Rewinding the brain

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first_img The Daily Gazette Sign up for daily emails to get the latest Harvard news. Professor Paola Arlotta awarded George Ledlie Prize New vista for brain disorder research Developmental neurobiologist honored for study of embryonic brain Neurons reprogrammed in animals Related Long-cultured organoids, networks of human nerve cells, prove diverse and mature Connections are properly ‘rewired,’ recognized, say researchers Human brain disorders have always presented researchers with a daunting challenge. They’re hard to study in laboratory mice because they affect the very organ that separates us from animals. And they’re difficult to study in humans because patient safety depends on noninvasive techniques.Enter the brain organoid. Advances in stem cell biology and a new appreciation of the self-organizing powers of developing brain tissue have allowed researchers to create 3-D clusters of living brain that open a new window onto brain development and disease.“I think that these brain organoids hold incredible potential for modeling human neurological disease in completely new ways,” said Paola Arlotta, the Golub Family Professor of Stem Cell and Regenerative Biology and chair of Harvard’s Department of Stem Cell and Regenerative Biology. “I like to imagine a future scenario where we will be able to ask very precise questions about what goes wrong in the context of psychiatric illness, for example.”Arlotta has devoted her career to understanding brain development and what goes wrong in disease. She twice has stood accepted wisdom on its head. In 2013, challenging the theory that neurons cannot change, she used lab mice to show that one type of neuron can be transformed into another. A year later, she demonstrated that the insulating sheath of nerve cells, thought to be distributed identically along the axons of all neurons, instead displays distinct patterns in different cells. That led to the reinterpretation of some theories regarding the role of that insulation, called myelin, and how neurons use it in complex behaviors.In recent years, Arlotta has become a pioneer in brain organoids, which she believes may one day shed light on little-understood conditions such as autism, schizophrenia, and bipolar disorder.Arlotta collaborator Jeff Lichtman, the Jeremy R. Knowles Professor of Molecular and Cellular Biology, has held a front row seat to all this mystery. Through his “Connectome” project, he is working to build a map of neural connections by taking high-resolution images of thin brain slices.“If getting to a full understanding of the brain is a mile, we have walked at least six inches,” Lichtman said. “You look at the actual structure of the brain or even an organoid and it’s just extraordinarily complicated. It’s much more complicated than anything humans have ever built. This is a little humbling.”One consequence of that lack of understanding, Arlotta said, is that theories can stagnate.“It is rather daunting,” Arlotta said. “How are we going to develop new treatments if we do not know what cell types, among the thousands present in the brain, are involved in psychiatric illness? How are we going to find molecular targets for new drugs if we cannot study the very organ that is affected? This is particularly problematic when diseases that start in the womb, during brain formation, manifest later in life.”Arlotta said that creating organoids from people afflicted with brain disorders is akin to going back in time to watch how development plays out.“What if we could somehow go back, so to speak?” she said. “What if we could take a sample of blood from a child with autism, make his or her own stem cells and turn those into a model of their brain? Could we then begin to watch in some small part how the brain had formed? And in so doing, will we have the unprecedented opportunity to shed light on what abnormalities have occurred?“I think that if, in the next decade, we will have built on the use of brain organoids to understand what the neurobiological substrate of psychiatric illness may be, then we would look very proudly at the work that we are doing today.”,‘Liberating’ progress Arlotta got her first glimpse of the potential for brain tissue to self-organize into 3-D organoids in 2012. She was watching a time-lapse video of human stem cells forming an early developing part of the eye called the optic cup. The video, recorded in the lab of Japanese scientist Yoshiki Sasai, showed development that seemed spontaneous, as if preprogrammed.“We all stopped for a moment and watched — mesmerized — the video of a community of stem cells folding, changing, and self-assembling until a primitive retina was made,” Arlotta recalled. “That told us that the nervous system may have an incredible capacity for self-making. And that, to me, was the eye-opener. If stem cells can do that — make an optic cup, layer a human retina — perhaps stem cells know more than we think they do and, with minimal input from outside, perhaps they can form more complex regions of the nervous system, like some parts of the brain.”When her lab began growing organoids from pluripotent stem cells about four years ago, she and her fellow investigators knew very little. The researchers tapped the expertise of Xander University Professor Doug Melton, who had begun growing pancreatic tissue, and borrowed protocols from other labs developing brain organoids to study early growth, a process in which pluripotent stem cells become brain tissue over the course of a few months.Interested in later stages of development, Arlotta needed to figure out how to extend that growth, a task she handed to postdoctoral fellow Giorgia Quadrato.Quadrato determined that a key variable is how many cells are initially used to “seed” the culture. She also tweaked the timing of when specific signaling molecules would be added to tell the stem cells to become brain tissue. By spring of this year, she had more than tripled the organoids’ longevity, allowing cells time to grow and differentiate.“These organoids have self-organizing abilities; they know what types of cells to become,” said Quadrato, who recently joined the faculty of the University of Southern California. “The cells have built in themselves the program. They know how to differentiate, they know when to differentiate and what to become.”,To determine whether the cells her lab was growing related to those of the human brain, Arlotta turned to Lichtman, who for many years had been able to look at the organ in super-high resolution.The goal was to identify protrusions on nerve cells called dendritic spines, where the synapses form that connect one cell to another. Embryonic nerve cells don’t have the spines, Arlotta said, so finding them would indicate the organoids were developing more mature neurons. It would also mean that the researchers could hope to explore a theory on schizophrenia that describes abnormal pruning of the spines in the teen years.“The question was, do organoids have neurons, number one, and, number two, if they have neurons, do they have these features that are necessary to make the kinds of neural circuits found in normal brains?” Lichtman said. “Sure enough, there were dendrites and they had spines and the spines were studded with synapses of axons that were contacting them.“So this was good news. It said these organoids to some degree were doing things that normal brains do.”Arlotta’s lab has started to explore how the brain changes in autism, using CRISPR/Cas9 gene-editing techniques to insert genetic mutations associated with autism into stem cells and allowing the cells to develop into organoids to study side by side with those without that mutation.“We have stem cells derived from patients with these diseases and already beginning to demonstrate that you can use organoids for the first time to tell what cell types are abnormal among the many, many in the brain,” Arlotta said. “That’s liberating.”Organoids provide a glimpse into previously inaccessible aspects of brain formation, but they are very primitive and plagued by high variability, Arlotta stresses. Next for researchers will be learning how to better control their growth to produce reliable models for specific parts of the brain and the effects of specific conditions.Alert to ethicsThough Arlotta strongly disputes characterizations of organoids as “mini-brains” or “brains in a dish” — descriptions that give the rice-grain-size lumps of tissue far too much credit, in her view — she acknowledges the ethical dimension of experimenting with the organ at the center of human consciousness.It’s important to make sure that the research goes hand in hand with conversations that bring together scientists, ethicists, and society at large, she said. It’s also crucial, she said, that the science be communicated correctly, to prevent ethical concerns fueled by perception rather than data.“There’s a need to be more rooted and real about what these models are,” Arlotta said. “These are not, I repeat not, ‘mini brains in a dish,’ and I think that nomenclature has negatively impacted the field.  . . .  It is important as a community to think about the implications of the work, but at the moment the risk is low.”Ethical concerns also exist on the other side of the issue, she said, citing a responsibility to understand and treat psychiatric and neurodegenerative disease.“We have the opportunity to study, understand, and inform treatment on human pathologies that have not seen a real new medicine in over 60 years, at a risk that is frankly not dissimilar to that of experiments that are very accepted in science, like the growing of human cells and neurons,” Arlotta said. “Should we not then take this opportunity to transform treatment?“As a society, we must consider the ethical structure of this work. As a scientist, I must consider also the responsibility I have to make a difference, now that we can, for patients affected with some of the most devastating diseases of our time. Is it ethical or unethical not to take this opportunity to understand disease to alleviate suffering? I think the choice there is very clear.”last_img read more

West Virginia’s River Surfing

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first_imgOCEANS AREN’T THE ONLY PLACE TO CATCH A WAVEWhat if you could get all the pleasure of surfing without ever getting sticky-saltwater-hair and sand in your ears? What if you could ride the perfect wave for minutes, hours even?Sounds like an impossible dream, but a growing community is taking surfing from the oceans to the rivers. Fayetteville, W.Va., is at the forefront of the river surfing movement in the East with two badass chicas at the helm—Melanie Seiler of the standup paddleboard (SUP) community and Meghan Roberts representing the short boards. Though these two ladies have paid their dues on the ocean, both can agree—nothing beats the river.For most of her life, 28-year-old Meghan Roberts has been riding boards—mainly snowboards and surfboards. When she landed in Fayetteville as a raft guide, she decided to take her surfboard to Canyon Doors, a popular boogie boarding spot on the Gauley River.“I was trying to surf on the wave not even knowing [river surfing] was a thing and people were actually doing it,” Roberts remembers.It was a complete failure at first. But then Roberts spotted a fatter foam surfboard for sale that, at first glance, appeared to be just an oversized boogie board. Something told her that this fatter foam board was the ticket to surfing Canyon Doors, so she bought it, took it to the wave a few weeks later, and stood up in her first few tries.“I remember standing there thinking, ‘Oh my God I’m doing it. It works!’ I was just shocked,” she says.Since that first ride, Roberts has been in constant search of the perfect wave, surfing everything she would have normally bypassed as a raft guide. There’s no easy way to get to most of these potential surf spots—some involve bushwhacking at least an hour to access—and more often than not, the weather is less than ideal. The surfing gets good when the weather gets bad, but according to Roberts, it’s all part of the adventure.“When you’re surfing, you don’t think about how cold it is or how deep you might go when you swim,” she says. “All you are thinking about is that feeling of water rushing at you.”Melanie Seiler agrees. Having lived in the whitewater hub of Fayetteville her whole life, Seiler thought she’d done it all—raft, kayak, ducky—until 2009 when a friend and fellow raft guide brought a couple stand up paddleboards to Gauley season.Seiler thrived on the new challenge. Suddenly, class I and II stretches of the New were exciting and difficult again. She suffered through frigid temps and lugged her board through dense swaths of rhododendron for hours to find new waves to surf.“On the one hand, it could be really, really frustrating,” Seiler says of those early days of learning, “but then it also showed me that you really have to work for [the surf] and you’re not just handed it.”In the six years since, Seiler has hosted four SUP races on the New River Gorge, and developed guided SUP tours for Adventures on the Gorge.“I love river surfing because you get on the wave and you can stay on it as long as you want,” she says. “That feeling is all about the sense of being in the moment.”FAQS: KNOW BEFORE YOU GOWhat’s the difference between ocean and river surfing?MS: The difference mainly is that you’re chasing after an ocean wave and riding it for a few seconds. For a river wave, it’s in one stationary place, and once you’re on it, you can ride it as long as your skills allow you to ride it.What type of board do you use?MR: When you’re looking for a river surfboard, you want one that’s wider in the tail—that will help keep you on the wave more. You will want a thicker board, so look for anything between 2.5 and 3 inches thick. Wider, too, at least 20-21 inches wide. That helps keep you in the wave longer. I use a 6’2” Boardworks Mini Mod.MS: The Badfish MVP and the Glide Sesh are my go-tos but a new one I’m checking out is the Paddlestroke G-Rocker which is a light inflatable surfboard.What gear will I need for river surfing?MR: Definitely a wakeboard vest. It’s flat so you can lay on the board better.MS: I usually wear a 6mm wetsuit, 7mm gloves, and 7 mm booties. When it’s really cold, sometimes I wear layers underneath the wetsuit. And when it’s below 35 degrees out, the wetsuit’s not warm enough for me, so I wear my drysuit with a wetsuit hood vest pulled over.Where is the best surfing?MR: For short boards, Diagonal Ledges on the Gauley River. At 3000 to 3,200cfs, it’s a big green wave. Canyon Doors needs 800cfs to surf.MS: For SUP surf, if you have some experience, the Perfect Wave on the Gauley is great at 1,800cfs and 6,500 cfs. Some people get intimidated when there’s higher water but in a lot of places it’s safer (think about it—more water, less rocks).Another fun spot is Canyon Doors. I would classify that as an intermediate surf wave with really easy access and a really easy eddy. The two big ones, ones you wait for the right water levels, are Diagonal Ledges and the New River Dries. Diagonal Ledges is good between 2,500 and 3,500cfs while the Dries is good when the Thurmond gauge reads 18,000 to 24,000cfs. The Dries are so wide and bubbling and churning and stomping. Putting on for the first time will about make you throw up.Where can I get more information?MR: riverbreak.comMS: supconnect.com, nrgsuprace.comlast_img read more

Cricket News Unbelievable! In India Vs South Africa Ranchi Test, Three ‘Captains’ Come Out For Toss

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first_img For all the Latest Sports News News, Cricket News News, Download News Nation Android and iOS Mobile Apps. New Delhi: The India Vs South Africa Test in Ranchi witnessed a very peculiar sight just before the toss. Virat Kohli, the Indian cricket team skipper and Faf du Plessis, the South Africa skipper came out for the toss as always. However, accompanying the South Africa captain was Temba Bavuma, the team’s vice-captain and the designated ‘proxy captain’ for the toss. Bavuma was given the chance to call the toss as Faf du Plessis had a horrible record with tosses in Asia, losing nine consecutive times before the Ranchi Test. However, Bavuma had no luck as South Africa lost the toss and India chose to bat on a pitch that would assist the spinners. Du Plessis, in the pre-match press conference, had stated that he might send someone else for the toss in Ranchi. “Probably we will change… send someone else to the toss tomorrow. I can give you that… because my records so far has not been great.” After losing the toss, du Plessis admitted that there was nothing else he could do. “It shows that it isn’t meant to be (about using Bavuma as a proxy skipper for luck). Important toss as this looks the driest surface of the series,” du Plessis rued. However, this was not the first time that a special ‘proxy captain’ was appointed for the toss in a cricket match. During the recent Women’s Twenty20 International series between Australia and Sri Lanka in Sydney, Australia skipper Meg Lanning appointed Alyssa Healy as a “specialist coin tosser.” The move came after Lanning’s poor toss record in the previous series against the West Indies, winning just one toss. The move worked and Australia won the toss and chose to bat against Sri Lanka. For Du Plessis, this was the second instance when he had appointed someone else for the toss. In October 2018, during South Africa’s game against Zimbabwe, du Plessis sent out JP Duminy for the toss. Duminy was not playing but he was appointed as du Plessis had a similar horror losing streak of six consecutive tosses. Duminy won the toss and South Africa dominated Zimbabwe.Also Read | Shahbaz Nadeem To Make Test Debut For India In Ranchi Test Vs South AfricaThe ICC’s playing regulations mandate time of the coin toss. It adds that it has to be done on the field of play and under the supervision of the ICC Match Referee, but they also allow for a deputy to act for the captain if they are “not available”.last_img read more