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Bioengineering, Imaging, Neuroscience, Research, Stanford News, Stem Cells

New way to watch what stem cells transplanted into the brain do once they get there

New way to watch what stem cells transplanted into the brain do once they get there

binocularsStem cell replacement therapy is a promising but problem-plagued medical intervention.

In a recent news release detailing a possible way forward, I wrote:

Many brain disorders, such as Parkinson’s disease, are characterized by defective nerve cells in specific brain regions. This makes disorders such as Parkinson’s excellent candidates for stem cell therapies, in which the defective nerve cells are replaced. But the experiments in which such procedures have been attempted have met with mixed results, and those conducting the experiments are hard put to explain them.

That’s because there’s been no good way to evaluate what those transplanted stems cells are doing once you’ve put them inside a living individual. I mean, you’re not gonna break into someone’s brain every couple of days to take a peek, right? Instead, you have to look for behavioral changes. Is the patient or experimental animal walking better (if you’re trying to treat Parkinson’s), or (if it’s Alzheimer’s) remembering better ? Then, even when you see those changes, you still don’t know whether new nerve cells derived from the newly transplanted cells integrated into the proper brain circuits and are now functioning correctly there, or whether the originally transplanted cells are just sitting around secreting some kind of feel-good factor to pep up ailing cells in the vicinity, juicing their  performance. Or maybe it was a placebo effect.

It’s hard to improve on a procedure when you don’t really know what went wrong – or even what went right – on the last attempt. Optimizing the regimen becomes a matter of guesswork and luck.

But in a new study in NeuroImage, neuroscientist/bioengineer Jin Hyung Lee, PhD, and her colleagues came up with a way to peer deep into the living brain and view the results of a stem-cell transplant procedure. They combined an established brain-imaging technique with a newer but increasingly widespread one, called optogenetics, that lets researchers stimulate specific cells.

The first step in optogenetics is to genetically modify the cells you want to stimulate, so that their surfaces become coated by a photosensitive protein that generates electric current in response to laser light. Lee’s team performed this operation on the stem cells before transplanting them into rats’ brains. This way, they could selectively stimulate nerve cells derived from those stem cells and,  using the brain-imaging technique, see if doing so triggered nerve-cell activity at the site of the transplant as well as other places in the brain with which the new cells had established connections.

In these experiments, the stem-cell-derived nerve cells survived, matured into nerve cells, integrated into targeted brain circuits and, most important, fired on cue and ignited activity in downstream nerve circuits. But had all that not happened, at least the researchers would have been able to pinpoint the weak link in the chain.

In principle, the new approach should be possible to use for all kinds of stem-cell therapies, and in humans as well as animals. As Lee told me when I interviewed her for my release on her new study, “If we can watch the new cells’ behaviors for weeks and months after we’ve transplanted them, we can learn – much more quickly and in a guided way rather than a trial-and-error fashion – what kind of cells to put in, exactly where to put them, and how.”

If this light-driven stem-cell-monitoring technique or some others I’ve reported on hold up, brave explorers may no longer have to poke around in the dark.

Previously: Alchemy: From liposuction fluid to new liver cells, Iron-supplement-slurping stem cells can be transplanted, then tracked to make sure they’re making new knees, You’ve got a lot of nerve! Industrial-scale procedure for generating plenty of personalized nerve cells and Nano-hitchhikers ride stem cells into heart, let researchers watch in real time and weeks later
Photo by Nicki Dugan Pogue

AHCJ15, Applied Biotechnology, Imaging, Mental Health, Neuroscience, Technology

Talking about “mouseheimers,” and a call for new neuroscience technologies

Talking about "mouseheimers," and a call for new neuroscience technologies

3723710203_1b8c9d96ed_zOur ability to technologically assess the brain has room for improvement, according to panelists at the recent Association of Health Care Journalism 2015 conference. Amit Etkin, PhD, MD, neuropsychiatrist and psychiatrist at Stanford, summed it up when he said, “We need to develop tools to answer questions we want to ask, rather than ask questions we can answer with the tools we have.”

Etkin asserted that there have been no fundamental advances in psychiatry since 1987; all the medications put out now are basically the same, and the treatments work partially, sometimes, and for only some people. Interdisciplinary work combining psychiatry, neuroscience, and radiology is the frontier: Researchers are just getting a sense of how “interventional neuroscience,” such as that pioneered at the interdisciplinary NeuroCircuit initiative at the Stanford Neurosciences Institute, can identify which brain regions control various processes. This involves looking at brain signatures that are common across disorders, instead of dividing and parsing symptoms, which is the approach of the Diagnostic and Statistical Manual of Mental Disorders.

Researchers are searching for an ideal marker for Alzheimer’s: something predictive (will you get the disease?), diagnostic (do you have the disease?), and dynamic (how severe is your disease right now?)

Michael Greicius, MD, MPH, professor of neurology and neurological sciences at Stanford, researches Alzheimer’s and has a bone to pick with media hype about Alzheimer’s research conducted in mice. What the mice have shouldn’t be considered the same condition, he says, so he’s termed it “mouseheimer’s.” Only 2 percent of the Alzheimer’s population has the dominant, inherited, exceedingly potent genetic form, which is the form used in research on rodents. Further, the mice are double or even triple transgenic. We still use these improbable biological hosts because we need an artificial model: Alzheimer’s is really just a human thing, and even great apes don’t get it. The next best modeling possibility, he suggested, are flies.

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Biomed Bites, Imaging, Neuroscience, Research, Science, Videos

Vrrrooom, vrrrooom vesicles: A Stanford researcher’s work on neurotransmission

Vrrrooom, vrrrooom vesicles: A Stanford researcher's work on neurotransmission

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

When one neuron wants to communicate with another neuron, it doesn’t talk, make gestures, or perform an interpretive dance. Instead, it ejects a vesicle filled with chemical information. That vesicle travels like an interstellar ship to the next neuron, which sucks it up, receiving the message.

And this isn’t a slow, hmm, maybe-I-should-send-this-out-sometime-today kind of message.

“The process of effusion of synaptic vesicles is very fast,” says Axel Brunger, PhD, in the video above. “It occurs on the order of a millisecond. It’s one of the fastest known biological processes, so we’re trying to understand this process at a molecular level and how it actually works is a big mystery at the moment.”

Brunger, the chair of the Department of Molecular and Cellular Physiology, and his team use a variety of optical imaging methods and high-resolution structural methods to examine the transmission of synaptic vesicles:

We’re now using our [in vitro] system to study the effect of a number of factors, including factors involved in a number of diseases.

What we are hoping from these studies is to obtain a better understanding of how these factors and then secondly and importantly, to develop new strategies or therapeutics to combat these diseases.

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

Previously: New insights into how the brain stays bright, Revealed: The likely role of Parkinson’s protein in the healthy brain and Examining the potential of creating new synapses in old or damaged brains 

Imaging, Research, Stanford News, Stroke, Technology

Image-interpretation software could open window of treatment for stroke

Image-interpretation software could open window of treatment for stroke

open windowRestoring blood flow to the brain quickly after a stroke is key to damage control as well as to optimal recovery. But restoring blood flow to brain tissue that is already dead can cause problems, like swelling and hemorrhage.

That makes the treatment of choice – an intravenous dose of a substance called tPA, which dissolves clots – a double-edged sword. The consensus in the medical community is that tPA is not a good idea once 4-1/2 hours have elapsed since a patient has suffered a stroke.

But the consensus is based on averages, derived from numerous studies. Clinicians have tended to treat that 4-1/2 hour time-point as analogous to a window slamming shut. Yet every stroke, and every patient who experiences one, is unique.

A new study published in the New England Journal of Medicine joins three earlier ones that show improved results when tPA administration is combined with the insertion of a device – a so-called stent retriever – that can mechanically break up clots in the brain.

Even more exciting, two of the four studies, including the new one, employed software called RAPID – designed and developed at Stanford at the instigation of Stanford neurologist Greg Albers, MD – that quickly interprets brain scans of patients and helps clinicians decide which patients will benefit from supplementing the standard intravenous tPA infusion with the stent retrieval procedure. In both of these two studies, substantial majorities of patients selected as good candidates for the combination had extremely high rates of solid recovery as measured three months after their stroke – the best results ever obtained in stroke studies.

Albers, who is also one of the co-authors of the new NEJM study, hopes to move stroke care away from the clock on the wall and instead focus on a biological clock – what the brain image shows to be going on inside this patient’s brain, now – so that each patient’s care can be individualized and optimized. It could turn out that for some patients, 4-1/2 hours after a stroke is already too late for aggressive clot-busting treatment, while for others the window remains wide open for 6, 7, 8 hours or longer.

Previously: Targeted stimulation of specific brain cells boosts stroke recovery in mice, Calling all pharmacologists: Stroke-recovery mechanism found, small molecule needed and Stanford neuroscientists uncover potential drug treatment for stroke
Photo by glasseyes view

Biomed Bites, Imaging, Neuroscience, Research, Technology, Videos

Peering under the hood – of the brain

Peering under the hood - of the brain

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

Fixing a broken brain is much like fixing a malfunctioning car, misbehaving computer or most anything else that isn’t working as it should.

“Whenever we’re trying to fix something that’s broken, it can be very helpful indeed to understand how that thing works,” says Stephen Smith, PhD, in the video above. “I believe the brain does not pose an exception to this rule.”

That’s why Smith, a professor of molecular and cellular biology, emeritus, has spent his career developing better ways to understand — and see — the brain.

Currently, he’s most excited about a technique called array tomography that allows researchers to observe the brain’s wiring, the linkages between neurons, and gain a better understanding of how it functions.

That technique, as well as others, offers real hope for fixing brains broken by autism, Alzheimer’s disease or other brain disorders. Here’s Smith:

I think the progress we’re making today in understanding basic brain mechanisms is likely to help us greatly as we develop new drugs that can help lessen or reverse the wide array of neurodegenerative or neurodevelopmental or injury-related disorders of the brain.

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

Previously: Visualizing the brain as a Universe of synapses, Examining the potential of creating new synapses in old or damaged brains and Fantastic voyage: Stanford researcher offers a virtual flight through the brain

Big data, Imaging, Neuroscience, Research, Science, Stanford News, Technology, Videos

All data – big and small – informs large-scale neuroscience project

All data - big and small - informs large-scale neuroscience project

The thought of gaining access to data from thousands of brains would make most neuroscientists salivate. But now, a team of Stanford and Oxford researchers is able to do just that. Led by Jennifer McNab, PhD, assistant professor of radiology, the group compares magnetic resonance images from as many as 100,000 people with in-depth 3-D scans developed using CLARITY, a technique developed at Stanford that visualizes intact tissue.

“This is a tremendous resource in terms of scientists being able to look and see who develops a particular disease and who does not and why that may be,” McNab said in the video above.

Her team — which includes Karl Deisseroth, MD, PhD; Michael Zeineh, MD, PhD and Michael Greicius, MD, MpH — is tapping the U.K. Biobank, which has about 500,000 participants. It also uses data from the NIH Human Connectome Project, which could include up to 1,200 MRI images. The project received a 2014 Big Data for Human Health Seed Grant and is part of Stanford Medicine’s Biomedical Data Science Initiative (BDSI), which strives to make powerful transformations in human health and scientific discovery by fostering innovative collaborations among medical researchers, computer scientists, statisticians and physicians.

The project uses two distinct types of “big data.” The large databases with hundreds of entries clearly falls under this umbrella, but even one dataset from CLARITY, which produces extremely high-resolution images, produces big data, she said.

The project may make it possible to glean more diagnostic information from MRIs, McNab said. “Then we can hopefully develop early biomarkers of disease that will ultimately help to guide treatment plans and preventative measures,” she said.

This project offers just a glimpse at the potential of data science. For more on important work being done in this area, mark your calendars for Stanford’s Big Data in Biomedicine conference May 20-22. More information is available here.

Previously: Registration for the Big Data in Biomedicine Conference now open, How CLARITY offers an unprecedented 3-D view of the brain’s neural structure and Euan Ashley discusses harnessing big data to drive innovation for a healthier world

Imaging, In the News, NIH, Pregnancy, Research, Women's Health

NIH puts focus on the placenta, the “fascinating” and “least understood” organ

NIH puts focus on the placenta, the "fascinating" and "least understood" organ

ultrasoundLast week, the NIH announced its support for an initiative to study how new technologies can shed light on the placenta’s function and health during pregnancy. Considering how crucial the placenta is to not only the health of a woman and her fetus during pregnancy, but also to the lifelong health of both, it’s surprising to hear the NIH call it “the least understood human organ.”

Currently, doctors and scientists can only gather information about the placenta by using ultrasounds and blood tests, and by examining it after delivery. What if new sensors could track how well blood, oxygen, and nutrients are flowing to the fetus, or if new imaging technologies could assess how well the placenta is attaching to the uterine wall? What if biotechnology could assess the effects of environmental factors on the placenta, such as air pollution, maternal diet, and medications?

Better understanding and monitoring of this temporary organ promises to improve maternal and child health. Placental issues can contribute to negative pregnancy outcomes such as preeclampsia, gestational diabetes, preterm birth, and stillbirth, and they’ve also been linked to a higher risk of heart disease later in life, for both mother and child.

This is the third and largest funding announcement for the NIH’s Human Placenta Project, led by the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development and cosponsored by the NIH’s National Institute of Biomedical Imaging and Bioengineering.

Calling the placenta a “fascinating organ” and the “lifeline that gives us our start in the world” Alan E. Guttmacher, MD, director of the NICHHD, also said in an NIH press release:

We hope this funding opportunity will attract a broad range of researchers and clinicians to help — placental biologists, obstetricians, and experts in imaging, bioengineering, and other arenas… For researchers who want to apply their skills in an area of medicine that isn’t being looked at as much as both scientific opportunity and human health warrant, this is a wonderful chance.

Previously: Placenta, the video game, The placenta sacrifices itself to keep baby healthy in case of starvation and Program focuses on the treatment of placental disorders
Related: Too deeply attached and A most mysterious organ
Photo by thinkpanama

Imaging, Neuroscience, Research, Videos

Exploring the science of decision making

Exploring the science of decision making

Every day we make decisions that affect our work, personal relationships and health. With stakes this high, it’s no wonder many of us dread decision-making and wish we knew how to make better choices.

The first step towards making better decisions is to understand how the process works. This animation from Worldview Stanford’s upcoming course, The Science of Decision Making, shows the regions of the brain that are activated as we evaluate information.

Enrollment is now open for this interdisciplinary course, which explores and applies the nitty-gritty science of making a choice. If you’re unable to participate in the class, but you’d like to learn more about how to make better decisions, you can visit the Worldview Stanford blog for a sample of animations, videos and content from this course and their other offerings (.pdf).

Previously: Exploring the intelligence-gathering and decision-making processes of infantsIs there a connection between consuming mass media and making healthy choices?Genetics may influence financial risk-takingStanford neurobiologist Bill Newsome: Seeking gains for the brain and How does the brain plan movement? Stanford grad students explain in a video

Cancer, Imaging, In the News, Research, Technology

Stanford instructor called out for his innovative – and beautiful – imaging work

Stanford instructor called out for his innovative - and beautiful - imaging work

breast cancer cells

I’ll skip the name word play – it’s just too obvious – but I won’t skip Michael Angelo’s work. Angelo, MD, a pathology instructor at Stanford, developed a new imaging technique that labels antibodies with metallic elements, then uses an ion beam to scan the tissue, revealing up to 100 proteins at once in a single cancer cell.

This technique, called multiplexed ion beam imaging, or MIBI, captured the attention of the National Institutes of Health, which featured Angelo in its NIH Director’s Blog this week. The images are lovely to look at, but also quite useful to learn more about tissue types.

Here’s Angelo describing the image above:

Angelo used MIBI to analyze a human breast tumor sample for nine proteins simultaneously—each protein stained with an antibody tagged with a metal reporter. Six of the nine proteins are illustrated here. The subpopulation of cells that are positive for three proteins often used to guide breast cancer treatment (estrogen receptor a, progesterone receptor, Ki-67) have yellow nuclei, while aqua marks the nuclei of another group of cells that’s positive for only two of the proteins (estrogen receptor a, progesterone receptor). In the membrane and cytoplasmic regions of the cell, red indicates actin, blue indicates vimentin, which is a protein associated with highly aggressive tumors, and the green is E-cadherin, which is expressed at lower levels in rapidly growing tumors than in less aggressive ones.

Taken together, such “multi-dimensional” information on the types and amounts of proteins in a patient’s tumor sample may give oncologists a clearer idea of how quickly that tumor is growing and which types of treatments may work best for that particular patient.  It also shows dramatically how much heterogeneity is present in a group of breast cancer cells that would have appeared identical by less sophisticated methods.

Angelo was given a NIH Director’s Early Independence Award last fall, and he’s ramping up his investigations of breast cancer.

Imaging, Mental Health, Neuroscience, NIH, Research, Stanford News

Study: Major psychiatric disorders share common deficits in brain’s executive-function network

Study: Major psychiatric disorders share common deficits in brain's executive-function network

marble brainPsychiatric disorders, traditionally distinguished from one another based on symptoms, may in reality not be as discrete as we think.

In a huge meta-analysis just published in JAMA Psychiatry, Stanford neuroscientist and psychiatrist Amit Etkin, MD, PhD, and his colleagues pooled the results from 193 different studies. This allowed them to compare brain images from 7,381 patients diagnosed with any of six conditions – schizophrenia, bipolar disorder, major depression, addiction, obsessive-compulsive disorder, and a cluster of anxiety syndromes – to one another, as well as to brain images from 8,511 healthy patients.

Compared with healthy brains, patients in all six psychiatric categories showed a loss of gray matter in each of three separate brain structures. These three areas, along with others, tend to fire in synchrony and are known to participate in the brain’s so-called “executive-function network,” which is associated with high-level functions including planning, decision-making, task-switching, concentrating in the face of distractions, and damping counterproductive impulses.

The findings call into question a longstanding tendency to distinguish psychiatric disorders chiefly by their symptoms

(“Gray matter” refers to information-processing nerve-cell concentrations in the brain, as opposed to the “white matter” tracts that, like connecting cables, shuttle information from one part of the brain to another.)

As Etkin told me when I interviewed him for the news release we issued on this study, “these three structures can be viewed as the alarm system for the brain.” More from our release:

“They work together, signaling to other brain regions when reality deviates from expectations – that something important and unpredicted has happened, or something important has failed to happen.” That signaling guides future behavior in directions more likely to obtain desired results.

The studies of psychiatric patients that Etkin’s team employed all used a technique that yields high-resolution images of the brain’s component structures but can say nothing about how or when these structures work or interact with one another. However, that kind of imaging data was available for the healthy subjects. And, on analysis, those healthy peoples’ performance on classic tests of executive-function (such as  asking the test-taker to note the color of the word “blue,” displayed in a color other than blue, after seeing it briefly flashed on a screen) correlated strongly with the volume of gray matter in the three suspect brain areas, supporting the idea that the anatomical loss in psychiatric patients was physiologically meaningful.

The findings call into question a longstanding tendency to distinguish psychiatric disorders chiefly by their symptoms rather than their underlying brain pathology – and, by implication, suggest that disparate conditions may be amenable to some common remedy.

As National Institute of Mental Health Director Thomas Insel, MD, told me in an interview about the study, the Stanford investigators “have stepped back from the trees to look at the forest and see a pattern in that forest that wasn’t apparent when you just look at the trees.”

Previously: Hope for the globby thing inside our skulls, Brain study offers intriguing clues toward new therapies for psychiatric disorders and Study shows abnormalities in brains of anxiety-disorder patients
Photo by Philippe Put

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