Stanford News

The National Academy of Sciences recently celebrated its 150th birthday by, among other things, conferring membership on Ben Barres, MD, PhD. Additional NAS admittees from Stanford were sleep scientist Emmanuel Mignot, MD, PhD, and bioengineer Steve Quake, PhD.

A distinguished scientist by anybody’s yardstick, as well as the chair of Stanford’s ironically named neurobiology department, Barres is a leading light in the study of glial cells (collectively known as glia), the 90 percent of all the cells in the brain that aren’t nerve cells.

The term”glia” is derived from the Greek word for glue. Like Rodney Dangerfield, glial cells once got no respect. They were thought of, in fact, as not much more than “brain glue”: mere structural scaffolds for the organ’s much more revered nerve cells.

Barres’ research has proved that hypothesis incorrect, to say the least. (For details, click here.) Discoveries coming out of his lab include, to name one example, glial cells’ crucial role in determining exactly when and where nerve-cell connections in the brain are made, tweaked to strengthen or weaken them, or destroyed.

You don’t get much more respectable than that: Those connections pretty much define the thoughts we have, the emotions and sensations we experience and the actions we take.

The man who, as much as anyone, has brought a set of unsung cells a newly elevated status would like to see another group get more respect: the estimated 0.3 percent of Americans who are transgender.

“I’m the first transgender scientist to make into the National Academy of Science,” says Barres, who began life under another first name: Barbara.

“We don’t know if other members past or present are or were transgender,” demurs an NAS representative. And after all, how would they? What kind of statistics could be compiled by an organization that doesn’t ask or track the sexual orientations, much less the gender identities, of its membership? Who would have even considered asking such a question 20 or 30 years ago, much less running sex-chromosome tests on cheek swabs from prospective, current or posthumous members?

But it’s a pretty safe bet that if any previously admitted NAS member were openly transgender, we’d have heard about it. (Transgendered computer scientist Lynn Conway was admitted to the National Academy of Engineering in 1989.)

One is tempted to compare Barres to Jackie Robinson, who broke the Major League Baseball’s color barrier in 1947 - except that the latter had to put up with a whole lot more grief from his fellow major-league ballplayers than Barres is likely to encounter from his peers.

“We heartily congratulate Prof. Barres on his election,” says NAS spokesperson Bill Skane.

In science, if anywhere, diverse perspectives drive innovation. ”Don’t ever let anyone make you feel bad about being different,” Barres tells young scientists. “Your difference is your greatest advantage.”

Previously: Malfunctioning glia - brains cells that aren’t nerve cells - may contribute big time to ALS and other neurological disorders, Neuroinflammation, microglia, and brain health in the balance and Unsung brain-cell population implicated in variety of autism

Among school-aged children in the United States an estimated one in 50 has been diagnosed with autism spectrum disorder, according to a recent survey (.pdf) from the Centers for Disease Control and Prevention. In addition to raising concerns among researchers and parents about why the number of cases has increased, the findings underscored the need to do more autism research and to provide support and services for families caring for autistic children.

To help parents and others in the local community better understand the growing prevalence of autism and to learn about treatments and research advancements, the Stanford Autism Center at Packard Children’s Hospital will host its sixth annual Autism Spectrum Disorders Update on June 1. The event offers an opportunity for exchange between parents, caregivers and physicians and provides an overview of the center’s clinical services and ongoing autism research at the School of Medicine.

In anticipation of the day-long symposium, we’ve asked Carl Feinstein, MD, director of the center, to respond to your questions about issues related to autism spectrum disorder and to highlight how research is transforming therapies for the condition.

At the Stanford Autism Center, Feinstein works with a multidisciplinary team to develop treatments and strategies for autism spectrum disorders. In providing care and support for individuals with autism and their families, Feinstein and colleagues identify ways of targeting the primary autism symptoms, while also paying attention to associated behavior problems that may hold a child back from school or community involvement or seriously disrupt family life.

Questions can be submitted to Feinstein by either sending a tweet that includes the hashtag #AskSUMed or posting your question in the comments section below. We’ll collect questions until Wednesday (May 15) at 5 PM Pacific Time.

When submitting questions, please abide by the following ground rules:

• Stay on topic
• Be respectful to the person answering your questions
• Be respectful to one another in submitting questions
• Do not monopolize the conversation or post the same question repeatedly
• Kindly ignore disrespectful or off topic comments
• Know that Twitter handles and/or names may be used in the responses

Feinstein will respond to a selection of the questions submitted, but not all of them, in a future entry on Scope.

Finally – and you may have already guessed this – an answer to any question submitted as part of this feature is meant to offer medical information, not medical advice. These answers are not a basis for any action or inaction, and they’re also not meant to replace the evaluation and determination of your doctor, who will address your specific medical needs and can make a diagnosis and give you the appropriate care.

Previously: New public brain-scan database opens autism research frontiers, New autism treatment shows promising results in pilot study, Autism’s effect on family income, Study shows gene mutation in brain cell channel may cause autism-like syndrome, New imaging analysis reveals distinct features of the autistic brain and Research on autism is moving in the right direction
Photo by Wellcome Images

Does it make a difference if a gene – or group of genes – is inherited from your mother or your father?

That’s the question behind the study of genomic imprinting, a phenomenon in which a small percent of genes are thought to be expressed differently depending on which parent they came from. In particular, animal research suggests imprinting may affect aspects of brain development. Researchers wonder if genomic imprinting might explain differences in brain anatomy seen between men and women, such as men’s larger brain volumes.

A new Stanford study, published today in the Journal of Neuroscience, adds to evidence that genomic imprinting is, in fact, happening in humans’ brains. The finding comes from MRI brain scans performed on a group of young girls with Turner syndrome, a chromosomal disorder in which a girl or woman has one missing or malfunctioning X chromosome. Turner syndrome gives an unusual opportunity to study genetic imprinting, because it allows comparisons of individuals who received a single X from Mom to those who got a single X from Dad. (The typical two-X-chromosome female body expresses a mosaic of Mom’s X and Dad’s X, making it impossible to tease apart the effects of the two parents. Males invariably get their single X chromosome from their mothers, so their cells always express the maternal X.)

The Stanford team, led by Allan Reiss, MD, documented several distinctions between the brains of Turner syndrome girls who have only a maternal X, those with only a paternal X, and typical girls with two X chromosomes, such as differences in the thickness and volume of the cortex, and in the surface area of the brain. The work helps clarify murky results from earlier studies of adults with Turner syndrome, the researchers say, because many adult women with Turner syndrome take estrogen supplements, which may have their own effects on brain development. None of the girls in the new study had taken estrogen.

The most tantalizing part of the paper is the scientists’ comment on the implications of their work for our general understanding of genetic imprinting. In part, they say:

By far, the most consistent finding with regard to sex differences in brain anatomy is the larger brain volume found in males compared with females. Although our groups did not differ on most whole-brain measures, our analyses revealed the existence of significant trends on total brain volume, gray matter volume and surface area, where these variables increased linearly from the Xp [paternal X] group being smallest, to the Xm [maternal X] group being largest, with typically developing girls in between. Considering that typically developing males invariably inherit the maternal X chromosome, while typically developing females inherit both and randomly express one of them in each cell, a linear increase in brain volume as seen in the present study is in agreement with what would be expected if imprinted genes located on the X chromosome were involved in brain size determination.

In other words, men may have their mothers to thank for their larger brains.

Karyotype image from a Turner Syndrome patient by S Suttur M, R Mysore S, Krishnamurthy B, B Nallur R - Indian J Hum Genet (2009).

Not long ago, Stanford computer scientist Debashis Sahoo, PhD, told investigators at the Stanford Institute for Stem Cell Biology and Regenerative Medicine that in a few seconds he could find many of the important stem cell genes that the researchers were used to finding only after spending millions of dollars and years in the lab. “We laughed and said, ‘That’s impossible,’” recalls Irving Weissman, MD, director of the institute, in a recent video. But Weissman went ahead and gave Sahoo information about two key genes - and within a few seconds, Sahoo had used his desktop computer to scour the world’s public gene databases, analyzed that information with the computer algorithm he had designed, and come up with over a dozen genes new genes that were involved in the development of certain kinds of cells. That search, Weissman estimates, saved his team a decade of work and about $2.5 million.

More details are shared in the video above. And as a reminder, big data - and the ways in which people like Sahoo are mining through vast amounts of publicly available information to further research and advance health care - is the focus of a Stanford/Oxford conference being held here later this month.

Previously: Atul Butte discusses why big data is a big deal in biomedicine and Mathematical technique used to identify bladder cancer marker

In an unusual collaboration, officials from the health-care and nuclear industries met last July to discuss each field’s similarities and differences between four topic areas, including diagnostic and prognostic technologies and human factors that affect risk and reliability. The Association for the Advancement of Medical Instrumentation recently released a 120-page monograph detailing the lessons learned during the tw0-day workshop.

Today’s issue of Inside Stanford Medicine includes a Q&A with David Gaba, MD, professor of anesthesia and the associate dean for immersive and simulation-based learning at the School of Medicine, discussing his participation in last year’s meeting and what health-care providers can learn from the nuclear industry. He says:

One big one is the need for standard operating procedures, where possible, which also retain flexibility as needed. A major spinoff of this principle, used extensively in nuclear power, is to provide graphically enhanced written protocols for emergency situations. It is long recognized that nuclear power operators cannot remember everything they need to know in managing an adverse event in a nuclear plant — memory is too fallible. Thus, the use of written procedures is a mainstay in this setting. Health care has long depended largely on the individual skill and memory of physicians and nurses. Protocols and checklists or emergency manuals were decried as cheat sheets or cribs. We now know that the best people use these kinds of supports — not because they are stupid but because that is the best way to get the best results in tough situations. My lab and other colleagues at Stanford have been working for some time on written cognitive aids and emergency manuals for anesthesia professionals. These have now been disseminated to all the anesthetizing locations in Stanford’s hospitals and those of its close affiliates. This lesson has clearly come from the nuclear industry and from others such as aviation.

Another lesson from the nuclear industry is the importance of the safety culture in an organization. When the organization favors throughput so heavily that people cut corners on safety, or when personnel are afraid to speak up when they see something unsafe, the risk climbs.

Something near and dear to my heart is the utility of simulation for training of skilled professionals. My lab’s development of simulators and simulation-based curricula in health care was triggered by knowing a little bit about how they are used in aviation and other industries like nuclear power. But I actually had no idea, until this workshop, just how much simulation is required for nuclear power operators. They spend six weeks doing their usual shifts in the control room, and the seventh week is spent in training simulations. All year round, no matter how much prior experience they have. Health care is just scratching the surface in simulation compared to that, but at least we have started our way down a similar road.

Previously: Sully Sullenberger talks about patient safety

We always want what we don’t have. My teenage daughter is tall and beautiful (in my naturally biased and loving view). But she’s always complaining about her thighs. She thinks they’re too big and don’t look good in skinny jeans. What I see is a young girl with a fresh face, beautiful curves and a youthful spring of energy.

As a molecular epidemiologist, I see one more thing. She has a so-called “pear-shaped” body, which means she has larger thighs relative to a smaller waist, with most of her fat deposited in the lower body. In contrast, people who have “apple-shaped” bodies are heavier in the middle and have their body fat accumulated around the waist, closer to the heart, putting them at a higher risk for abdominal obesity. Many studies have shown that abdominal obesity has a more detrimental effect than overall obesity (as measured by body mass index, the metric calculated using height and weight) on a number of diseases, including type II diabetes, cardiovascular disease and certain cancers (such as those of the breast, ovary, gallbladder and kidney). The specific biological mechanisms are not entirely clear, but we do know from recent research that fat (adipose tissue) is an endocrine organ that actively secretes a variety of chemicals, such leptin, adiponectin, estrogen and other hormones, and inflammatory cytokines. These markers have been linked to growth and proliferation of cancer cells.

The Stanford Cancer Institute and its affiliated research partner, the Cancer Prevention Institute of California (CPIC), currently are conducting studies to understand more clearly the molecular mechanisms underlying the adverse effects of abdominal obesity on cancers. A better understanding of how leptin and inflammatory markers associated with abdominal obesity can influence cancer risk at the molecular level will help clarify the specific steps involved in carcinogenesis, which in turn can aid the development of effective preventive strategies to stop or slow down cancer development.

Our genetic makeup determines largely which body type we are born with, pear or apple. But our eating habits, physical activity and weight management can also affect fat distribution and disease susceptibility. Regular exercise (three times a week) helps increase muscle mass, which in turn can enhance metabolism and lower the risk of metabolism-related conditions, including certain cancers. Whether cancer prevention and weight reduction guidelines differ for those with different body types is another important topic for future studies.

My daughter is the apple of my eye. But I’m glad that, unlike me, she’s a pear. She inherited her father’s body type. In theory, her risk of certain hormone-related cancers or metabolic disorders is lower than mine. So next time she complains about her thighs, I’ll share with her my recent work on abdominal obesity and cancer and try to convince her that she’s lucky to have “big” thighs.

Ann Hsing, PhD, MPH, is director of research for the Cancer Prevention Institute of California (CPIC). Part of the Stanford Cancer Institute, the CPIC conducts population-based research to prevent cancer and reduce its burden where it cannot yet be prevented.

Photo by KDL Designs

In a novel combination of biochemical experimentation and data mining, Stanford researchers and postdoctoral scholars Cigall Kadoch, PhD, and Diana Hargreaves, PhD, have identified a large protein complex that appears to be significantly involved in cancer development in humans.

The multisubunit is a member of a family of chromatin-regulatory complexes that keep DNA tightly packed in a cell’s nucleus. Originally thought of as a kind of housekeeping, or maintenance, protein in the cell, it’s now becoming apparent that these complexes are really important in development and cancer.

Kadoch, working in the laboratory of developmental biologist Gerald Crabtree, MD, used biochemical techniques to identify seven previously unidentified members of the complex, which is called BAF (or mSWI/SNF). She and Hargreaves then analyzed 44 pre-existing studies that detailed the DNA sequences of primary human tumors of all types. They calculated the likelihood that any protein component of the large group was mutated. (The approach varies from others that analyze the mutation rates of individual proteins.)

As described in our release:

The results, once the newly discovered members were included, were surprising: 19.6 percent of all human tumors displayed a mutation in at least one of the complex’s subunits. In addition, for some types of cancers (such as synovial sarcoma), every individual tumor sample examined had a mutation in a BAF subunit. The results suggest that the BAF complex, when unmutated, plays an important protective role against the development of cancer in many different tissues.

Crabtree, who is also a Howard Hughes Medical Institute investigator, described his lab’s long-standing interest in BAF and other similar protein complexes:

Somehow these chromatin-regulatory complexes manage to compress nearly two yards of DNA into a nucleus about one one-thousandth the size of a pinhead. And they do this without compromising the ability of the DNA to be replicated and selectively expressed in different tissues - all without tangling. In 1994 we reported that complexes of this type were likely to be tumor suppressors. Here we show that they are mutated in nearly 20 percent of all human malignancies thus far examined.

The work was published yesterday in Nature Genetics. The researchers are now working to understand exactly how the mutations they’ve observed affect the function of the BAF complex.

Previously: Dumb, dumber and dumbest? Stanford biologist suggests humans on a downward slide and New clues arise in pancreatic cancer from Stanford researchers
Photo of (left to right) Cigall Kadoch, Gerald Crabtree and Diana Hargreaves, by Nathaniel Hathaway

On Wednesday, Stanford Hospital & Clinics officially broke ground on a new 824,000-square-foot hospital at an event attended by 400 community members, donors, and administrators. As my colleague mentioned in an earlier Scope post, the new building “will feature amenities intended to enhance both physical and emotional healing with the latest in medical, surgical and diagnostic technology.”

This photo of bright red shovels being dug into ceremonial dirt that afternoon distinctly captures this exciting new chapter in Stanford’s history.

Previously: A new chapter for Stanford Hospital, Growing up: The expansion of Lucile Packard Children’s Hospital, Hospital mock-ups help refine plans before construction begins and City of Palo Alto approves rebuilding and expansion of Stanford Hospital and Lucile Packard Children’s Hospital
Photo by Norbert von der Groeben

I was so happy to learn that Stanford stem cell researcher Marius Wernig, MD, (here describing his research as part of the California Institute for Regenerative Medicine’s recent Elevator Pitch competition) has been selected by the International Society for Stem Cell Research to receive its Outstanding Young Investigator of the year at the organization’s annual meeting in June in Boston.

My colleagues at CIRM beat me to the punch yesterday (Wernig is a CIRM grant recipient) with a nice blog post about the award.

I’ve written several times (here and elsewhere) about Wernig’s research as part of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. Essentially, he’s shown that it’s possible to directly convert adult, terminally differentiated cells directly into other types of cells like neurons, without first having to force the cells through a stage called induced pluripotency. It’s exciting stuff.

Wernig, who was in a former life a composer of classical music, joins Stanford researcher Joanna Wysocka, PhD, in the ISSCR hall of fame. She won the award in 2010.

Previously: Stanford scientists turn human skin cells directly into neurons, skipping iPS stage, The end of iPS? Stanford scientists directly convert mouse skin cells to neural precursors and Stanford researcher wins Outstanding Young Investigator Award from international stem cell society.
Video courtesy of the California Institute for Regenerative Medicine

Yesterday marked a big day for Stanford and the local community: Ground was broken for the new Stanford Hospital & Clinics. As Ruth Schechter reports in our online story:

Scheduled to open to patients in 2018, the new building will optimize the hospital’s services and infrastructure, adding more beds, private rooms, state-of-the-art operating suites, expanded emergency services and the flexibility the hospital needs to adapt to advancing technologies and more streamlined services.

The new 824,000-square-foot hospital will increase patient capacity to 600 beds and feature 368 individual patient rooms, an enlarged level-1 trauma center and an emergency department nearly three times the size of the current capacity. Designed by the internationally recognized firm Rafael Viñoly Architects, the project will feature amenities intended to enhance both physical and emotional healing with the latest in medical, surgical and diagnostic technology. The new building will be connected to the current hospital by a bridge and tunnel.

The new hospital will feature individual patient rooms centered on health and well-being, with expansive windows that provide natural light and integrated accommodations for family members to visit and spend the night. Patient rooms will be modular, allowing them to accommodate any level of acuity. A roof garden setting will create a quiet retreat for patients and families, and landscaping will feature native and drought-tolerant plants. The building also incorporates the latest innovations in green technology to reduce the hospital’s environmental impact.

About 400 community members, donors, and administrators, including Amir Dan Rubin, the hospital’s president and CEO, and Lloyd Minor, MD, dean of the School of Medicine, were on hand late yesterday to watch as “shiny red shovels were put to ceremonial dirt.”

Previously: Growing up: The expansion of Lucile Packard Children’s Hospital, Hospital mock-ups help refine plans before construction begins and City of Palo Alto approves rebuilding and expansion of Stanford Hospital and Lucile Packard Children’s Hospital
Rendering of new hospital from Rafael Viñoly Architects