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Autism, Mental Health, Neuroscience, Research, Science, Stanford News, Stem Cells

Brain cell spheres in a lab dish mimic human cortex, Stanford study says

Brain cell spheres in a lab dish mimic human cortex, Stanford study says

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Mental disorders like autism and schizophrenia are notoriously difficult to study at the molecular level. Understandably, people are reluctant to donate pieces of living brain for study, and postmortem tissue lets researchers see the structure, but not the function, of the cells.

Now researchers in the laboratories of psychiatrist Sergiu Pasca, MD, and neurobiologist Ben Barres, PhD, have found a way to make balls of cells that mimic the activity of the human cortex. They use a person’s skin cells, so the resulting “human cortical spheroid” has the same genetic composition as the donor. The research was published in Nature Methods yesterday.

According to our release:

Previous attempts to create patient-specific neural tissue for study have either generated two-dimensional colonies of immature neurons that do not create functional synapses, or required an external matrix on which to grow the cells in a series of laborious and technically difficult steps.

In contrast, the researchers found they were able to easily make hundreds of what they’ve termed “human cortical spheroids” using a single human skin sample. These spheroids grow to be as large as 5 millimeters in diameter and can be maintained in the laboratory for nine months or more. They exhibit complex neural network activity and can be studied with techniques well-honed in animal models.

The researchers, which include neonatology fellow Anca Pasca, MD, and graduate student Steven Sloan, hope to use the technique to help understand how the human brain develops, and what sometimes goes wrong. As described by Barres:

The power and promise of this new method is extraordinary. For instance, for developmental brain disorders, one could take skin cells from any patient and literally replay the development of their brain in a culture dish to figure out exactly what step of development went awry — and how it might be corrected.

The research is starting to garner attention, including this nice article from Wired yesterday. Pasca’s eager to note, however, that he’s not working to create entire brains, which would be ethically and technically challenging, to say the least. But simply generating even a few of the cell types in the cortex will give researchers a much larger canvas with which to study some devastating conditions. As Pasca notes in our release:

I am a physician by training. We are often very limited in the therapeutic options we can offer patients with mental disorders. The ability to investigate in a dish neuronal and glial function, as well as network activity, starting from patient’s own cells, has the potential to bring novel insights into psychiatric disorders and their treatment.

Previously: More than just glue, glial cells challenge neuron’s top slot and Star-shaped cells nab new starring role in sculpting brain circuits
Photo of spheroid cross-section by Anca Pasca

Bioengineering, Research, Science, Stanford News

Fly-snatching robot speeds biomedical research

Fly-snatching robot speeds biomedical research

The drosophila hangs unharmed lifted by the robot’s suction tube.

It looks like nothing so much as a miniature UFO hovering over a plate of unsuspecting flies. When it’s ready to strike, it flashes a brief infrared blast of light that reflects off the animals’ backs, indicating the location of each insect. Then, a tiny, narrow suction tube strikes an illuminated thorax, painlessly sucking onto the fly and carrying it away.

It’s not the greatest new gadget to rid your kitchen of unwelcome pests, it’s the latest biomedical research tool from applied physicist Mark Schnitzer, PhD.

The flies in question are commonly studied in biology labs as a proxy for our own harder-to-access cells and organs. As I wrote in a press release:

Although flies and humans have obvious differences, in many cases our cells and organs behave in similar ways and it is easier to study those processes in flies than in humans. The earliest information about how radiation causes gene mutations came from fruit flies, as did an understanding of our daily sleep/waking rhythms. And many of the molecules that are now famous for their roles in regulating how cells communicate were originally discovered by scientists hunched over microscope staring at the unmoving bodies of anesthetized flies.

Until now, scientists have had to anesthetize the flies and painstakingly assess them by microscope. The robot and its machine vision can assess physical features more quickly and in finer detail than lab personnel and can carry out behavioral studies of awake flies.

I spoke with Joan Savall, PhD, a visiting scientist from the Howard Hughes Medical Foundation, who led the development of the robot. He says it will speed research because the robot is both faster and less sleepy that your average graduate student, but what’s really cool is that it opens up entirely new areas of research.

“In the end you can really push many fields at the same time,” he told me.

Previously: Thoughts light up with new Stanford-designed tool for studying the brain and New tool for reading brain activity of mice could advance study of neurodegenerative diseases
Image by Linda Cicero

Cancer, Research, Science, Stanford News

Kidney cancer secrets revealed by Stanford researchers

Kidney cancer secrets revealed by Stanford researchers

I enjoyed recently writing about a collaboration among researchers from Stanford’s School of Medicine and the School of Humanities and Sciences. Oncologist Dean Felsher, MD, PhD, and chemist Richard Zare, PhD, joined forces to learn more about a kidney cancer called renal cell adenocarcinoma; their research was published in the Proceedings of the National Academy of Sciences earlier this week.

In the future, we hope to use this model to… identify those kidney cancer patients who might respond favorably to specific therapies

Together Felsher and Zare found that an aggressive form of kidney cancer has a distinct lipid profile (lipids are a class of molecules found in cell membranes; they also function in cellular signaling pathways and in energy storage). To do so, they used a new technology called desorption electrospray ionization mass-spectrometric imaging, or DESI-MSI. It sounds complicated, but it led directly to a new, previously unsuspected therapeutic approach that may soon be tested in humans. As I described in my article:

DESI-MSI creates a highly detailed, two-dimensional map of the chemical composition of a tissue sample through a process that can be loosely compared to a specialized car wash. Samples are sprayed with a thin, high-powered stream of liquid droplets that dissolve their outer surface. The resulting back spray, which contains molecules from the surface of the sample, is collected and analyzed by mass spectrometry. By moving the tissue sample around in a two-dimensional plane, it’s possible to make a chemical map of its composition.

The researchers found that the cancerous kidney tissue had a chemical composition distinct from that of healthy tissue. In particular, it had higher-than-normal levels of molecules generated as glutamine is metabolized. Blocking the activity of a protein called glutaminase, which is responsible for metabolizing glutamine, caused the animals’ tumors to grow more slowly when [Myc expression was activated].

To conduct the work, researchers in Felsher’s laboratory genetically engineered a strain of mice that could be triggered to express high levels of a cancer-associated protein called Myc in the tubules of their kidneys. These mice quickly developed an aggressive form of kidney cancer when Myc was expressed. Conversely, the kidney tumors shrank significantly when Myc expression was halted. As Felsher told me:

In the future, we hope to use this model to categorize different types of kidney cancer and identify those patients who might respond favorably to specific therapies. In the near term, we can test whether blocking glutamine metabolism is a viable approach for people with Myc-dependent liver cancer.

Previously: Unraveling the secrets of a common cancer-causing gene and Smoking gun or hit-and-run? How oncogenes make good cells go bad

In the News, Medical Education, Research, Science, Stanford News

Medical students explore the wide, wide world of research at annual Stanford symposium

Medical students explore the wide, wide world of research at annual Stanford symposium

Research SymposiumTraining medical students in research skills has long been a focus at Stanford. To get an inside glimpse of how this works, read my story on the Stanford Medical Student Research Symposium, an annual event where students present poster boards of their research for judging by faculty.

The depth and breadth of individual research accomplished by medical students who, at the same time are juggling classroom and clinical education, is impressive. The faculty representative at the event explained the educational process to me:

“Stanford tries really hard to open doors in the area of scientific research and give students a little nudge to go through,” said Laurence Baker, PhD, director of the Scholarly Concentration program, a required program of study for medical students that promotes in-depth learning and scholarship. Each of Stanford’s medical students are required to complete at least one quarter’s worth of research, but most do more, he said.

“We train the kind of doctors who become leaders,” Baker said. “Whether that involves publishing, clinical work, research or patenting — education in scientific research is a key element of training.”

My story also provides a taste of the conversation between one of the students who used the Veterans Administration database to conduct his research of opioid drug use and a judge of the event, who plays the dual role of evaluator and teacher. She provides both constructive criticism and encouragement to the budding physician-scientist:

In a dress shirt and tie, Raymond Deng, a third-year medical student, stood next to a poster describing his research on opioid use among veterans. “I’m interested in addiction medicine,” he said. “Prescription drug abuse is huge.” He was discussing his findings with Sonoo Thadaney, director of the Program in Bedside Medicine… Thadaney, the symposium judge, listened intently to his description, nodding her head in encouragement. “Why did you pick this study?” she said, clipboard in hand. “Personal reasons,” Deng said, adding that someone in his life has a heroin addiction, and that an epidemic in prescription drug abuse has been shown to have contributed to an increase in heroin use. She nodded again. “The great thing with data like this is that the data itself can bring up questions that we didn’t think of,” she said. “If the Googles and the Yahoos of the world can use data like this for research, so can we. Great work. Go crazy with it.”

Previously: Contemporary health issues focus of Stanford med students research presentation, As part of annual tradition, budding physician-scientists display their work and New class of physician-scientists showcase research.
Photo by Norbert von der Groeben

Behavioral Science, In the News, Mental Health, Neuroscience, Research, Science

Inside the brain of optogenetics pioneer Karl Deisseroth

Inside the brain of optogenetics pioneer Karl Deisseroth

brain-494152_1280Lighting the brain,” a recent New Yorker profile, offers insight into the brain of Karl Deisseroth, MD, PhD, the well-known innovator of both optogenetics and CLARITY. (Optogenetics is a genetic engineering feat that allows researchers to control neurons in living animals using light. CLARITY is a technique that makes individual neural connections visible.)

Deisseroth, readers of the article learn, is a guy who shows up to his leading scientific laboratory wearing jeans and a t-shirt and who doesn’t let a little fender bender tweak his mood.

Yes, he’s brilliant. His ability to instantly memorize information morphed into a “circus act” of sorts when he was in elementary school. He began medical school at age 20. But, he’s also driven and hard working. When optogenetics encountered early resistance and doubt after its initial publication in 2005, Deisseroth “began working furiously,” the article states. Into work before 6 a.m., Deisseroth slaved over his brainchild often until 1 a.m., his wife, Michelle Monje, MD, PhD, reported.

It took a few more papers — and demonstrations of the applicability of optogenetics to examine real diseases — for the scientific community to catch on. But then, like a contagion of scientific glee, optogenetics rocked the neuroscience community.

Monje realized its popularity at a recent scientific conference:

“People were stopping us at the airport asking to take a picture with him, asking for autographs,” she said. “He can’t walk through the conference hall—there’s a mob. It’s like Beatlemania. I realized, I’m married to a Beatle. The nerdy Beatle.”

For more on the “nerdy Beatle,” and the science behind both optogenetics and CLARITY, check out the article for yourself. It’s well worth your brain power.

Previously: Stanford’s Karl Deisseroth awarded prestigious Albany Prize, Lightning strikes twice: Optogenetics pioneer Karl Deisseroth’s newest technique renders tissues transparent, yet structurally intact and New York Times profiles Stanford’s Karl Deisseroth and his work in optogenetics
Image by Tumisu

Health Disparities, In the News, NIH, Research, Science, Women's Health

Research for All: Congressional bill aims to bring gender equality to medical research

Research for All: Congressional bill aims to bring gender equality to medical research

Gender matters in medical research. That’s the reasoning behind the Research for All Act (.pdf), a recently introduced Congressional bill that would require scientists conducting NIH-funded research to look at male and female animals and cells. The legislation would also require the FDA “to guarantee that clinical drug trials for expedited drug products are sufficient to determine safety and effectiveness for both men and women.”

As noted in a press release on the bill from U.S. Rep. Jim Cooper (D-Tenn.):

Women compose more than half the U.S. population, but most medical research focuses exclusively on men…

For example, the unique way women metabolize drugs was ignored when researchers determined the dosage for Ambien sleeping pills; as a result, the initial recommended dosage was double what it should have been for women.

Additionally, cardiovascular disease is the leading killer of all Americans, but only one-third of subjects in cardiac clinical trials are women.

In a Nature piece published last spring, Londa Schiebinger, PhD, director of Stanford’s Gendered Innovations in Science, Health & Medicine, Engineering, and Environment, highlighted the “male default” in science and outlined the benefits of taking gender into account during research:

Including gender analysis in research can save us from life-threatening errors… and can lead to new discoveries. Gender analysis has led to better treatments for heart disease in women. Identifying the genetic mechanisms of ovarian determination has enhanced knowledge about testis development. Analysing how sex affects donor–recipient matching is improving stem-cell therapies. And exploring how sex-specific biological factors and gender-specific behaviours interact has helped researchers to understand how nutrients trigger cell functions, and may assist in the fight against obesity.

Previously: Stanford professor encourages researchers to take gender into account, A look at NIH’s new rules for gender balance in biomedical studies, Why it’s critical to study the impact of gender differences on diseases and treatments, Stanford Gendered Innovations program offers tools for improving scientific research and Women underrepresented in heart studies
Via The Hill
Photo by Benita Denny/Wellcome Images

Biomed Bites, Genetics, Medicine and Society, Microbiology, Research, Science, Videos

From yeast to coral reefs: Research that extends beyond the lab

From yeast to coral reefs: Research that extends beyond the lab

Welcome to Biomed Bites, a weekly feature that introduces readers to some of Stanford’s most innovative researchers. 

John Pringle, PhD, focused most of his career on yeast. Easy to culture in the lab, yeast offer scientists a malleable model to learn about all types of cells, including human cells.

As a professor of genetics, he still does a bit of that. But now, his heart is focused on saving the world’s coral reefs – no small task given that these living ecosystems are vulnerable to temperature changes, carbon dioxide concentrations and overfishing.

Pringle’s research concentrates on a small sea anemone known as Aiptasia pallida, as he explains in the video above:

We picked an experimental system that has huge advantages over the corals themselves and we try to learn basic things about their molecular and cellular biology that will help us with the more complex and less experimentally tractable system of the reefs.

Just as with his yeast work, the lessons learned from the anemones are directly applicable to human well-being. “Corals are important to hundreds of millions of people around the world for livelihood and for the beauty they bring and the food they provide,” he says. “We have the hopes that by doing basic research, we’ll contribute to an understanding of how coral reefs might be preserved.”

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

Previously: Bubble, bubble, toil and trouble — yeast dynasties give up their secrets, Yeast advance understanding of Parkinson’s disease, says Stanford study and My funny Valentine — or, how a tiny fish will change the world of aging research

AHCJ15, Science, Science Policy, Stem Cells

Stanford stem cell experts highlight “inherent flaw” in drug development system

Stanford stem cell experts highlight "inherent flaw" in drug development system

Academic institutions are in a much better position than pharmaceutical companies to make the best decisions about which therapies deserve further development. That was the underlying message from a pair of Stanford researchers at a panel on stem cell science at last weekend’s Association of Health Care Journalism 2015 conference.

“There’s an inherent flaw in our system,” said Irving Weissman, MD, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. “Companies are driven by the desire for profits rather than the desire to find the best therapy, and they often give up on discoveries too early.”

Weissman cited studies that were done long ago at Stanford and proven in mouse models or human clinical trials that pharmaceutical companies have failed to develop. “In mice, transplantation of purified blood stem cell and insulin producing cells from closely related mice leads to a permanent cure,” Weissman says. “We discovered that 16 years ago, and a therapy is still not available.”

A therapy involving high-dose chemotherapy followed by purified stem cell transplant for stage 4 breast cancer cured a relatively high number of women in a small trial almost 20 years ago but the pharmaceutical company with the rights to the technology decided not to develop the treatment, Weissman says. A larger trial of this therapy is currently being planned at Stanford.

Maria Grazia Roncarolo, MD, co-director of the institute, spoke about her own experience in an academic environment developing therapies for diseases that pharmaceutical companies deem to rare to merit their attention. Only after she showed that a therapy for severe combined immune deficiency could work did pharmaceutical companies get interested.

“Academic researchers should have the ability to test a therapy, to have control of the design and execution of the clinical trials, and pharmaceutical companies should do the production and marketing,” Roncarolo told the journalists attending the session.

Allowing academic institutions to run clinical trials is “a big effort that will require a team, institutional commitment and robust funding,” Roncarolo said. Comparing the situation in the United States to that in Europe, where she has done much of her research, she notes that “in this country there is little funding for proof of concept trials to bring therapies from the lab bench to the bedside.”

Previously: An inside look at drug development, Stanford’s Irving Weissman on the (lost?) promise of stem cells and The largest stem cell research building in the U.S.

FDA, Medicine and Society, Men's Health, Research, Science, Women's Health

Sex matters: Why we shouldn’t conduct basic research without taking it into account

Sex matters: Why we shouldn't conduct basic research without taking it into account

2593063816_9a4eaba16e_zIn a PNAS opinion piece (.pdf) published last week, two Stanford faculty are among the authors arguing that sex shouldn’t be overlooked in basic research studies. Londa Schiebinger, PhD, director of the Gendered Innovations in Science, Health & Medicine, Engineering, and Environment program, and Marcia L. Stefanick, MD, director of the Stanford Center for Health Research on Women and Sex Differences in Medicine, take issue with the fact that much of the research that leads to drugs, devices, and our conclusions about biology comes from studies conducted on non-human animals and cell cultures without considering their sex.

Evolutionarily speaking, sex is one of the most well-conserved biological differences, of fundamental importance to 100 percent of the population. Paying more attention to it, the authors claim, would help biomedical research disaggregate data and explain heterogenous outcomes. While some think it would create unnecessary duplication to account for sex earlier in the research process, before drugs and treatments are tested on humans, the authors argue that such practices would save money and be more efficient in the long run. Early tests are far less expensive than removing something from the market because it has adverse effects on half the population. Moreover, preventing such adverse outcomes would keep people of both sexes safer and healthier.

The article states that the FDA is beginning to reconsider whether unisex dosing is accurate and safe for many drugs, and cites that “about 80% of rodent drug studies are conducted only on males, and 8 of 10 drugs withdrawn from the US market from 1997 to 2000 posed greater health risks for women than for men.”

Previously: Stanford professor encourages researchers to take gender into account, A look at NIH’s new rules for gender balance in biomedical studies and Why it’s critical to study the impact of gender differences on diseases and treatments
Photo by Rick Eh?

Applied Biotechnology, Bioengineering, Ophthalmology, Research, Science, Technology

New retinal implant could restore sight

New retinal implant could restore sight

2618400441_c19946dff4_zIf your car battery runs out of juice, the car won’t run, but that doesn’t mean it’s time to scrap the car. Similarly (at least slightly), if your photoreceptors are worn out due to a disease such as retinitis pigmentosa or macular degeneration, then you might not be able to see, but your eyes still have a lot of functioning parts.

That’s the principle behind a new retinal implant developed by team of Stanford-led researchers. Unlike previous devices, which require wires and unwieldy surgeries, the new implant is wireless and needs only a minimally invasive surgery to inject a small, photovoltaic chip inside the eye. The team published their results in Nature Medicine.

That chip capitalizes on the remaining capabilities of existing retinal cells known as bipolar and ganglion cells and produces more refined images than existing devices. The chip responds to signals from special glasses worn by the recipient.

“The performance we’re observing at the moment is very encouraging,” Georges Goetz, a lead author of the paper and graduate student in electrical engineering at Stanford, said in our press release. “Based on our current results, we hope that human recipients of this implant will be able to recognize objects and move about.”

The implant has only been used in animal studies, but a clinical trial is planned next year in France.

“Eventually, we hope this technology will restore vision of 20/120,” co-senior author Daniel Palanker, PhD, told me. “And if it works that well, it will become relevant to patients with age-related macular degeneration.”

Previously: Stanford researchers develop solar powered wireless retinal implant, Factors driving prescription decisions for macular degeneration complex — and costly and Tiny size, big impact: Ultrasound powers miniature medical implant 
Photo by Ali T

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