology and virology, then become interested in viral cancers and ultimately human cancers. In a way, I sort of backed into medicine by becoming interested in human biology and virology research first, and then decided to pursue clinical medicine as well.

It seems the more we learn about cancer, the more complicated it becomes…

Just because something turns out to be more complex that we initially thought does not mean that we cannot simplify it. The complexity allows us to evaluate what the reality is, and our interventions depend on us teasing out which part of the complexity are relevant and which parts are not. Complexity is just a description of the physiology of cancer, and interventions can follow from that. We should not be daunted by the fact that cancer is complex, and scientists aren’t, because the complexity makes our understanding deeper and more real.

In fact, there is an argument that cancer’s complexity may be its weakness. The fact that cancer cells have to create such interconnected networks of behavior just to sustain growth may make cancer more vulnerable to disruptions in those networks. Just because a chain is longer does not necessarily make it stronger, and cancer’s chain may have profoundly weak links. We just have to continue to work to find what they are and how to exploit them.

You’ve written cancer’s biography; will its obituary ever be written?

Cancer will always be in our midst for one simple scientific reason: the very genes that allow us to grow and adapt, when mutated, lead to cancer. And these are not incidental genes – we are not talking about the periphery of human physiology – we are talking about the genes that function as the centerpieces of normal cellular growth and development.

So, I think cancer will always be with us, but we will continue to evolve our interaction with the different forms of cancer in the future. We will learn to prevent some forms, learn to treat some and learn to cure some. We will turn some cancers into chronic conditions. And this sort of cat and mouse game with cancer will go on for a long time. This will be a reiterative contest that we will have to play over and over again. And I believe that as soon as we declare victory over cancer, then that will be the beginning of our defeat.

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Chronic Disease, In the News, Patient Care, Public Health

Physicians advocate for “more educated and deliberative decision making” about dialysis

Physicians advocate for "more educated and deliberative decision making" about dialysis

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More than 20 million Americans, one in 10 adults, have some form of chronic kidney disease. For those suffering from chronic kidney disease or end-stage renal disease, dialysis is a commonly recommended treatment. But a story published today in the New York Times reports that for older patients the treatment is increasingly being seen as an choice, not an imperative, and “a growing number of nephrologists and researchers are pushing for more educated and deliberative decision making when seniors contemplate dialysis.”

Paula Span writes:

Unquestionably, dialysis has helped save lives. The mortality rate for patients with chronic kidney disease decreased 42 percent from 1995 to 2012, according to the most recent report from the United States Renal Data System.

The picture for older patients, in particular, is less rosy. About 40 percent of patients over age 75 with end-stage renal disease, or advanced kidney failure, die within a year, and only 19 percent survive beyond four years, the renal data system has reported.

In a Canadian survey, 61 percent of patients said they regretted starting dialysis, a decision they attributed to physicians’ and families’ wishes more than their own. In an Australian study, 105 patients approaching end-stage kidney disease said they would willingly forgo seven months of life expectancy to reduce their number of dialysis visits. They would swap 15 months for greater freedom to travel.

In real-world hospitals and nephrologists’ offices, of course, patients aren’t offered such trade-offs. “People drift into these decisions because they’re presented as the only recourse,” said Dr. V. J. Periyakoil, a geriatrician and palliative care physician at Stanford University School of Medicine.

The moving video above, which was produced by Periyakoil, tells the story of one older man’s decision to stop dialysis after 12 years. (“It takes a lot out of you – it’s a long drawn-process,” Christopher Whitney explained in the piece. “If I would get a kidney now, it would be a waste… I’m not the person I used to be.”) About the difficult decision-making process that faces patients like Whitney, Periyakoil said in an email this morning:

Persons with kidney failure often struggle with making decisions related to dialysis. These decisions impact not only the patient but also their family members. For some, these decisions have ethical and moral implications as well. You may have questions like “Should I start dialysis right away or can I wait? Is it okay to refuse dialysis? I have been on dialysis and feel tired all the time and have poor quality of life – is it okay to stop dialysis? If I stop dialysis how long will live?”

Periyakoil urges patients to “think about what your life goals are as well as what matters most to you at life’s end. Be sure to discuss these important issues with your doctor so you can make your wishes known and make decisions that are right for you and your family.”

Previously: How best to treat dialysis patients with heart disease, Keeping kidney failure patients out of the hospital, Study shows higher Medicaid coverage leads to lower kidney failure rates and Benefits of dialysis for frail elderly debated

In the News, NIH, Parenting, Pediatrics, Pregnancy, Research

Maternal interaction helps pre-term infants grow, study shows

Maternal interaction helps pre-term infants grow, study shows

new mom with baby

It’s not surprising that interaction with their mothers is helpful to babies who are born prematurely – but new research spotlights some of the specific benefits. Featured in an NIH press release today, a study of a method called H-HOPE (Hospital to Home: Optimizing the Premature Infant’s Environment) found that it correlated with a marked improvement in infant weight gain, length growth, and muscular ability to feed from a bottle.

The H-HOPE program has two parts: First, it teaches mothers to use a multi-sensory intervention that features auditory, tactile, visual, and vestibular stimulation (an “ATVV intervention”), and then it trains mothers to recognize their infants’ subtle communication cues, which are much more discreet than those of term infants. Instead of crying and putting their hand in their mouth to indicate hunger, for example, pre-term babies may weakly lift their hand towards their mouth. The fifteen-minute ATVV intervention, which was administered twice daily before feedings, started with a soft female voice, followed by a gentle massage, eye-to-eye contact, and then rocking-in-arms.

The initial study, published in the Journal of Perinatology, was headed by Rosemary C. White-Traut, PhD, RN, professor emeritus in the department of Women, Children and Family Health Science at the University of Illinois at Chicago College of Nursing. The 183 babies in the study were born between 29 and 34 weeks gestation, and their mothers were involved in the H-HOPE program from the time the baby reached 31 weeks until one month after the approximate date the baby would have been born had the pregnancy reached term. The mothers each received visits from a nurse-community health advocate to make sure the procedures were going smoothly, twice in the hospital and twice after discharge.

Each of the participants had at least two social-environmental risk factors, and half of them were Hispanic, a group with a high rate of prematurity. As White-Traut commented in the release, “When we planned our research, we thought that preterm infants from impoverished backgrounds likely would benefit the most from this intervention. Poverty is linked to poorer long-term health and infant development. And as with other negative health influences, preterm infants usually are affected more strongly than term infants.”

White-Traut’s study showed improved weight gain and growth in the babies; a follow up study (to be published in Advances in Neonatal Care) showed that infants also had better muscular ability to suck from a bottle just after receiving the ATVV intervention, via a sensor placed on the bottle’s nipple while they ate.

Continue Reading »

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