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  • richardmitnick 12:40 pm on November 22, 2017 Permalink | Reply
    Tags: , , , Medicine, Sangeeta Bhatia,   

    From Brown: Women in STEM- “Building a Better Way” Sangeeta Bhatia 

    Brown University
    Brown University

    November/December 2017
    Louise Sloan

    Sangeeta Bhatia. Geordie Wood


    Be Recognized for Who You Are

    Sangeeta Bhatia ’90 may not have had many role models to look up to as a woman engineer, but that doesn’t mean she didn’t learn a lot of lessons along the way. Here’s some of her advice for people from any group that has been historically underrepresented in the field.

    STAY CONFIDENT. Being one of the only women or people of color in your field is difficult. Keep focused on your strengths. Bhatia says she struggled with “imposter syndrome.” “There’s this feeling that you don’t belong, and you’re always second guessing yourself. That does diminish with time.”

    TAKE THAT MEETING. With famous scientists or engineers, Bhatia learned to ask questions or strike up a conversation about the person’s most recent paper. The collaboration that led to one of her most important breakthroughs was a result of following up on a colleague’s offer of an introduction. Worst case, making connections can make a dull meeting more interesting. “Okay, I’m at a conference,” she’d tell herself; “Who are the people I want to meet? What the heck? Let’s meet them.”

    SPEAK UP EARLY ON. In business meetings, Bhatia says, often “I was the only woman, only engineer, only person of color.” And she looked young. “One thing I quickly realized was that I needed to make a comment or ask an insightful question pretty early in the convening of a group.” It wasn’t her personal style to do this, but, she realized, “there are times where you’ve got a group of really high-powered people together, and you’re there for an hour, and nobody knows who you are. You have something important to add. You have to make it clear early in the conversation why you’re at the table.”

    IDENTIFY MENTORS. When Bhatia and Theresia Gouw ’90 were seniors and looked into what made some women stay in engineering while so many others left, they found that what the women who’d stayed all had in common was mentors—whether that was a professor, parents, or a family friend. Bhatia concedes it’s hard to force these relationships. It’s clear that her mentors came not just through luck but also through her own efforts in cultivating relationships with key people around her and following up on any advice and opportunities.

    STUDY SUCCESS. Identify your weaknesses and look around at who is doing that thing well. Bhatia says she was comfortable expressing her ideas one-on-one, and as a professor she also became comfortable speaking to a lecture hall. But groups of between 10 and 30 people in faculty meetings or on advisory boards felt awkward to her. “I started studying it and looking at who is really effective in this setting. How have they managed to be effective? At what points are they choosing to speak up? What offline work have they done to grease this conversation so that by the time they speak up, they’re able to carry the room? I made kind of a project of it, trying to figure it out, because I realized I wasn’t actually naturally good at that.”

    BE YOUR OWN BOSS. “This is something Theresia has taught me, which is that one of the answers to diversity is to create your own organization, put yourself at the top, make the culture that you want it to be.
    Lego characters designed by Maia Weinstock ’99, Photo by Erik Gould
    Lego minifigures, like engineers, are disproportionately
 male. But Sangeeta Bhatia ’90 has her own, custom-made in 2015 by Maia Weinstock ’99. It’s a fitting tribute to the engineer, physician, biotech entrepreneur, and mom who takes tiny pieces and puts them together in unexpected ways.

    Bhatia is literally a soccer mom when she’s not coming up with incredible scientific breakthroughs. Her husband, Jagesh Shah, coaches their daughters’ teams. But take heart, mere mortals. “My car is a mess; it smells like a dead animal right now,” she has admitted. “I don’t cook. At all.”

    Bhatia does a lot of things a little differently. She has used microfabrication, the technology behind microchips, to grow human liver cells outside the body. This has allowed drug companies to test toxicity on these “micro livers” in the lab and to hope that they can someday manufacture whole human livers for transplant patients. She is a senior scientist at a top institution, but instead of spending nights and weekends at the lab, she insists on balance so that, for example, Wednesdays are “Mommy Day” spent with her kids.

    Her very presence in the field of bioengineering as an engaging, stylish woman of color is de facto doing things differently. “Many people still have this image of an engineer as a kind of nerdy guy, interested in taking things apart,” Bhatia said in an October 2015 speech at Brown celebrating the groundbreaking of the new engineering building (it just opened this fall). “Someone who stays up all night playing video games and eating Doritos, with very few social skills. Right?”

    Bhatia, a petite figure in a sleeveless top and capri pants, her toenails a chic shade of blue, is not that guy. She took a gap year after Brown in which she backpacked and taught aerobics. She does classical Indian dance to relax—she thinks that’s what caught the attention of Brown’s admission office—and, with husband Jagesh Shah, a professor at Harvard, she runs her kids’ elementary school science fair. She’s literally a soccer mom—Shah coaches their daughters’ teams. But take heart, mere mortals. “My car is a mess; it smells like a dead animal right now,” she admitted to Nova ScienceNOW when they profiled her in 2009. “I don’t cook. At all.”

    What she does do, with the team she’s assembled at her lab at MIT, is figure out which sequences of amino acids can get into a tumor, then put them on synthetic materials that are way smaller than the diameter of a human hair, and use that to detect cancer. They’ve managed to grow the dormant version of malaria in a dish so drugs can be tested in vitro before being tested in humans. They’ve also prototyped breathalyzer and urine tests for cancer.

    Bhatia has been elected to the National Academy of Sciences and the National Academy of Inventors, and she was one of the youngest women ever elected to the National Academy of Engineering. She’s won prestigious national prizes and awards, including the Lemelson-MIT Prize, known as the “Oscar for inventors.” In addition to having her own lab, the Laboratory for Multiscale Regenerative Technologies, she recently launched The Marble Center for Cancer Nanomedicine at MIT. The prize for cleanest car in the Boston area can probably wait.

    The door to her future was in the Biomed Center

    Bhatia, who was born and raised in Boston, got interested in bioengineering at Brown when, in order to get to her human physiology lab, she had to walk past a door in the Biomed Center that was labeled “artificial organs.” That sounded cool to her, so one day she knocked on the door. “I begged them to let me intern,” she says. She spent the summer working on using electricity-producing plastics (piezoelectrics) to enhance nerve regeneration and became hooked on the field that is now called tissue engineering. After Brown and that post-undergrad gap year, in which she also worked for a pharmaceutical company pressing pills (“it was really boring”), she started grad school at MIT.

    Her parents approved. Bhatia’s father was an engineer, and her mother was one of the first women in India to earn an MBA. They considered three careers acceptable: doctor, engineer, or entrepreneur. So when Bhatia said she wanted to pursue a PhD because bioengineering bosses seemed to have them, her father, who felt PhDs are often impractical, asked, “When are you going to start a company?”

    It took a few years. In 2008 she launched Hepregen to bring the artificial liver technology to the commercial market, and she started Glympse Bio in 2015 to commercialize the urine-test diagnostics, with investment from her Brown roommate, longtime friend, and venture capitalist Theresia Gouw ’90. “We are scheduled to start, we hope, our first clinical trials next year,” Bhatia says, “It’s like having another child.”

    Bhatia’s work producing artificial livers started in her second year at MIT, when she joined the lab of Mehmet Toner, a biomedical engineer who was trying to develop a device that would use human liver cells to process the blood of patients with liver failure. Bhatia set out to figure out how to get liver cells to grow outside the body. She tried and failed for two years. Then she had a breakthrough.

    In the body, liver cells don’t just grow on their own, Bhatia explains. They grow in a particular structure—a community, she calls it—with connective tissue cells. But just throwing both types of cells into a petri dish didn’t work. Instead, Bhatia hit on the idea of creating the right structure for these cells by using microfabrication techniques designed to create computer chips. Instead of putting tiny circuits on a chip, she etched a glass culture dish with the geometric configuration in which liver cells grow in the body. Success: the liver cells, organized in the right way and supported by connective tissue cells, could live for several weeks outside the body. Today, pharmaceutical companies around the world use Bhatia’s micro livers, grown from human liver cells, to test whether or not their drugs are toxic to humans before they try them on actual people.

    While Bhatia worked in Toner’s lab, she started taking the year’s worth of medical school classes at Harvard that her biomedical engineering program required. Fascinated, she added even more med school classes. Then after she finished up her bioengineering PhD, she transferred into Harvard Medical School as a third-year med student—a foray into one of her other parentally approved career paths. But she still threw her hat in the ring for academic gigs and later that year accepted a junior professor position at UC San Diego. So in 1999, her fourth year of medical school, she multitasked, working at both a hospital (“for inspiration”) and a research lab (“where my heart is”). The combination remains crucial for her work, Bhatia says. “Over my career, I have always looked to the clinic to recognize what the real unmet medical needs are,” she explains.

    In 2005, after six years in San Diego, Bhatia returned with Shah and their first daughter to Boston to accept a professorship at MIT.

    How to build a kinder, gentler top academic lab

    When Bhatia was in grad school she looked “up the pipeline” to the lives of research scientists and engineers, and she didn’t like what she saw. When she popped into the lab one Saturday night at 3 am, her colleagues were still working. When she thought about her future, she says, “I realized I didn’t want to be there every Saturday night.” So when she set up her own lab at MIT, she prioritized excellence but she had other key concerns.

    As with the liver cells she studies, she feels people thrive best in a community and with support. For her own sake and to enhance the success of her lab, Bhatia makes it a priority to hire people who aren’t just great at what they do but can also get along well with others. Like some high-tech entrepreneurs, she encourages them to both work hard and live a balanced life—and to spend 20 percent of their work time “tinkering” on creative projects that may or may not pan out. (The breathalyzer test for cancer came out of one of these “submarine” projects, so called because they’re hidden from Bhatia unless they succeed.) Bhatia’s lab manager, Lian-Ee Ch’ng, says the lab, a warren-like series of rooms on the fourth floor of MIT’s Koch Institute for Integrative Cancer Research, feels very different from others she has worked in. “Sangeeta has a very personal touch,” Ch’ng says.

    Thirty people work in Bhatia’s lab, including a research director, scientists, and the grad students. It looks like any top facility, with row after row of workstations and separate rooms for incubators, specialized microscopes, ultra-low-temperature freezers, and massive tanks of liquid nitrogen. They have a 3-D printer and, perhaps the most high-tech piece of equipment in the lab, Ch’ng says, the Pannoramic 250, a high-speed, five-color slide scanner that produces beautiful digital images of the cells on a microscope slide.

    It looks like a place built for workaholics, where it would be easy to keep your head down and your focus on yourself. But Bhatia doesn’t allow it. She sets a tone of collegiality, Ch’ng says, which really makes a difference: “People talk to each other.”

    There’s an inherent tension, Bhatia admits, in bringing together excellent, ambitious people and also prioritizing work-life balance, community, and citizenship. “They’re not all exactly the same thing,” she says. But this combination of priorities may be an important reason why the Bhatia lab has a staff that’s about half female. “I have an orientation that attracts young moms,” she says. Her male staff members who have kids are probably able to be better dads, too.

    “I think Sangeeta’s a wonderful role model for women,” then-grad student Geoffrey Von Maltzahn told Nova. “But she’s a terrific role model for anybody. One of the hardest things in life is to make a clear distinction between how much time you’re going to dedicate to your work and how much time you’re going to dedicate to your family and your friends. She’s able to manage that with a sense of ease that I think is inspirational, independent of whether you’re a man or a woman.”

    However, when Bhatia started working from home on Wednesdays so that she could pick up her daughters from school, she felt it was professionally risky. So at first she called it “working off campus.” Now, everyone knows it’s “Mommy Wednesday.” She makes a point of modeling work-life balance to show that it can be done without sacrificing success.

    She’s also purposely using her visibility as a top scientist to be a role model for women in engineering. “There are not a lot of engineers that look like me, still.” Yet when she first got to Brown, she didn’t see what all the “diversity” fuss was about. “I looked around the classroom and thought that there were plenty of women.”

    Then, when she was a senior, she and her friend Theresia Gouw looked around again, and there were many fewer women—only seven in a class of 100. “We realized that we had just witnessed the so-called disproportionate attrition, the leaky pipeline.”

    Bhatia started reading about the subtle bias and the feeling of “not belonging” that discourages many women from pursuing the field. She and Gouw surveyed the other women who stayed in engineering and found that “every one of them had had mentors or parents who encouraged them.”

    As a newcomer to MIT, and as one of the few women engineering graduate students, Bhatia got a clear taste of that “not belonging” feeling when a thermodynamics professor asked her, on the first day, if she was in the right class. At first, Bhatia says she did what she could to downplay her femininity, wearing pants and not much makeup, trying to disappear. But later, she realized she had to be visible to make a difference and help patch up that leaky pipeline. So she makes a point of speaking openly and specifically about being a woman engineer.

    Bhatia thinks her attitude stems from the orientation towards public service she got in college. “I think that’s very Brown,” she says. “Not just noticing, but taking action.” But she says that her commitment to gender and other types of diversity also happens to be good business. “Just look at the metrics,” she points out. “Quality of ideas, return on investment, time to profitability, every objective metric has shown to be improved with diversity.”

    Though living a balanced life was important to Bhatia, she feared the consequences on her career. “I said to myself, ‘This is a tradeoff I’m willing to make. If it means I’m not at the top of my field, that’s absolutely a decision I’m making with my eyes open.’”

    Instead, she found that her choice to have a life outside the lab had the opposite effect: it helped her excel. “You have to find a way to sustain your energy and your creative spirit,” she says. As many workplace productivity studies have shown, having downtime increases productivity, and Bhatia is no exception to this rule. “I feel like if I worked the way that I thought I was supposed to, I actually think I wouldn’t be as productive. For me it’s helpful to come in and out of those worlds.”

    The tiniest tools 
on earth

    Bhatia’s still working with livers, but microfabrication is now old technology. Much of her current work uses nanotechnology: “You make materials so tiny that they can circulate in the body,” she explains.

    It’s with these insanely small tools that Bhatia set out to find better ways to diagnose and treat cancer. While still at UC San Diego, she began collaborating with renowned cancer researcher Erkki Ruoslahti, who had figured out how to engineer viruses so they’d home in on tumors. Bhatia replicated that, not with viruses but with materials, such as quantum dots (qdots), little semiconductor crystals that are more than ten thousand times smaller than the width of a strand of human hair.

    Bhatia coated qdots with peptide sequences that would allow them to enter tumor cells. Then she injected the qdots into mice that had cancer. Sure enough, the qdots homed in on the tumors. In 2002, Bhatia and Ruoslahti published a paper on their findings. “A lot of people say it was one of the first of its kind in what later became this field of nanomedicine,” Bhatia says.

    The urine test for cancer was an outgrowth of that work—and a happy accident. In the Bhatia lab, they were trying to make “smart contrast agents,” materials that would light up in tumors and thus show up on an MRI. “That was when the students noticed that whenever the animals were tumor-bearing, the bladder would light up,” Bhatia says. “Then we realized we didn’t need an MRI at all, that we had created this kind of urine diagnostic.” All they had to do was create a paper test to detect the biomarker that appeared in the urine and voilà, an inexpensive and relatively noninvasive test for cancer.

    “We think it’s a platform technology,” says Bhatia, who is investigating the use of this type of diagnostic with other diseases, including liver disease, which could help patients avoid expensive and invasive biopsies. The test works great in mice, so their biggest hurdle is to work with the FDA so that it can be tested on people.

    The “blue-sky” goal

    One of Bhatia’s dreams is to create a functioning human liver made outside the body that can be implanted into it. That goal is still far away, but it’s getting closer. In June, she published a paper that explained her group’s successful attempt to grow working livers in mice.

    Building on her micro liver technology, they used a 3-D printer to produce tiny liver “seeds” that they populated with a community of liver cells and helper cells. The configuration, they thought, would allow the cells to respond to regeneration cues—the liver being one of the only organs in the body that can regenerate.

    They implanted these seeds in mice with failing livers—and the lab-created livers grew 50 times larger in the mice’s bodies. They also looked a lot like real livers and performed liver functions. Making a liver for a human obviously requires many more cells than making one for a mouse, though.

    “We think you probably need about 10 billion cells to get up to clinically relevant tissue, which is a lot and too many to print practically in a reasonable amount of time,” Bhatia says. “We have a long way to go.”

    In the meantime, they have found another use for the micro livers: testing malaria drugs. “There’s a really elusive dormant form of vivax malaria that can hide out in a liver,” Bhatia explains. The only drug that’s been known to clear this dormant form of the disease is primaquine, which has been around since World War II. But it can cause blood damage in patients, and some strains of the dormant malaria have developed resistance to it. “There’s been a big push for new drugs since 2008, when the World Health Organization announced a new malaria eradication campaign,” Bhatia says.

    What Bhatia’s team has been able to do is grow this dormant strain of malaria in their micro livers, allowing drugs to be tested against it. “Now we’re trying to molecularly describe it, which has never been done,” she says.

    The malaria work came about because a lab member, graduate student Nil Gural, wanted to work on the untreatable form of the disease. “When she came, we had never grown [the dormant strain] before. We had no access to it.” Gural, who is originally from Turkey, said she was willing to live in Bangkok for a while to get it going.

    Gural has now been working on this for a couple of years, going back and forth from Boston to Bangkok. The work is going really well, Bhatia says. The lab is working with Medicine for Malaria Ventures, the organization that is coordinating the effort to develop new drugs that will work on the dormant stage of the disease. Given that there are about 212 million malaria cases that cause nearly half a million deaths each year, according to the World Health Organization, it’s research that has great potential for positive impact.

    Bhatia says her commitment to malaria work comes out of her entrepreneurial instincts as shaped by Brown. “My professional work has started out in what I would say is a very high-tech place,” she says, “and that’s growing 3-D livers. That’s probably going to be an expensive solution for patients with liver failure. The same thing for our cancer work. We’re working on really, really, really cutting-edge but still expensive ideas.”

    Expensive ideas are, of course, where the profit lies for an entrepreneur. But Bhatia says Brown taught her to look beyond profit to ask, “What can you do to make the world a better place?” For Bhatia, that’s finding global health applications for her work, such as taking the micro livers and using them to help eradicate malaria, or using the nanotechnology the lab comes up with to create inexpensive paper-based diagnostic urine tests for lung, colon, and ovarian cancers, allowing patients to be tested and even treated right on the spot, including in remote areas of developing countries where follow-up can be next to impossible. That’s still a dream, but as she said in her Spring 2017 TED Talk, “We already have this working in mice.”

    Half of Bhatia’s staff crowds into her office every Friday—it switches back and forth between the cancer and liver groups. It’s a medium-sized office with a desk, a small table, and a small couch. Behind her desk is a large framed print of something that looks like a lush white flower in full bloom. It’s actually a genetically engineered colony of yeast. Her Lego figure is perched on a window sash, and below it an unusual clock keeps the time. Six metal figures in the clock itself appear to hoist a seventh who hangs below, though every time the seventh figure gets almost to the top, it falls down again. Her husband gave it to her as a present when she got tenure. “What he said was, ‘Look at all these people helping you climb. You’re leading a team and they’re helping you achieve your vision.”

    “I was like, that’s nice, but once you get tenure”—the figure plummets to the bottom again as if to illustrate her point—“you climb the next ladder.”

    Fifteen people assemble in this space that would comfortably seat half as many. “They sit on the floor and the table,” Bhatia says. “We keep saying maybe we should move to the conference room but I think they like the intimacy of barreling into my office for 90 minutes.” The group uses the time to talk about early results of experiments and to “cross-fertilize.”

    “I’m continually reinforcing that,” Bhatia says. “Otherwise they don’t talk to each other.” Science is a lot of failure, she adds. “You have to think of all different ways to keep your team energized and excited and engaged. The best way is if they’re constantly learning.”

    Bhatia has improved and perhaps saved many lives already, thanks to the drugs that now are not tested in humans if they are toxic to micro livers. An off-the-shelf liver or a urine test for cancer or liver disease could also be lifesaving.

    But when asked what she’s proudest of, she says it’s her students, because she gets to be what she calls a “multiplier.” She trains her grad students and post-docs in a way of working and a way of thinking, and then they go out into the world. “I feel like they’ve all gone on to do really interesting things,” Bhatia says. “One of them is a venture capitalist and serial entrepreneur. He built a bunch of companies. Some of them are professors training their own students. There’s a lot of them out there. It’s the most amazing thing to feel like you’ve played a role in that.”

    See the full article here .

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    Welcome to Brown

    Brown U Robinson Hall
    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.

  • richardmitnick 2:20 pm on November 18, 2017 Permalink | Reply
    Tags: , , , Medicine, Stanford University-Engineering,   

    From Stanford University – Engineering: “An advance in stem-cell development could help lead to new therapies” 

    Stanford University Name
    Stanford University – Engineering

    November 02, 2017
    Andrew Myers

    Stem cells hold the promise of being able to cure ills ranging from spinal cord injuries to cancers. | Image by: luismmolina/Getty Images

    In many ways, stem cells are the divas of the biological world. On the one hand, these natural shapeshifters can transform themselves into virtually any type of cell in the body. In that regard, they hold the promise of being able to cure ills ranging from spinal cord injuries to cancers.

    On the other hand, said associate professor of materials science and engineering Sarah Heilshorn, stem cells, like divas, are also mercurial and difficult to work with.

    “We just don’t know how to efficiently and effectively grow massive numbers of stem cells and keep them in their regenerative state,” Heilshorn said. “This has prevented us from making more progress in creating therapies.”

    Until now, that is. In a recent paper in Nature Materials, Heilshorn described a solution to the dual challenges of growing and preserving neural stem cells in a state where they are still able to mature into many different cell types. The first challenge is that growing stem cells in quantity requires space. Like traditional farming, it is a two-dimensional affair. If you want more wheat, corn or stem cells, you need more surface area. Culturing stem cells, therefore, requires a lot of relatively expensive laboratory real estate, not to mention the energy and nutrients necessary to pull it all off.

    The second challenge is that once they’ve divided many times in a lab dish, stem cells do not easily remain in the ideal state of readiness to become other types of cells. Researchers refer to this quality as “stemness.” Heilshorn found that for the neural stem cells she was working with, maintaining the cells’ stemness requires the cells to be touching.

    Heilshorn’s team was working with a particular type of stem cell that matures into neurons and other cells of the nervous system. These types of cells, if produced in sufficient quantities, could generate therapies to repair spinal cord injuries, counteract traumatic brain injury or cure some of the most severe degenerative disorders of the nervous system, like Parkinson’s and Huntington’s diseases.

    Seeking stemness

    Heilshorn’s solution involves the use of better materials in which to grow stem cells. Her lab has developed new polymer-based gels that allow the cells to be grown in three dimensions instead of two. This new 3-D process takes up less than 1 percent of the lab space required by current stem cell culturing techniques. And because cells are so tiny, the 3-D gel stack is just a single millimeter tall, roughly the thickness of a dime.

    “For a 3-D culture, we need only a 4-inch-by-4-inch plot of lab space, or about 16 square inches. A 2-D culture requires a plot four feet by four feet, or about 16 square feet,” more than 100-times the space, according to first author Chris Madl, a recent doctoral graduate in bioengineering from Heilshorn’s lab

    In addition to the dramatic savings of lab space, the new process demands fewer nutrients and less energy, as well.

    The gels the team developed allow the stem cells to remodel the long molecules and maintain physical contact with one another to preserve critical communication channels between cells. “The simple act of touching is key to communication between stem cells and to maintaining stemness. If stem cells can’t remodel the gels, they can’t touch one another,” Madl explained.

    “The stem cells don’t exactly die if they can’t touch, but they lose that ability to regenerate that we really need for therapeutic success,” Heilshorn added.

    Striking results

    This need for neural stem cell to remodel their environment differs from what Heilshorn has found in working with other types of stem cells. For those cells, it is the stiffness of the gels – not the ability to remodel – that is the key factor in maintaining stemness. It is as if for these other types of stem cells, gels must mimic the rigidity of the tissue in which the cells will eventually be transplanted. Not so with neural progenitors, said Heilshorn.

    “Neural cell stemness is not sensitive to stiffness and that was a big surprise to us,” she said.

    The result was so striking and unexpected that Heilshorn, at first, didn’t believe her own results. The lab ended up testing three entirely different gels to see if their conclusion held, an unusual supplementary step in this kind of research. With each new material, they saw that those that could be remodeled produced quality stem cells; those that could not be remodeled had a negative effect on stemness.

    Next up on Heilshorn’s research agenda is to create gels that can be injected directly from the lab dish into the body. The possibilities have her feeling optimistic about stem cell therapies again. For a time, she said, it felt as if the field had hit a wall, as initial excitement for regeneration gave way to uninspiring results in the clinic. With her new finding, she said, it feels like new things may be just around the corner.

    “There’s this convergence of biological knowledge and engineering principles in stem cell research that has me hopeful we might finally actually solve some big problems,” she said.

    See the full article here .

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  • richardmitnick 8:20 pm on November 16, 2017 Permalink | Reply
    Tags: , , Medicine, , The focus of the study were blood samples from Ebola patients that were obtained during the outbreak in Sierra Leone in 2014, The scientists found that levels of two biomarkers known as L-threonine (an amino acid) and vitamin-D-binding-protein may accurately predict which patients live and which die, The team found that survivors had higher levels of some immune-related molecules and lower levels of others compared to those who died, The team looked at activity levels of genes and proteins as well as the amounts of lipids and byproducts of metabolism   

    From PNNL: “Unlocking the secrets of Ebola” 

    PNNL Lab

    November 16, 2017
    Tom Rickey
    (509) 375-3732

    PNNL scientists and their collaborators have identified molecules in the blood that indicate which patients with Ebola virus are most likely to have a poor outcome. (Credit: Photo courtesy of PNNL)

    Scientists have identified a set of biomarkers that indicate which patients infected with the Ebola virus are most at risk of dying from the disease.

    The results come from scientists at the Department of Energy’s Pacific Northwest National Laboratory and their colleagues at the University of Wisconsin-Madison, Icahn School of Medicine at Mount Sinai, the University of Tokyo and the University of Sierra Leone. The results were published online Nov. 16 in the journal Cell Host & Microbe.

    The findings could allow clinicians to prioritize the scarce treatment resources available and provide them to the sickest patients, said the senior author of the study, Yoshihiro Kawaoka, a virology professor at the UW-Madison School of Veterinary Medicine.

    The focus of the study were blood samples from Ebola patients that were obtained during the outbreak in Sierra Leone in 2014. The Wisconsin team obtained 29 blood samples from 11 patients who ultimately survived and nine blood samples from nine patients who died from the virus. The Wisconsin team inactivated the virus according to approved protocols, developed in part at PNNL, and then shipped the samples to PNNL and other institutions for analysis.

    The team looked at activity levels of genes and proteins as well as the amounts of lipids and byproducts of metabolism. The team found 11 biomarkers that distinguish fatal infections from non-fatal ones and two that, when screened for early upon symptom onset, accurately predict which patients are likely to die.

    “Our team studied thousands of molecular clues in each of these samples, sifting through extensive data on the activity of genes, proteins, and other molecules to identify those of most interest,” said Katrina Waters, the leader of the PNNL team and a corresponding author of the paper. “This may be the most thorough analysis yet of blood samples of patients infected with the Ebola virus.”

    The team found that survivors had higher levels of some immune-related molecules and lower levels of others compared to those who died. Plasma cytokines, which are involved in immunity and stress response, were higher in the blood of people who perished. Fatal cases had unique metabolic responses compared to survivors, higher levels of virus, changes to plasma lipids involved in processes like blood coagulation, and more pronounced activation of some types of immune cells.

    Pancreatic enzymes also leaked into the blood of patients who died, suggesting that these enzymes contribute to the tissue damage characteristic of fatal Ebola virus disease.

    The scientists found that levels of two biomarkers, known as L-threonine (an amino acid) and vitamin-D-binding-protein, may accurately predict which patients live and which die. Both were present at lower levels at the time of admission in the patients who ultimately perished.

    The team found that many of the molecular signals present in the blood of sick, infected patients overlap with sepsis, a condition in which the body – in response to infection by bacteria or other pathogens – mounts a damaging inflammatory reaction.

    Fifteen PNNL scientists contributed to the study. Among the corresponding authors of the study are three PNNL scientists: Waters, Thomas Metz and Richard D. Smith. Three additional PNNL scientists – Jason P. Wendler, Jennifer E. Kyle and Kristin E. Burnum-Johnson – are among six scientists who share “first author” honors.

    Other PNNL authors include Jon Jacobs, Young-Mo Kim, Cameron Casey, Kelly Stratton, Bobbie-Jo Webb-Robertson, Marina Gritsenko, Matthew Monroe, Karl Weitz, and Anil Shukla.

    Analyses of proteins, lipids and metabolites in the blood samples were performed at EMSL, the Environmental Molecular Sciences Laboratory, a DOE Office of Science User Facility at PNNL.

    The study was funded by a Japanese Health and Labor Sciences Research Grant; by grants for Scientific Research on Innovative Areas from the Ministry of Education, Cultures, Sports, Science and Technology of Japan; by Emerging/Re-emerging Infectious Diseases Project of Japan; and by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. Support was also provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai and by a grant from the National Institute of General Medicine.

    See the full article here .

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    Pacific Northwest National Laboratory (PNNL) is one of the United States Department of Energy National Laboratories, managed by the Department of Energy’s Office of Science. The main campus of the laboratory is in Richland, Washington.

    PNNL scientists conduct basic and applied research and development to strengthen U.S. scientific foundations for fundamental research and innovation; prevent and counter acts of terrorism through applied research in information analysis, cyber security, and the nonproliferation of weapons of mass destruction; increase the U.S. energy capacity and reduce dependence on imported oil; and reduce the effects of human activity on the environment. PNNL has been operated by Battelle Memorial Institute since 1965.


  • richardmitnick 7:43 am on November 14, 2017 Permalink | Reply
    Tags: , Introducing Titin - the Protein That Rules Our Hearts, Medicine,   

    From U Arizona: “Introducing Titin, the Protein That Rules Our Hearts” 

    U Arizona bloc

    University of Arizona

    Nov. 13, 2017
    Emily Walla

    UA scientists have solved a muscle mystery by proving that the protein titin acts as a molecular ruler, determining the length of muscle fibers and influencing the strength of the muscles that make our hearts beat and bodies move.

    Henk Granzier: “Biologists have always wondered what makes (muscles) so precisely structured.” No image credit.

    Although scientists have long speculated that a protein named titin measures thick filaments — the proteins that make muscles contract — no one has been able to provide evidence to support their theories.

    No one, that is, until a team of researchers in the University of Arizona’s Department of Cellular and Molecular Medicine took on the case. In a recent study published in Nature Communications, the team presented definitive proof that titin acts as a molecular ruler for the muscle’s thick filament.

    Throughout the muscles of the heart and body, the thick filaments have precise, uniform lengths.

    “Functionally and clinically, it is very important to regulate the thick filament precisely, otherwise muscles would not function well,” said Henk Granzier, senior author of the study and professor of molecular and cellular medicine. “Biologists have always wondered what makes them so precisely structured.”

    Studying mice with certain mutations in the gene encoding the blueprint for the titin protein, the researchers found that when titin was shortened, so were the thick filaments, resulting in weakened muscles and dilated cardiomyopathy, a condition that leads to heart failure.

    “We genetically engineered a mouse that doesn’t have normal titin,” said Granzier, a member of the BIO5 Institute. “It has a piece from titin deleted. Since titin is involved in somehow regulating the thick filament, then you expect if you make titin shorter, the thick filament length will be altered as well. And, lo and behold, that is the case.”

    A typical protein is made of a few hundred amino acids linked in a chain. Though still microscopically small, titin is gigantic compared to other proteins. Comprised of more than 30,000 amino acids, the supersize protein is made from super-repeated structures. The amino acid super-repeats of titin are like tick marks on a yardstick, measuring out uniform sections of the thick filament.

    By altering the gene for titin, Granzier’s team was able to make a mouse whose titin was missing several of its super-repeats.

    The resulting mice showed symptoms of dilated cardiomyopathy, or DCM. This condition stretches out the muscle in the heart and prevents it from pumping efficiently. While the heart still contracts, the muscle is weak, so each contraction only moves a fraction of the blood pumped by a normal heart.

    In humans, the most frequent cause of DCM is a mutation in titin that shortens the protein. DCM affects 1 in 500 people, and often patients must undergo a heart transplant to survive. Understanding the cause of the condition can better arm researchers as they search for novel ways to combat it.

    Methods of Discovery

    “In science, if you want to do conclusive work, you have to test your hypothesis multiple ways and get consistent results,” Granzier said. This meant that any abnormalities detected in the genetically engineered mice had to be deeply investigated.

    After testing the strength of the mice, his team removed the muscles of interest to inspect them in a setting they controlled, instead of a setting controlled by the complex biological systems of the mice. To make certain that differences in the mice were caused by titin, the muscle tissues were observed in vitro by removing them from the animals and artificially stimulating them to show that they produced less force. In the body, muscles contract when activated by calcium; under the microscope, flooding the isolated muscle tissue with a calcium solution mimics this activation process.

    Using ultrasound, the team showed that the hearts of the engineered mice were larger than those of mice with normal titin. The next step was to investigate how this enlargement weakened the heart.

    How Titin Controls Strength

    “The sarcomere is the smallest muscle unit you can tease out and still have all the properties of muscle: force development and shortening,” Granzier said.

    The sarcomeres are linked end-to-end in a chain that spans the entirety of a muscle. Just as a strong chain is made from links that are well made and uniform, sarcomere health and uniformity is vital to muscle strength.

    Each sarcomere is comprised of three filaments: thick, thin and titin filaments. The motor driving contraction — myosin — is held at precise points within the thick filament, and it pulls the thick filament across the thin filament, causing muscle contraction. Muscles are strongest when the thick and thin filaments overlap at an optimal length — around 2 micrometers, or one ten-thousandth of an inch. Stretch out the muscle, and the filaments cannot reach the point of optimum overlap, so the muscle is weakened. Overstretch the muscle, and the filaments do not overlap at all; the muscle cannot exert any force.

    When titin is mutated and short, the resulting shortened fibers cannot reach the optimal point of overlap, and the muscle cannot exert much force. The muscle is further weakened because shorter thick filaments cannot hold the optimal number of myosin motors. The thin and thick filaments do not overlap properly nor contract effectively when the thick filament is short.

    Paula Tonino and Balazs Kiss, lead authors of the study and scientific investigators in Granzier’s lab, observed the muscle fibers under electron and super-resolution microscopes. They determined that in the muscles of engineered mice, not only were the thick filaments shortened, but also that they were shortened by precise, uniform lengths that corresponded to the size of the super-repeats removed from titin.

    “We showed that titin is the regulator of the thick filament,” Granzier said, confirming that titin determines the strength of muscles and health of hearts.

    “You might say titin rules.

    See the full article here .

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    U Arizona campus

    The University of Arizona (UA) is a place without limits-where teaching, research, service and innovation merge to improve lives in Arizona and beyond. We aren’t afraid to ask big questions, and find even better answers.

    In 1885, establishing Arizona’s first university in the middle of the Sonoran Desert was a bold move. But our founders were fearless, and we have never lost that spirit. To this day, we’re revolutionizing the fields of space sciences, optics, biosciences, medicine, arts and humanities, business, technology transfer and many others. Since it was founded, the UA has grown to cover more than 380 acres in central Tucson, a rich breeding ground for discovery.

    Where else in the world can you find an astronomical observatory mirror lab under a football stadium? An entire ecosystem under a glass dome? Visit our campus, just once, and you’ll quickly understand why the UA is a university unlike any other.

  • richardmitnick 8:46 am on November 10, 2017 Permalink | Reply
    Tags: , , Essential amino acid methionine, Medicine, , SAMTOR, The mTOR cellular pathway connects nutrition metabolism and disease   

    From MIT: “New player in cellular signaling” 

    MIT News
    MIT Widget

    MIT News

    November 9, 2017
    Nicole Giese Rura | Whitehead Institute

    The mTOR cellular pathway connects nutrition, metabolism, and disease. Image courtey of Steven Lee/Whitehead Institute.

    Researchers have identified a key nutrient sensor in the mTOR pathway that links nutrient availability to cell growth.

    To survive and grow, a cell must properly assess the resources available and couple that with its growth and metabolism — a misstep in that calculus can potentially cause cell death or dysfunction. At the crux of these decisions is the mTOR pathway, a cellular pathway connecting nutrition, metabolism, and disease.

    The mTOR pathway incorporates input from multiple factors, such as oxygen levels, nutrient availability, growth factors, and insulin levels to promote or restrict cellular growth and metabolism. But when the pathway runs amok, it can be associated with numerous diseases, including cancer, diabetes, and Alzheimer’s disease. Understanding the various sensors that feed into the mTOR pathway could lead to novel therapies for these diseases and even aging, as dialing down the mTOR pathway is linked to longer lifespans in mice and other organisms.

    Although the essential amino acid methionine is one of the key nutrients whose levels cells must carefully sense, researchers did not know how it fed into the mTOR pathway — or if it did at all. Now, Whitehead Institute Member David Sabatini and members of his laboratory have identified a protein, SAMTOR, as a sensor in the mTOR pathway for the methionine derivative SAM (S-adenosyl methionine). Their findings are described in the current issue of the journal Science.

    Methionine is essential for protein synthesis, and a metabolite produced from it, SAM, is involved in several critical cellular functions to sustain growth, including DNA methylation, ribosome biogenesis, and phospholipid metabolism. Interestingly, methionine restriction at the organismal level has been linked to increased insulin tolerance and lifespan, similar to the antiaging effects associated with inhibition of mTOR pathway activity. But the connection between mTOR, methionine, and aging remains elusive.

    “There are a lot of similarities between the phenotypes of methionine restriction and mTOR inhibition,” says Sabatini, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT. “The existence of this protein SAMTOR provides some tantalizing data suggesting that those phenotypes may be mechanistically connected.”

    Sabatini identified mTOR as a graduate student and has since elucidated numerous aspects of its namesake pathway. He and his lab recently pinpointed the molecular sensors in the mTOR pathway for two key amino acids: leucine and arginine. In the current line of research, co-first authors of the Science paper Xin Gu and Jose Orozco, both graduate students Sabatini’s lab, identified a previously uncharacterized protein that seemed to interact with components of the mTOR pathway. After further investigation, they determined that the protein binds to SAM and indirectly gauges the pool of available methionine, making this protein — SAMTOR — a specific and unique nutrient sensor that informs the mTOR pathway.

    “People have been trying to figure out how methionine was sensed in cells for a really long time,” Orozco says. “I think that this is the first time in mammalian cells a mechanism has been found to describe the way methionine can regulate a major signaling pathway like mTOR.”

    The current research indicates that SAMTOR plays a crucial role in methionine sensing. Methionine metabolism is vital for many cellular functions, and the Sabatini lab will further investigate the potential links between SAMTOR and the extended lifespan and increased insulin sensitivity effects that are associated with low methionine levels.

    “It is very interesting to consider mechanistically how methionine restriction might be associated in multiple organisms with beneficial effects, and identification of this protein provides us a potential molecular handle to further investigate this question,” Gu says. “The nutrient-sensing pathway upstream of mTOR is a very elegant system in terms of responding to the availability of certain nutrients with specific mechanisms to regulate cell growth. The currently known sensors raise some interesting questions about why cells evolved sensing mechanisms to these specific nutrients and how cells treat these nutrients differently.”

    This work was supported by the National Institutes of Health, the Department of Defense, the National Science Foundation, and the Paul Gray UROP Fund.

    See the full article here .

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    The mission of MIT is to advance knowledge and educate students in science, technology, and other areas of scholarship that will best serve the nation and the world in the twenty-first century. We seek to develop in each member of the MIT community the ability and passion to work wisely, creatively, and effectively for the betterment of humankind.

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  • richardmitnick 7:28 am on November 10, 2017 Permalink | Reply
    Tags: , , Medicine, PROTACs-Proteolysis Targeting Chimeras,   

    From Yale: “Cellular clean-up can also sweep away forms of cancer” 

    Yale University bloc

    Yale University

    November 9, 2017
    Bill Hathaway

    Cells treated (right) or untreated (left) with a PROTAC that degrades the target protein (green). No image credit.

    Two new research papers reinforce the benefits of a novel therapy that hijacks the cell’s own protein degradation machinery to destroy cancer cells, Yale researchers report Nov. 9 in the journal Cell Chemical Biology.

    The new approach to drug discovery, called Proteolysis Targeting Chimeras or PROTACs, was developed in the laboratory of Craig Crews, the Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology, professor of chemistry and pharmacology, as well as executive director of the Yale Center for Molecular Discovery.

    The system engages the cell’s own protein degradation machinery to destroy targeted proteins by tagging them for removal. Most drugs are based on the ability of small molecules to bind to and block the function of disease-causing proteins, but some proteins are resistant to such intervention.

    “This system will help us change the current small-molecule drug paradigm that fails to target 75% of rogue proteins,” said Crews, scientific founder of Arvinas LLC, the New Haven biotechnology company developing the concept.

    The first paper, [Cell Chemical Biology] shows for the first time that PROTAC system can target mutant RTK proteins, which have been linked to several forms of cancer. The second paper [Cell Chemical Biology] proves that the PROTAC system can target rogue proteins with greater specificity than traditional approaches.

    Yale’s George M. Burslem and Blake E. Smith are first authors of the first paper. Smith and Yale’s Daniel P. Bondeson are co-first authors of the second paper.

    The two papers were primarily funded by the National Institutes of Health. Crews is a shareholder of Arvinas, which also provided researchers to the projects.

    See the full article here .

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    Yale University Campus

    Yale University comprises three major academic components: Yale College (the undergraduate program), the Graduate School of Arts and Sciences, and the professional schools. In addition, Yale encompasses a wide array of centers and programs, libraries, museums, and administrative support offices. Approximately 11,250 students attend Yale.

  • richardmitnick 7:12 am on November 10, 2017 Permalink | Reply
    Tags: A very low calorie diet can rapidly reverse type 2 diabetes in animal models, Medicine, PINTA, , Yale University   

    From Yale: “Study reveals how a very low calorie diet can reverse type 2 diabetes” 

    Yale University bloc

    Yale University

    November 9, 2017
    Ziba Kashef

    (© stock.adobe.com)

    In a new study, a Yale-led research team uncovers how a very low calorie diet can rapidly reverse type 2 diabetes in animal models. If confirmed in people, the insight provides potential new drug targets for treating this common chronic disease, said the researchers.

    The study is published in Cell Metabolism.

    One in three Americans will develop type 2 diabetes by 2050, according to recent projections by the Center for Disease Control and Prevention. Reports indicate that the disease goes into remission in many patients who undergo bariatric weight-loss surgery, which significantly restricts caloric intake prior to clinically significant weight loss. The Yale-led team’s study focused on understanding the mechanisms by which caloric restriction rapidly reverses type 2 diabetes.

    The research team investigated the effects of a very low calorie diet (VLCD), consisting of one-quarter the normal intake, on a rodent model of type 2 diabetes. Using a novel stable (naturally occurring) isotope approach, which they developed, the researchers tracked and calculated a number of metabolic processes that contribute to the increased glucose production by the liver. The method, known as PINTA, allowed the investigators to perform a comprehensive set of analyses of key metabolic fluxes within the liver that might contribute to insulin resistance and increased rates of glucose production by the liver — two key processes that cause increased blood-sugar concentrations in diabetes.

    Using this approach the researchers pinpointed three major mechanisms responsible for the VLCD’s dramatic effect of rapidly lowering blood glucose concentrations in the diabetic animals. In the liver, the VLCD lowers glucose production by: 1) decreasing the conversion of lactate and amino acids into glucose; 2) decreasing the rate of liver glycogen conversion to glucose; and 3) decreasing fat content, which in turn improves the liver’s response to insulin. These positive effects of the VLCD were observed in just three days.

    “Using this approach to comprehensively interrogate liver carbohydrate and fat metabolism, we showed that it is a combination of three mechanisms that is responsible for the rapid reversal of hyperglycemia following a very low calorie diet,” said senior author Gerald I. Shulman, M.D., the George R. Cowgill Professor of Medicine and Cellular and Molecular Physiology and an investigator at the Howard Hughes Medical Institute.

    The next step for the researchers will be to confirm whether the findings can be replicated in type 2 diabetic patients undergoing either bariatric surgery or consuming very low calorie diets. His team has already begun applying the PINTA methodology in humans.

    “These results, if confirmed in humans, will provide us with novel drug targets to more effectively treat patients with type 2 diabetes,” Shulman said.

    Other study authors are Rachel J. Perry, Liang Peng, Gary W. Cline, Yongliang Wang, Aviva Rabin-Court, Joongyu D. Song, Dongyan Zhang, Xian-Man Zhang, Yuichi Nozaki, Sylvie Dufour, and Kitt Falk Petersen.

    This study was supported by grants from the United States Public Health Service.

    See the full article here .

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    Yale University Campus

    Yale University comprises three major academic components: Yale College (the undergraduate program), the Graduate School of Arts and Sciences, and the professional schools. In addition, Yale encompasses a wide array of centers and programs, libraries, museums, and administrative support offices. Approximately 11,250 students attend Yale.

  • richardmitnick 2:29 pm on November 4, 2017 Permalink | Reply
    Tags: , , Brain waves, , Medicine,   

    From INVERSE: For All of my Friernds in Neuroscience: “Nobody Knows Where Brainwaves Come From” 



    August 7, 2017 [Just now in social media]
    Rafi Letzter

    Wub-wub-wub-wub. Brainwaves are electromagnetic proof that we are alive. Decades of research have shown that these pulses of electrical potential reflect events at the root of our impulses and thoughts. As such, they underlie one of humanity’s weightiest moral decisions: deciding whether or not a person is officially dead. If a person goes 30 minutes without producing brainwaves, even a functioning heartbeat can’t convince doctors they’re alive.

    But as much as brainwaves loom in our understanding of the brain, not a single scientist has any idea where they come from.

    At least one researcher, Michael X. Cohen, Ph.D., an assistant professor at the Donders Institute for Brain, Cognition, and Behavior in the Netherlands, thinks it’s time to fix that. In an April op-ed in the journal Trends in Neurosciences, Cohen argued that the time has come for researchers to figure out what those brainwaves they’ve been recording for decades are really all about.

    “This is maybe the most important question for neuroscience right now,” he said to Inverse, but he added that it will be a challenge to convince his colleagues that it matters at all.

    Today, as Facebook races to read your brainwaves, roboticists use them to develop mind control systems, and cybersecurity experts race to protect yours from hackers, it’s clear that Cohen’s sense of urgency is justified.

    Connecting brainwaves to neuron behavior is the next great challenge in neuroscience. No image credit

    What we do know about brainwaves is that when doctors stick silver chloride dots to a person’s scalp and hook the connected electrodes up to an electroencephalography (EEG) machine, the curves that appear on its screen represent the electrical activity inside our skulls. The German neuroscientist Hans Berger spotted the first type of brainwave — alpha waves — back in 1924.

    Researchers soon discovered more of these strange oscillations. There’s the slow, powerful delta wave, which shows up when we’re in deep sleep. There’s the low spikes of the theta wave, whose functions remain largely mysterious. Faster and even stranger is the gamma wave, which some researchers suspect plays a role in consciousness.

    These waves are at the root of our understanding of the shape and structure of human thought, as well as the methods doctors use to figure out how brains break down. It’s thought that alpha waves, for example, are a sign the brain is inhibiting certain mental systems to free up bandwidth for other tasks, like sleeping or imagining. But where does it come from in the first place?

    So far, there’s been no satisfactory answer to this question, but Cohen is determined to find it.

    An alpha brainwave resembles a sine wave. No image credit.

    As one of the world’s leading researchers on the brain’s electrical activity, he hooks people up to EEG machines to figure out how their brains behave when they see a bird, think through a complex decision, or feel sad. But Cohen is the first to admit that what’s lacking in his research is context. Not understanding how those patterns relate to the actual meat of the brain — neurons firing or not firing, getting excited, or shutting down — leaves a huge mystery right at the center of brainwave neuroscience, he says.

    “Over time it started bothering me more and more,” Cohen told Inverse. “There’s so much complexity going on at smaller spatial scales, and we have literally no fucking clue how to get from this big spatial scale to this smaller spatial scale.”

    Part of the reason why it’s so hard to understand neuroscience research in the context of the brain, Cohen explains, is because neuroscientists themselves work in discrete, isolated sub-fields based on how big a chunk of the brain they study. Researchers studying the brain at the smallest level peel open individual neurons and watch the proteins inside them fold. Microcircuit neuroscientists map out the connections between neurons. Cohen zooms out a little further, connecting electrical patterns and human thought, rarely concerning himself with single cells or small groups of neurons.

    But as we begin to fully grasp how complex the brain really is, Cohen says, it’s increasingly imperative to find a way to bridge the research that happens at the macro and micro scales. Finally understanding brainwaves, he says, could be the key to doing so.

    No image caption or credit.

    That’s because brainwaves pulse at every single level of the brain, from the tiniest neuron to the entire 3-pound organ. “If you’re recording from just one neuron, you’ll see oscillations,” Cohen says, using the scientific term for wobbling brainwaves.

    “If you’re recording from a small ensemble of neurons, you’ll see them. And if you’re recording from tens of millions of neurons, you’ll see oscillations.”

    For Cohen, brainwaves are the common thread that can unify neuroscience. But the problem is, most research deals only with the electrical activity produced from tens of millions of neurons at a time, which is the highest resolution a typical EEG machine can capture without needlessly cutting into an innocent study subject’s head. The problem is that this big, rough EEG research in humans isn’t very compatible with the intricate, neuron-scale research done in lab rats. Consequently, we have plenty of information about the brain’s parts but no understanding of how they work together as a whole.

    “It’s the difference between ‘What do Americans like?’ and ‘What does any individual American like?’” Cohen said. “And that’s a huge difference — between what any individual does and what you can say as a generality about an entire culture.”

    While we know that all that electrical activity is the result of charged chemicals sloshing around in our brains in rhythmic, patterned waves, that doesn’t tell us anything about the most important question: Why they’re generated in the first place.

    “The problem with these answers is that they’re totally meaningless from a neuroscience perspective,” Cohen says. “These answers tell you about how it’s physically possible, how the universe is constructed such that we can make these measurements. But there’s a totally different question, which is, what do these measurements mean? What do they tell us about the kinds of computations that are taking place in the brain? And that’s a huge explanatory gap.”

    Despite some puzzlement from fellow scientists, Cohen plans to collect brainwave data from rodents. No image credit.

    There are a few ways to bridge that gap. Scientists like those at the Blue Brain Project in Switzerland are trying to do so by building a computerized brain simulation that’s detailed enough to include the whole organ, as well as individual neurons, which they hope can reveal a kind of cell activity that would cause different kinds of common EEG patterns to appear. The one huge challenge to this approach, however, is that there’s no computer that can simulate a brain’s computations in real time; just a millisecond of one neuron’s time in a simulation can take 10 seconds of real-world time for a computer to figure out. It’s certainly possible, but doing so would cost billions of dollars.

    Cohen’s plan, which relies on real-world experiments, is much simpler.

    Since you can’t cut open a human brain and start sticking electrodes in there to record activity (even in “human rights-challenged places,” Cohen says), he’s relying on rodents instead. But what makes his work different is that he’s hooking those rodents up to EEG machines, which researchers don’t usually do. “They say, why are you wasting your time recording EEG from rats? EEG is for when you don’t have access to the brain, so you record from outside,” he says.

    But rodents have brainwaves, too, and their data can provide much-needed insight into how to bridge the neuron-brainwave divide. His experiments will create two huge data sets that researchers can cross-reference to figure out how neuron function and EEG behavior relate to one another. With the help of some deep-learning algorithms, they’ll then pore over that data to build a map of how individual sparks of neural activity add up to recognizable brainwaves. If Cohen’s experiments are very successful, his team will be able to look at a rodent’s EEG and predict — with what he hopes is more than 98 percent accuracy — exactly how the neural circuits are behaving in its brain.

    “I think we’re not that far away from breakthroughs. Some of these kinds of questions are not so difficult to answer, it’s just that no one has really looked,” he said. But he admits that he’s worried that the segmentation of neuroscience research will get in the way of this whole-brain approach.

    “So this is very terrifying for me and also very difficult, because I have very little experience in the techniques that i think are necessary,” he said.

    Having to admit on his grant applications that his work would employ unfamiliar techniques he has never used made it difficult to get funding, but Cohen ultimately received a grant from the European Union. Now, with the aid of a lab fully staffed with experts in rodent brains, Cohen is ready to get to work.

    Soon enough, we might finally get some answers to one of the oldest and strangest mysteries in neuroscience: where all those wub-wubs really come from and what they really mean.

    See the full article here .

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  • richardmitnick 1:16 pm on November 3, 2017 Permalink | Reply
    Tags: Allysa Kemraj, , EDS-Ehlers-Danlos Syndrome (EDS), Jean Baum's lab uses sophisticated instruments to study proteins at the atomic level, Medicine, Nuclear magnetic resonance (NMR) spectrometers, ,   

    From Rutgers University: Women in STEM- “Inside a Rutgers Lab, a Student Learns About Her Illness and Finds Her Calling” Allysa Kemraj 

    Rutgers University
    Rutgers University

    John Chadwick

    Investigating how abnormal proteins lead to disease.

    Professor Jean Baum and her research team study proteins at the atomic level to better understand illnesses such as Parkinson’s disease.

    Allysa Kemraj was in high school when doctors diagnosed her with a rare genetic disorder.

    Allysa Kemraj. No image credit

    At Rutgers, she was surprised—and thrilled—to find a research lab that explores the science associated with her illness, Ehlers-Danlos Syndrome (EDS), a disease that affects the body’s connective tissue.

    She soon began working in the lab.

    “I was looking for research opportunities that would be a good fit,” says the senior from Roselle, New Jersey. “Then I found this lab, and I was completely floored.”

    Kemraj is an undergraduate research assistant in a lab run by Jean Baum, a professor in the Department of Chemistry and Chemical Biology in the School of Arts and Sciences. Baum studies the interactions of proteins in the body and their role in Parkinson’s disease and other types of illnesses, including EDS, and a disease that affects patients receiving long-term dialysis treatment.


    “Most people, understandably, don’t spend a lot of time thinking about the interactions between infinitesimal protein molecules in the body,” Baum says. “But when the interactions are disrupted or altered, serious illness can result.”

    Baum’s lab uses sophisticated instruments to study proteins at the atomic level. And that helps break new ground on illnesses such as Parkinson’s disease, in which researchers have discovered proteins that fold abnormally and form long chains called fibrils.

    Ehlers-Danlos Syndrome, meanwhile, refers to a group of disorders that include loose joints, stretchy skin, and excessive scar formation. These illnesses are linked to flawed collagen molecules, the most abundant protein in the body.

    In high school, Kemraj noticed she was sustaining an inordinate number of injuries, such as dislocations and torn ligaments. “I played soccer and ran track,” she says. “I thought maybe it was growing pains.”

    But then she began suffering from fainting spells and nausea. She and her family eventually went to the Mayo Clinic where doctors said she had EDS. Although she has a moderate form of the disease, Kemraj battles symptoms that include gastro-intestinal dysmotility, fatigue, and heart palpitations and arrhythmia. She makes frequent hospital visits. During her sophomore year at Rutgers, she sustained two ruptured discs in her back and required extensive medical attention and rehabilitation.

    “I am lucky because when I go for medical care, I am able to leave the hospital and resume my life,” she says. “But that is not true for a lot of patients with EDS and other genetic disorders.”

    Kemraj spends up to 20 hours a week in the Baum lab, working under Cody Hoop, a scientist who studies collagen illnesses like brittle bone disease. Hoop’s EDS research is supported by the American Heart Association because the disease in its most serious form can affect blood vessels and cause aortic aneurisms and ruptures.

    For Kemraj, working so closely with her own illness is both an educational and edgy experience.

    “I’ll be reading the medical literature and I’m, like, ‘Yup, that’s what’s going on in my body,’’’ she says. “It’s a little scary, but most of the time, it’s fascinating.”

    Scientists studying proteins, a field known as structural biology, say their work offers hope for patients, particularly through drug discovery.

    Andy Nieuwkoop

    “If you know the shape of a protein and know the shape of a drug molecule that’s acting on that protein, you’ve got a good foundation from which to work to improve that drug,” says Andy Nieuwkoop, a professor in the chemistry and chemical biology department.

    Both Baum and Nieuwkoop oversee research teams that use nuclear magnetic resonance (NMR) spectrometers—instruments that allow them to examine proteins at the atomic level. Protein samples are placed in a powerful magnetic field and bombarded with radio waves so that they send out distinct frequencies. Researchers use those signals to build models that show the location of each atom.

    “They’re like MRIs, except for proteins rather than people,” says Nieuwkoop, whose team studies proteins and cell membranes, an emerging area that has implications for cancer and other diseases.

    “The equipment we have at Rutgers is as good as anywhere in the world,” he says. “The technological advancements have gotten to the point where we can do experiments we could only dream about 10 years ago.”

    The field attracts talented researchers, both graduate and undergraduate, who are drawn to the human health mission and eager to work with the NMR technology.

    “I was drawn to the Baum lab because of its theme of protein-to-protein interaction,” says Hoop, a post-doctoral fellow who earned her Ph.D. at the University of Pittsburgh’s School of Medicine. “It’s important to understand how these interactions happen so that we can design drugs that can encourage or discourage interactions that may be connected to disease.”

    Tamr Atieh

    Tamr Atieh, a chemistry major as a Rutgers undergraduate and now a graduate student, says the study of proteins is an increasingly influential field.

    “A lot of the new drugs coming out are proteins,” he says.

    Kemraj, meanwhile, said the Baum lab has had a major influence on her plans. She wants to go for an M.D./Ph.D. and devote her life to studying collagen and treating children.

    “I want be a doctor and a specialist who can look my patients in the eye and say, ‘I, too, know what it’s like to have a chronic illness. And I’m going to do everything I can to help you.”’

    See the full article here .

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  • richardmitnick 11:33 am on November 3, 2017 Permalink | Reply
    Tags: , , , For this study the researchers focused primarily on the calcium sodium potassium and other ions in cerebral fluid, LMIS4-Microsystems Laboratory 4, Medicine, Reading our brain chemistry   

    From EPFL: “Reading our brain chemistry” 

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    École Polytechnique Fédérale de Lausanne EPFL

    Clara Marc

    © Guillaume Petit-Pierre – Perfusion microdroplet allowing the extraction of interstitial liquid using the system developed by EPFL researchers.

    Researchers at EPFL have developed a new device and analysis method that let doctors measure the neurochemicals in a patient’s brain. The Microsystems Laboratory 4 (LMIS4)’s system involves collecting microdroplets of cerebral fluid and analyzing them to obtain chemical data that can help doctors diagnose and treat neurodegenerative diseases.

    Neurologists often use electrical impulses to stimulate and read brain signals. But the chemicals that neurons produce in response to these impulses are poorly understand at this point, even though they can provide valuable information for understanding the mechanisms behind neurodegenerative diseases like Alzheimer’s and Parkinson’s. “Neurons can be read two ways: electrically or chemically,” says Guillaume Petit-Pierre, a post-doc researcher at LMIS4 and one of the study’s authors. “Reading their electrical behavior can provide some limited information, such as the frequency and pace at which neurons communicate. However, reading their neurochemistry gives insight into the proteins, ions and neurotransmitters in a patient’s cerebral fluid.” By analyzing this fluid, doctors can obtain additional information – beyond that provided by neurons – and get a complete picture of a patient’s brain tissue metabolism.

    Collecting information through microchannels

    The EPFL researchers developed a system that can both collect a patient’s neurochemical feedback and form electrical connections with brain tissue. Their device is made up of electrodes and microchannels that are about half a hair in diameter. Once the device is placed inside brain tissue, the microchannels draw in cerebral fluid while the electrodes, which are located right at the fluid-collection interface, make sure that the measurements are taken at very precise locations. The microchannels subsequently create highly concentrated microdroplets of cerebral fluid. “The microdroplets form directly at the tip of the device, giving us a very high temporal resolution, which is essential if we want to accurately analyze the data,” says Petit-Pierre. The microdroplets are then placed on an analytical instrument that was also developed by scientists at the LMIS4 and the nearby University Centre of Legal Medicine which has expertise in this type of complex analysis. As a last step, the microdroplets are vaporized with a laser and the gas residue is analyzed. Both the researchers’ device and their analysis method are totally new. “Today there is only one method for performing neurochemical analyses: microdialysis. But it isn’t very effective in terms of either speed or resolution,” says Petit-Pierre. Another advantage of the researchers’ method is that it is a minimally invasive way to collect data. Currently scientists have to work directly on the brains of rats afflicted with neurodegenerative diseases, meaning the rats must be sacrificed to take the measurements. Their research was published in Nature Communications.

    Direct applications

    For this study, the researchers focused primarily on the calcium, sodium, potassium and other ions in cerebral fluid. They worked with EPFL’s Neurodegenerative Disease Laboratory to compare the measurements they took on rats with those reported in the literature – and found that the results were well correlated. The next step will be to develop a method for analyzing the proteins and neurotransmitters in cerebral fluid, so that their implications in neurodegenerative diseases can be further studied. “Doctors could measure neurochemical responses to help them make diagnoses, such as for epilepsy, when they use electricity to measure signals from a patient’s cortex,” says Guillaume, “or to improve the efficiency of treatments like deep brain stimulation (DBS) for Parkinson’s disease.” Their research could also soon find direct applications in other medical fields. Guillaume currently works on a start-up project to develop a catheter for patients affected by hemorrhagic stroke. Based on a similar technology, his catheter would let doctors treat a common yet serious complication of this condition and thereby reduce the risk of death.

    This research was carried out jointly by EPFL’s Laboratory of Microsystems 4 (LMIS4), EPFL’s Neurodegenerative Disease Laboratory (LEN), the Unit of Toxicology at the University Centre of Legal Medicine (CURML, CHUV and HUG) and the University of Lausanne’s Faculty of Biology and Medicine (FBM, UNIL).

    See the full article here .

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    EPFL campus

    EPFL is Europe’s most cosmopolitan technical university with students, professors and staff from over 120 nations. A dynamic environment, open to Switzerland and the world, EPFL is centered on its three missions: teaching, research and technology transfer. EPFL works together with an extensive network of partners including other universities and institutes of technology, developing and emerging countries, secondary schools and colleges, industry and economy, political circles and the general public, to bring about real impact for society.

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