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Cancer, Research, Science, Stanford News, Stem Cells

A stem cell “kill switch” may make therapies safer, say Stanford researchers

A stem cell "kill switch" may make therapies safer, say Stanford researchers

3225255407_596aa5bdff_zStem cell biologist Hiromitsu Nakauchi, MD, PhD, and his colleagues published an interesting article today about how to use stem cell technology to boost our body’s own immune cells to fight cancer or chronic viral infections like HIV or Epstein Barr virus. Because there’s a possible cancer risk with the use of induced pluripotent stem cells, or iPS cells, in humans, he and his colleagues have devised an innovative way to specifically eliminate these cells within the body if they start to cause problems. Their research appears today in Stem Cell Reports.

As Nakauchi explained to me in an email:

The discovery of induced pluripotent stem cells created promising new avenues for therapies. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern that must be addressed before iPS cell-based therapies can be routinely used in the clinic.

The researchers studied a type of immune cell called a cytotoxic T cell. These cells recognize specific sequences, or antigens, on the surface of other cells. Some antigens indicate that the cell is infected with a virus; others are found on cells that have become cancerous. When a cytotoxic T cells sees these antigens, it moves in to kill the cell and remove the threat.

In order to ensure that our immune systems recognize the widest variety of antigens, developing T cells randomly shuffle their genes to create unique antigen receptors. Researchers have found that it’s possible to identify, and isolate, T cell populations that specifically recognize cancer cells. By growing those cells in the laboratory, and then injecting them back into a patient, clinicians can give a boost to the immune response that can help kill tumor cells. The technique is known as adoptive immunotherapy, and it’s shown promise in treating melanoma. However, these cytotoxic T cells can become exhausted as they fight the cancer and become less effective over time.

Recently researchers in Nakauchi’s lab showed that it’s possible to create induced pluripotent stem cells from cytotoxic T cells. These iPS cells are then induced to again become cytotoxic T cells. These rejuvenated T cells, or rejT cells, recognize the same antigen they did before their brief dip in the pluripotency pool, but they are far more sprightly than the cells from which they were derived – they can divide many more times and have longer telomeres (an indicator of youthfulness).

So far, so good. But, as Nakauchi mentioned above, iPS cells carry their own set of risks. Because they are by definition pluripotent (they can become any cell in the body), they can easily grow out of control. In fact, one way of proving a cell’s pluripotency is to inject it into an animal and see if it forms a type of tumor called a teratoma, which is made up of multiple cell types.

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Ethics, Events, Medical Education, Medicine and Literature, Stanford News

During their first days at Stanford, medical students ponder the ethical challenges ahead

During their first days at Stanford, medical students ponder the ethical challenges ahead

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In an effort to help prepare this year’s crop of new medical students for the future challenges of keeping true to the spirit of the Hippocratic Oath – to first do no harm ‑ Stanford’s School of Medicine held a new discussion session during orientation.

In between learning about housing and schedules and all the necessary details of starting medical school, the 90 new students who started class on Monday joined with two deans of the school last week to discuss one of the most controversial topics in the world of medicine: euthanasia.

Included among the students’ summer reading assignment was the book Five Days at Memorial, a blow-by-blow account of the days medical staff and patients spent trapped in a New Orleans hospital after Hurricane Katrina struck. Left without electricity or sanitation, staff slept little and worked endlessly to care for the sick and dying patients not knowing if any of the patients – or anyone else trapped at the hospital — would survive. An online story explains why the book was assigned as summer reading:

Most [new students] had not yet faced the responsibilities they will encounter routinely as physicians. It was the ethical and emotional challenges ahead that [Lloyd Minor, MD, dean of the medical school, and Charles Prober, MD, senior associate dean of medical education] hoped to explore during the book discussion. “I think one of the key lessons from this book: If we’re going to make progress in medicine, we’re going to have to face realistically when we make errors,” Minor said. “Progress only occurs when we are able to frankly address those situations and acknowledge those errors.”

The book describes health-care workers treating patients in a way that could arguably violate tenets of the Stanford Affirmation. “You will be reciting this later today after you receive your white coats and stethoscopes,” Prober said. “Hopefully, the affirmation will have more meaning to you. It will help you to reflect more deeply on the words as you ponder it into the future.”

The book describes how medical staff and patients had to fend for themselves in the days following Hurricane Katrina. After the waters receded, and authorities entered the hospital, 41 bodies were found. Three health-care professionals, including one physician, were arrested for murder. A New Orleans grand jury ultimately refused to indict them on charges of involuntary euthanasia and murder, but exactly what happened during those five days, when temperatures soared, sleep was rare and proper sanitation was nonexistent, remains unclear.

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Genetics, Microbiology, Neuroscience, Research, Science, Stanford News

Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Amyotrophic lateral sclerosis, or ALS, is a progressive, fatal neurodegenerative disease made famous by Lou Gehrig, who was diagnosed with the disorder in 1939. Although it can be inherited among families, ALS more often occurs sporadically. Researchers have tried for years to identify genetic mutations associated with the disease, as well as the molecular underpinnings of the loss of functioning neurons that gradually leaves sufferers unable to move, speak or even breathe.

We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions

Now Stanford geneticist Aaron Gitler, PhD, and postdoctoral scholar Ana Jovicic, PhD, have investigated how a recently identified mutation in a gene called C9orf72  may cause neurons to degenerate. In particular, a repeated sequence of six nucleotides in C9orf72 is associated with the development of ALS and another, similar disorder called frontotemporal dementia. They published their results today in Nature Neuroscience.

As Gitler explained in our release:

Healthy people have two to five repeats of this six-nucleotide pattern. But in some people, this region is expanded into hundreds or thousands of copies. This mutation is found in about 40 to 60 percent of ALS inherited within families and in about 10 percent of all ALS cases. This is by far the most common cause of ALS, so everyone has been trying to figure out how this expansion of the repeat contributes to the disease.

Gitler and Jovicic turned to a slightly unusual, but uncommonly useful, model organism to study the effect of this expanded repeat:

Previous research has shown that proteins made from the expanded section of nucleotides are toxic to fruit fly and mammalian cells and trigger neurodegeneration in animal models. However, it’s not been clear why. Gitler and Jovicic used a yeast-based system to understand what happens in these cells. Although yeast are a single-celled organism without nerves, Gitler has shown that, because they share many molecular pathways with more-complex organisms, they can be used to model some aspects of neuronal disease.

Using a variety of yeast-biology techniques, Jovicic was able to identify several genes that modulated the toxicity of the proteins. Many of those are known to be involved in some way in shepherding proteins in and out of a cell’s nucleus. They then created neurons from skin samples from people with and without the expanded repeat. Those with the expanded repeat, they found, often had a protein normally found in the nucleus hanging out instead in the cell’s cytoplasm.

Jovicic and Gitler’s findings are reinforced by those of two other research groups, who will publish their results in Nature tomorrow. Those groups used different model organisms, but came to the same conclusions, suggesting that the researchers may be close to cracking the molecular code for this devastating disease.

As Jovicic told me, “Neurodegenerative diseases are very complicated. They likely occur as a result of a defect or defects in basic biology, which is conserved among many distantly related species. We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions.”

Previously: Stanford researchers provide insights into how human neurons control muscle movement, Researchers pinpoint genetic suspects in ALS and In Stanford/Gladstone study, yeast genetics further ALS research

Aging, Podcasts, Public Health, Research, Stanford News

Stanford doctor on a mission to empower patients to talk about end-of-life issues

Stanford doctor on a mission to empower patients to talk about end-of-life issues

Each year, about 2.6 million people die in America. Although past research has shown that 7 out of 10 of us prefer to die at home, an estimated 70 percent of people die in the hospital, nursing home or long-term care facility. The disconnect between where people die and how they would prefer to spend their final days often happens because loved ones and doctors don’t know their end-of-life wishes. Only 20 to 30 percent of Americans have completed advanced directives.

It’s not easy to talk about death, and the terminology used in advanced directives can be confusing. I remember having to complete the form with my husband shortly before the birth of my first child. Despite having been in a relationship for 12 year, we had never discussed end-of-life issues. Imagining the scenarios that might lead to either of us being in a life-threatening situation was an extremely emotional exercise — especially as we awaited our son’s arrival. Did we want doctors to use every intervention possible to save our life? What if it meant sacrificing our quality of life? Did we want to be on life support? If so, how long?

We eventually turned to a friend, who was also a physician, to help us sort through the process. But we didn’t talk to our own primary care doctors and, to this day, our doctors have never asked us if we have an advance directive or about our end-of-life preferences. And this isn’t unusual. Recent research from VJ Periyakoil, MD, director of Stanford’s Palliative Care Education and Training, shows that most doctors struggle to talk with patients about what’s important to them in their final days, particularly if the patient’s ethnicity is different than their own.

In the latest 1:2:1 podcast, Periyakoil discusses her study findings and why it’s critical for all adults to complete an advance directive and initiate a conversation about their end-of-life wishes with their doctor and family. To get these conversations started and help patients navigate the emotionally-charged process, she launched the Stanford Letter Project, which provides templates in a range of languages asking patients simple questions about how they want to die.

Listen to the full podcast to learn more about the project and hear from Stanford Letter Project users about how they want to spend their final days.

Previously: How would you like to die? Tell your doctor in a letterIn honor of National Healthcare Decisions Day: A reminder for patients to address end-of-life issues, Study: Doctors would choose less aggressive end-of-life care for themselves and On a mission to transform end-of-life care

Medical Education, Stanford News

Stanford Medicine’s white coat and stethoscope ceremony, in pictures

Stanford Medicine’s white coat and stethoscope ceremony, in pictures

Friday was a big day for Stanford’s 90 new medical students, who – as my colleague Tracie White once eloquently put it – took their “symbolic first step on a journey to physicianhood.” The school’s white coat and stethoscope ceremony was held in the afternoon, and photographer Norbert von der Groeben was there to capture some special moments.

Previously: Stanford Medicine’s commencement, in picturesMedical students start “transformational” journey and “Something old and something new” for Stanford medical students

Ask Stanford Med, Health and Fitness, Nutrition, Obesity, Precision health, Stanford News

A Stanford physician takes a precision health approach to living a healthier lifestyle

A Stanford physician takes a precision health approach to living a healthier lifestyle

timthumbNearly 70 percent of Americans ages 20 or older are overweight or obese, including Larry Chu, MD, a Stanford anesthesiologist and executive director of Medicine X.

Chu, who has struggled with his weight for over a decade, knew he was overweight but didn’t think it was a serious threat to his health. This changed during a routine doctor’s visit. As he explains in a podcast, Chu was shocked to learn that lab results showed he was at high risk for stroke and heart attack. He decided to take action and launch precision:me, a personal blog project chronicling the first 90 days of his journey to live a healthier lifestyle.

Why most of us try to slim down by shunning carbs, stepping up our exercise routines and secretly weighing ourselves each morning, Chu is tracking his health data using a range of gadgets and other tools and sharing the every detail of his progress publicly on his blog. He is also posting photos and podcasts.

Below Chu discusses why he choose to take this unique approach to achieve his weight-loss goals, how he hopes it will inform the broader conversation about obesity and its potential to demonstrate the value of digital tools in enhancing personal health.

What was the catalyst for precision:me?

One of the misconceptions about obesity is that it is a lifestyle disease and if people would only eat less and move more they would be fit. In my case, this is a health journey I have been struggling with since my residency training at Stanford. Using precision health tools to address obesity is a new approach that we are focusing on in precision:me. Stanford has recently announced exciting plans for precision health. I thought it was a good time to share how we at Medicine X see precision health as a novel approach that individuals and their providers can use today to tailor precise and individualized care. It is a very practical and personal dive into developing and implementing a precise plan to modify my diet and metabolic profile to forestall the development of more significant chronic diseases, such as diabetes and heart disease, using data and analytics provided through digital health tools and expert medical, nutritional and fitness collaborators.

Why did you decide to make all of your health data available online for public consumption?

It was an easy and difficult decision at the same time. There is incredible stigma associated with obesity, which we discuss on the precision:me website. Being overweight or obese is a subject that many of us find difficult to talk about. Sharing information can make it easier to start a dialogue. Advances in precision health at Stanford and around the world will depend upon patients sharing their personal health data in a secure and protected fashion with researchers. By sharing my data with the public, I hope to help everyone see what it is like to live with obesity as a condition, break down misconceptions and misperceptions about the disease, and help shine a light on the value of sharing data to help others.

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Global Health, Health Policy, Stanford News

E-cigarettes a growing cause for concern in the developing world

E-cigarettes a growing cause for concern in the developing world

11505926173_7be7ca343b_zIt is a common misconception that e-cigarettes are a problem only in wealthy nations, say two Stanford global health researchers in a commentary published today in the Journal of the American Medical Association. In the piece, co-authors Michele Barry, MD, FACP and Andrew Chang, MD, call attention to the widespread availability of e-cigarettes in the developing world and a growing concern over the potential health implications unique to low- and middle-income countries.

Chang, an internal medicine resident in Stanford’s Global Health track planning to specialize in cardiology, has been closely tracking the conversation around global tobacco control, but noticed e-cigarettes have been largely absent from the discussion. With support from Barry, director of the Center for Innovation in Global Health, Chang dug deeper and found that while U.S. health officials and researchers have been grappling with uncertainties around e-cigarette regulation and health impacts, the rise of e-cigarettes has in fact become a global threat.

The authors point to a 2014 survey from the World Health Organization suggesting that already, more than half of the world’s population is living in countries where e-cigarettes – or electronic nicotine delivery systems (ENDS) – are available. Public awareness in many of these countries is high and the devices are cheap.

But in some parts of the world, notably Africa and South Asia, there is little to no data on e-cigarette awareness and usage trends. This is of particular concern, say Barry and Chang, as regions like Africa and South Asia represent vast potential markets and are likely to be hit hardest by the growth of e-cigarettes.

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Microbiology, Pregnancy, Research, Stanford News

Stanford microbiome research offers new clues to the mystery of preterm birth

Stanford microbiome research offers new clues to the mystery of preterm birth

preemie-holdinghandsPremature birth affects 450,000 U.S. babies each year and is the leading cause of newborn deaths. But in about half of cases, doctors never figure out what triggered premature labor in the pregnant mom.

Now, there’s a new clue: A Stanford study, published today, gives important details of how the microbiome – the body’s community of bacteria – behaves in women whose pregnancies go to the full 40-week term, and what’s different in women whose babies come three weeks, or more, early. A specific pattern of vaginal bacteria was linked to greater risk of preterm delivery, and the longer the pattern persisted, the greater the risk, the study found.

The work is one piece of a larger effort by the March of Dimes Prematurity Research Center at Stanford to bring experts from many branches of science together to work on preterm birth. The researchers collected weekly bacterial samples throughout pregnancy from four body sites for 49 pregnant women, of whom 15 delivered prematurely. Patterns of vaginal bacteria that were dominated by lactobacillus bacteria were linked to low prematurity risk. Such patterns had already been shown to be linked to health in non-pregnant women.

A pattern of high bacterial diversity, low lactobacillus and high levels of gardnerella and ureaplasma bacteria was linked to higher prematurity risk, the study also showed. This was especially true if the high-diversity pattern persisted for several weeks. From our press release about the new research:

“I think our data suggest that if the microbiome plays a role in premature birth, it may be something that is long in the making,” said the study’s lead author, Daniel DiGiulio, MD, a research associate and clinical instructor in medicine. “It may be that an event in the first trimester or early second trimester, or even prior to pregnancy, starts the clock ticking.”

The researchers also followed the women’s bacterial communities for up to a year after their deliveries and found that all new mothers shifted to the high-risk pattern, regardless of if their babies were born early or on time or if they had a c-section or vaginal delivery. This finding may help explain why women with closely-spaced pregnancies are more likely to have a preterm baby the second time around, however more work is needed to better understand this discovery, concluded researchers.

Ultimately, the research team hopes to use their findings to develop interventions that could prevent preterm birth. That would definitely be good news for moms and babies.

Previously: Counseling parents of the earliest-born preemies: A mom and two physicians talk about the challenges, Stanford/VA study finds link between PTSD and premature birth and Maternal obesity linked to earliest premature births, says Stanford study
Photo by bradleyolin

Medicine and Literature, Stanford News

Charlotte Jacobs on finding “snippets during every day” to balance careers in medicine and literature

Charlotte Jacobs on finding "snippets during every day" to balance careers in medicine and literature

Stanford oncologist Charlotte Jacobs, MD, loved reading biographies as a child. But it wasn’t until years later, while on sabbatical at Stanford, that she decided to take a creative writing course and begin cultivating a second career as a biographer.

Her first biography, Henry Kaplan and the Story of Hodgkin’s Disease, was published in 2010 and chronicled the life and work of one of the foremost physician-scientists in the history of cancer medicine. Her latest book, Jonas Salk: A LIFE, tells the remarkable story of the man who conquered polio. The New York Times called Jacobs latest biography, “science writing at its best.”

In a recently published Q&A on the Department of Medicine website, Jacobs discusses how she balances her roles as mother, physician and author. “I could find snippets during every day to write. Even today I find that to be the case,” she says.

On the topic of being able to meld her doctor life with her writer life, Jacobs says:

I don’t meld the two at all. When I’m writing or doing research on one of my books, I’m totally focused on that. And when I’m with my patients, I’m totally focused on them. One thing I learned from Henry Kaplan, who had a whirlwind of activity surrounding him, was that when he was in the exam room, the patient was his only concern.

“I do think my background in science helped me be a better writer, though. I chose subjects who were in the field of science or medicine because that is what I know. One of the hardest tasks was interpreting my subjects’ work to the general public. I used to think if my next-door neighbor, who was a smart housewife, couldn’t understand and enjoy the books, I had failed.

“Knowing academic medicine also helped. Jonas Salk ran into major political hurdles, and he was not treated kindly—some of which was his own doing. Having spent my entire career in academic medicine, I could understand the world in which he worked.

Previously: Stanford doctor-author brings historic figure Jonas Salk to lifePrescribing a story? Medicine meets literature in “narrative medicine”, Literature and medicine at life’s end, Poetry’s connection to medicine and the body and More than medicine: Stanford medical students embrace their artistic passions through unique program

Imaging, Microbiology, Stanford News

When bacteria swarm: H. pylori home in on our stomach cells

Imagine you’re thrown into wild ocean waters, battered by waves until you can’t tell which way is up. Your only chance of survival is to somehow sense the location of a rock outcropping and cling to it. Now factor in that the churning water is highly acidic and lethal – that’s the predicament facing Helicobacter pylori, a bacterium that makes its home in one out of every two human stomachs and, for an unfortunate 20 percent of its hosts, causes ulcers.

H. pyloris safe haven is our stomach’s lining with its protective mucus and nutrient-rich cells. New research from the lab of Stanford microbiologist Manuel Amieva, MD, PhD, published today in Cell Host & Microbe demonstrates that the bacteria are able to detect and home in on metabolic molecules released by human stomach cells. The behavior, captured in the video above, shows H. pylori swarming to a microscopic needle releasing either a solution collected from stomach cells or the molecule urea.

The corkscrew-shaped bacterium moves with the help of its tail-like flagella. The bundle of flagella spin in one direction to propel the bacteria forward. When they reverse the spin, said Amieva, the flagella become like helicopter blades, pulling H. pylori backwards.

Previous experiments have shown the bacteria swim away from acid and H. pylori is known to have four chemical sensing receptors. “But this is the first time we’ve observed in real time the bacteria swimming towards something,” said graduate student and lead author, Julie Huang, referring to the technique that allowed the lab to watch H. pylori’s swimming behavior directly.

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