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History, Neuroscience, Research, Science, Stanford News

Illustration from 1881 resolves century-old brain controversy

Illustration from 1881 resolves century-old brain controversy

Figure2_WernickeThese days, a person can get through graduate school in the sciences practically without touching a physical publication. Most journals are available online going back decades. So it was a bit unusual when graduate student Jason Yeatman and postdoctoral scholar Kevin Weiner found themselves in the basement of Lane Medical Library trying to get to the bottom of a medical mystery.

It all started when Yeatman found a nerve pathway in brain images he’d taken as part of his work studying brain changes as kids learn to read.  This pathway didn’t appear anywhere in the available literature. He and Weiner became curious how this pathway – which clearly showed up in their work – could have escaped the notice of previous neuroscientists.

Their curiosity eventually led them back to an 1881 publication, still available in the basement of Lane Medical Library, where Carl Wernicke, MD, described identifying this brain pathway. Weier said, “That was a really cool experience that most people don’t have anymore, when you have to check your belongings at the door because the book you are about to look at is worth thousands of dollars per page. You are literally smelling 100 year-old ink as you find the images you have been searching for.”

Wernicke’s discovery contradicted theories by the eminent neuroanatomist at the time, Theodor Meynert, MD. I describe the controversy that led to this pathway expulsion from the literature in this Stanford News story:

Meynert strongly believed that all of the brain’s association pathways run from front to back – horizontal. This pathway, which Wernicke had called the vertical occipital fasciculus, or VOF, ran vertically. Although Yeatman and Weiner found references to the VOF under a variety of different names in texts published for about 30 years after Wernicke’s original discovery, Meynert never accepted the VOF and references to it became contentious before eventually disappearing entirely from the literature.

The group, whose work was published this week in the Proceedings of the National Academy of Sciences, says this was all more than just an exercise in curiosity. Psychologist Brian Wandell, PhD, in whose lab Yeatman was working, says it also shows the value of modern publishing methods, where making data available means scientists worldwide can try to reproduce results. He says it’s now less likely that a dispute could lead to a discovery being lost to history.

Image courtesy of PNAS

Clinical Trials, Immunology, Research, Transplants

Transplant without lifelong drugs gives patient another chance

Transplant without lifelong drugs gives patient another chance

"DCIM100GOPRO"Imagine learning you have an illness. It’s the same illness that killed your mother. You watched her fade, the last years of her life dreadful to watch, unimaginably tough to endure. The same fate awaits you. Until… it doesn’t. Now there’s a therapy that just might save you.

That’s the story of San Francisco Bay Area resident Cynthia Alcaraz-Jew, featured in the fall issue of Stanford Medicine Magazine. Now in her late 40s, Alcaraz-Jew, like her mother, suffers from a rare genetic condition called Alport Syndrome. The ailment leads to kidney, ear and eye problems.

Alcaraz-Jew didn’t immediately luck out. Her kidneys failed first and her younger brother, Xavier, a perfect immunologic match, offered to donate his kidney. Great news, of course, but a transplant usually means years of immunosuppressive drugs, which leave bones brittle and can lead to infections, heart disease, or even, ironically kidney failure.

Thanks to her perfectly matched kidney, Alcaraz-Jew was able to enroll in a trial led by Stanford immunologist Samuel Strober, MD, that aims to wean transplant patients off immunosuppressive drugs. From the article:

Of the 24 kidney transplant patients with perfectly matched donors who enrolled in the trial beginning in 2000, 16, including Alcaraz-Jew, are living drug free, and three others are working to get off the medications, Strober says. The team is planning to publish a paper summarizing the research results in the near future.

And the photo? That’s Alcaraz-Jew and her husband swimming with whale sharks in Mexico earlier this year.

Previously: Stanford Medicine magazine traverses the immune system, Kidney-transplant recipients party without drugs — immune-suppressing anti-rejection drugs, that is, Might kidney-transplant recipients be able to toss their pills?  and Marked improvement in transplant success on the way, says Stanford immunologist
Photo courtesy of Cynthia Alcaraz-Jew

Biomed Bites, Genetics, Research, Stem Cells, Videos

Working on a gene therapy for muscular dystrophy

Working on a gene therapy for muscular dystrophy

Here’s this week’s Biomed Bites, a weekly feature that highlights some of Stanford’s most innovative research and introduces Scope readers to innovators in a variety of biomedical disciplines. 

The most common form of muscular dystrophy, Duchenne muscular dystrophy, is genetic, resulting from a defective gene on the X chromosome, so it affects primarily boys. That makes it a prime target for genetic therapy – currently the goal of Stanford geneticist Michele Calos, PhD.

Calos started out as a basic scientist, examining the nature of DNA and the controls of genes; they developed techniques used to insert new genes into existing cells and ensure they are turned on.

Now, Calos has found applications for her earlier research. Capitalizing on the work that won the 2012 Nobel Prize in Medicine, Calos and her team have set their sights on developing healthy muscle cells that can restore function for muscular dystrophy patients. Here’s Carlos in the video above:

We’re repairing the mutation in the patients’ cells… then putting back the correct copy of the gene, differentiating them into muscle precursors and injecting them into muscles where they can form healthy muscle fibers.

Calos said she and her team are currently perfecting the technique in mice, before it can be used in human patients. “Our dream really is to develop a therapy in the lab that would be translatable to clinical use in the future,” she said.

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

Previously: Elderly muscle stem cells from mice rejuvenated by Stanford scientists, New mouse model for muscular dystrophy provides clues to cardiac failure and Visible symptoms: Muscular-dystrophy mouse model’s muscles glow like fireflies as they break down

Anesthesiology, Neuroscience, Research, Stanford News, Surgery

Stanford anesthesiologist explores consciousness – and unconsciousness

Stanford anesthesiologist explores consciousness - and unconsciousness

face-275015_1280Anesthesiologist Divya Chander, MD, PhD, is one of a leading group of neuroscientists and anesthesiologists who are using high-tech monitoring equipment in the operating room to explore the nature of consciousness – which isn’t quite as simple as on or off, asleep or awake.

Stanford Medicine magazine profiled Chander’s work last summer, but I came across it when the title of one of Chander’s recently published papers grabbed my eye: “Electroencephalographic Variation During End Maintenance and Emergence from Surgical Anesthesia.” Okay, that might not pique your curiosity, but when I spotted the words, “for the first time” in the abstract I was hooked. I read on to learn that Chander and her team attach electrodes to the foreheads of patients during surgery, measuring the brain’s electrical signals.

After a bit of scrambling you might expect when trying to get in touch with someone who spends her days in the operating room, I managed to reach Chander on the phone. Our conversation strayed far from the bounds of her paper:

In this work, what did you do for the first time?

It’s not that no one has ever used an EEG during anesthesia. During the middle of the 20th century, several anesthesiologists attempted to record brain activity under increasing levels of anesthesia, just as many neuroscientists were using the EEG to characterize the stages of sleep. The process of recording EEG was really cumbersome back then, unlike today when you can stick a frontal set of leads on a patient’s forehead in the OR in a matter of seconds. Certain general stages of anesthesia were identified, but a formalized staging nomenclature, based on the relative contribution of dominant slow-wave oscillations in the EEG, had never been defined. Non-REM (slow-wave) and REM (rapid eye movement sleep) were staged in this way by sleep neurobiologists, but not anesthesiologists. In our study, we built upon the sleep stage classification system, to define maintenance patterns of general anesthesia. The formalized nomenclature helps us examine the stages of unconsciousness under anesthesia and communicate with other anesthesiologists.

What did you find?

We recorded the frontal EEGs (from the forehead) of 100 patients undergoing routine orthopedic surgeries. We discovered four primary electrical patterns that patients exhibit when they’re unconscious, and also as they’re waking up from anesthesia. The unconscious patterns show variety – not all patients’ brains look the same under anesthesia, despite similar drug exposure, meaning there are ‘neural phenotypes,’ or patterns of neuronal activity. The emergence patterns from anesthesia (pathways people’s brains take to reestablish conscious awareness after the anesthetic is turned off) bear some similarity to those pathways traversed when people are awakening from sleep.

When wakening from anesthesia, some people spend a relatively long time in non slow-wave anesthesia, which is similar to REM, the stage of sleep where dreams occur that usually precedes awakening. Others go straight from deep anesthesia, what we call slow-wave anesthesia (because of its dominant EEG patterns) to awakening. Interestingly, these patients were more likely to experience post-surgical pain, a situation akin to awakening from a deep sleep and experiencing confusion or discomfort; some childhood parasomnias like sleep terrors are characterized by moving abruptly from slow wave sleep to waking.

We began to see some tantalizing suggestions certain patterns of wake-ups from anesthesia might be more preferable. Could paying attention to these emergence trajectories prevent some problematic complications, like post-operative cognitive dysfunction? Could we ‘engineer’ or optimize anesthetic delivery to favor certain types of maintenance and emergence patterns? Can we monitor these patterns in a way that makes delivering anesthesia safer? Recognizing the variety of maintenance and emergence patterns under anesthesia also opens an entirely new possibility in the field of personalized medicine – imagine tailoring anesthetics to a person’s genome? I am trying to develop an initiative that addresses this in collaboration with Stanford’s new GenePool Biobank program.

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History, Medicine and Society, Research, Stanford News

Stanford Egyptologist discovers that public health care has ancient roots

Stanford Egyptologist discovers that public health care has ancient roots

Anne Austin

Anne Austen, PhD, a post-doctoral researcher in Stanford’s history department, recently conducted the first detailed study of human remains at what is now called Deir el-Medina, an ancient town outside of the Valley of the Kings in Egypt. She found that these Egyptians likely had state-sponsored health care with “modern” benefits like paid sick days and clinics. They also felt a strong pressure to do grueling work, yet took care of their disabled and infirm.

Austen works in the relatively new field of osteo-archaeology, which enables researchers to deduce details about people’s daily lives from their skeletal remains. Archaeologists have always been interested in how remains are positioned relative to the rest of the site, but Austen tested the bones themselves to determine what diseases the people were experiencing, and then contextualized that information within the copious written records from Deir el-Medina in its heyday, when it was a bustling village of workers building the pyramids. She has added a new dimension to the picture of ancient medicine and care already gleaned from this uncommonly literate group’s receipts, personal letters, bills, prayers, and lawsuits, found on shards of clay or scraps of papyrus.

During her current tenure in the Andrew W. Mellon Fellowship of Scholars in the Humanities, she is continuing the PhD research she conducted in 2012 while at UCLA. In a Stanford News piece, she commented, “The more I learn about Egypt, the more similar I think ancient Egyptian society is to modern American society. Things we consider creations of the modern condition, such as health care and labor strikes, are also visible so far in the past.”

Austin thinks that research about Egyptians is particularly compelling for thinking about today’s questions of wellness and social responsibility because they thought of health and disease in ways surprisingly similar to our own. In contrast to the Greeks, who, as Austin points out in the article, thought of disease as an imbalance of the body’s four fluid humors, Egyptians thought of disease as a contamination, a foreign substance that must be purged. This is essentially analogous to modern germ theory. Furthermore, they negotiated the question that underlies much current American discussion about healthcare: Who is responsible for whose health, and why? Austen explains:

At Deir el-Medina, we see two health care networks happening. There’s a professional, state-subsidized network so the state can get what it wants – a nice tomb for the king. Parallel to this, there’s a private network of families and friends. And this network has pressure to take care of its members, for fear of public shaming, such as being divorced for neglect or even disinherited.

Photo courtesy of Anne Austin

Genetics, NIH, Research, Science, Stanford News, Technology

Of mice and men: Stanford researchers compare mammals’ genomes to aid human clinical research

Of mice and men: Stanford researchers compare mammals' genomes to aid human clinical research

Scientists have long considered the laboratory mouse one of the best stand-ins for researching human disease because of the animals’ genetic similarity to humans. Now Stanford researchers, as part of a consortium of more than 30 institutions, have confirmed the mouse’s utility in clinical research by showing that the basic principles controlling genes are similar between the two species. However, they also found some important differences.

From our press release on the work:

“At the end of the day, a lot of the genes are identical between a mouse and a human, but we would argue how they’re regulated is quite different,” said Michael Snyder, PhD, professor and chair of genetics at Stanford. “We are interested in what makes a mouse a mouse and a human a human.”

The research effort, Mouse ENCODE, complements a project called the Encyclopedia of DNA Elements, or ENCODE, both funded by the National Human Genome Research Institute. ENCODE studied specific components in the human genome that guide genes to code for proteins that carry out a cell’s function, a process known as gene expression. Surrounding the protein-coding genes are noncoding regulatory elements, molecules that regulate gene expression by attaching proteins, called transcription factors, to specific regions of DNA.

The Mouse ENCODE consortium annotated the regulatory elements of the mouse genome to make comparisons between the two species. Because many clinical studies and drug discovery use mice as model organisms, understanding the similarities and differences in gene regulation can help researchers understand whether their mouse study applies to humans.

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Aging, Chronic Disease, Pediatrics, Research

“The child is father of the man”: Exploring developmental origins of health and disease

"The child is father of the man": Exploring developmental origins of health and disease

3801281145_1f3fb2c8bf_z Among scientific communities, there is a small but growing segment of research concerned with “DOHaD” – the developmental origins of health and disease. The work usually focuses on how childhood, including birth, the fetal period, and sometimes even pre-conception events, affects a person’s lifelong health and well-being and is the topic of a recent article (subscription required) published in Pediatrics by researchers at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The phrase “the child is father of the man” is a line from William Wordsworth’s “My Heart Leaps Up” and also the title of the article, whose authors added, commendably, “and the mother of the woman.”

DOHaD gained acceptance within the medical community starting with the “Barker Theory” in 1995, when David Barker, MD, showed that babies with low birth weights were at higher risk for coronary heart disease later in life. Prior to his work, the dominant model was that the health of those who survived childhood without major disease or disability was sort of “reset” in adulthood, to decline from then into old age. This is increasingly understood to be a simplistic model.

Resistance to the idea stems from the fact that links between child and adult health are associative and not proven to be causative; therefore, the article’s authors Alan E. Guttmacher, MD, and Tonse N.K. Raju, MD, call for scientists to do more mechanistic research investigating causation, and “more importantly, to devise treatments and preventions, for the many “adult-onset” conditions that actually are rooted in much earlier exposures and events.” Such research is difficult because of the incredible number of variables that occur over an entire lifespan, and even within the category “perinatal risk factors.”

In the piece, the authors describe the importance of DOHaD and how a better understanding of it could affect pediatrics and health care:

Arguably the most important advance in the health care of children, and in establishing pediatrics as a medical specialty, was the cultural awakening that children were not simply small adults. Ironically, DOHaD greatly expands the impact of pediatrics by reversing that shift and focusing on how children actually are smaller versions of the adults they will become.

Once the biological and behavioral pathways that underlie DOHaD are identified and understood, the role of pediatrics should expand in fundamental and powerful ways. Anticipatory guidance in the future will not be just about the next 6 weeks or 6 months or even 6 years of the child’s life, but the entire life span. The pediatrician and other children’s health care providers will inform parenting and behaviors, including diet and exercise, and even prescribe presymptomatic medication targeted to the individual child. The pediatrician will become the gatekeeper to lifelong health.

Photo by Brad Brundage

Big data, Cardiovascular Medicine, Chronic Disease, Research, Science, Stanford News, Videos

Big data approach identifies new stent drug that could help prevent heart attacks

Big data approach identifies new stent drug that could help prevent heart attacks

Ziad Ali, MD, PhD, was a cardiovascular fellow at Stanford with a rather unique skill when a 6-year study published today online in The Journal of Clinical Investigation first began.

The multi-talented physician-scientist – who is now associate director of translational medicine at Columbia University Medical Center – had figured out a way to put tiny little stents into mice with clogged arteries as a PhD student.

The skill would become key as he and colleagues set out to find a better pharmaceutical for the drug-eluting stents that are used in combination with angioplasty to treat coronary artery disease. In order to prevent stent disease, the often serious medical problem caused by stents themselves, chemotherapy drugs were added to bare metal stents. But these drug-eluting stents have their own problems: The drugs work like “hitting a pin with a sledgehemmer,” as Ali describes it, often damaging the lining of the arteries which can lead to heart attacks. As a result, patients are required to take blood thinners for up to a year after the procedure to prevent clots.

“A lot of our patient population is on the elderly side with bad hips or diabetes,” Ali told me. “Once you get a drug-coated stent, you can’t have surgery for a year. And if you stop the blood thinners for any reason, you’re at risk of a stent clotting off. And that actually causes a heart attack. Stent thrombosis has a high mortality rate.”

By using a “big data” computational approach, learning about the genetic pathways involved in coronary artery disease, then testing the new theories on mice models in the lab, researchers were able to pinpoint a potential new treatment for patients: Crizotinib, a pharmaceutical approved by the FDA for treatment in certain cases of lung cancer.

“This could have major clinical impact,” Euan Ashley, MD, PhD, senior author of the study, who discusses the work alongside Ali in the video above, said.

Previously: Euan Ashley discusses harnessing big data to drive innovation for a healthier world, New computing center at Stanford supports big data, Trial results promising for new anti-clotting drug and A call to use the “tsunami of biomedical data” to preserve life and enhance health
Photo in featured entry box by Mark Tuschman

Obesity, Parenting, Pediatrics, Research

Study shows that toddlers benefit from rules about eating habits

Study shows that toddlers benefit from rules about eating habits

toddler_eatingA recent study from pediatrics researchers at the University at Buffalo suggests that toddlers who are faced with parental rules about what to eat develop better eating habits later in their childhood, regardless of the self-restraint they demonstrate. The connection between self-restraint and eating habits has been studied widely in adults and adolescents, but this research is among the first to investigate it in very young children.

The findings suggest that self-restraint in two year-olds doesn’t itself lead to healthier habits by the time the child is four; it must be combined with parental rules about eating. Neha Sharma, a co-author of the paper, explained the significance when presenting the research at ObesityWeek 2014 in Boston, as quoted in a University of Buffalo news release:

It is amazing to see that a parental rule about which types of food a child can and cannot eat could have such a great impact on child eating habits. Without these boundaries set by caregivers, the benefits of high self-regulation on weight gain and childhood obesity could be diminished. This illustrates just how important parental involvement is in influencing child eating habits.

Seventeen percent of American children age 2-19 are obese, as are nearly 35 percent of adults, according to the Center for Disease Control and Prevention. Obesity is well-known as a pressing public health issue, and children who are obese are much less likely to attain healthy weights as adults.

Furthermore, a study published this week in Pediatrics suggests that obese youth are very likely to become obese teens, contrary to a popular idea that overweight adolescents have “baby fat” that will disappear with puberty. Researchers found that a child’s weight at age 11 is a good indicator of his or her weight at age 16: 83 percent of obese fifth-graders remained obese, and 87 percent of normal-weight fifth graders remained at a normal weight five years later.

By setting guidelines and rules for toddlers, parents and caretakers can play a key role in guiding society’s very youngest members towards healthy eating habits with life-long impacts.

Previously: No bribery necessary: Children eat more vegetables when they understand how food affects their bodies, Examining why instilling healthy eating and exercise habits in children may not prevent obesity later in life and How to combat childhood obesity? Try everything
Photo by David Goehring

Aging, Genetics, In the News, Research, Stanford News

“A lot more data” needed to determine what makes supercentenarians live so long

"A lot more data" needed to determine what makes supercentenarians live so long

Scientists from Stanford and elsewhere have been hunting for a genetic explanation for extreme longevity for the past four years and are realizing that it is a more difficult proposition than they initially hoped.

Their research compared the genomes of 17 “supercentenarians” – those who have lived 110 years and beyond – with those of 4,300 “regular” people recorded earlier in a National Institutes of Health study. The study was geared toward finding a single gene or group of genes responsible for a particular trait – in this case longevity – similar to genes which have been found to cause disease or confer immunity. But they have had no luck. Stuart Kim, PhD, a Stanford geneticist and molecular biologist and founder of the Kim Lab for the study of aging, commented in a San Francisco Chronicle piece:

We were looking for a really simple explanation in a single gene, and we know now that it’s a lot more complicated, and it will take a lot more experiments and a lot more data from the genes of more supercentenarians to find out just what might account for their ages.

However, data about the oldest people in the world still suggests that the reason they can live so long has to do with their genes, and not with lifestyle choices. The supercentenarians have average rates of cancer, heart disease, and stroke, although they have escaped many age-related diseases, and their smoking, alcohol, exercise and diet appear no different than among ordinary people. Furthermore, as noted in the article, the parents, siblings and children of the centenarians have also lived well beyond average.

Previously: Unlocking the secrets to human longevity and California’s oldest person helping geneticists uncover key to aging

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