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.”
Alecta CEO Magnus BillingMichael Kjeller, head of asset management and sustainability at Folksam said: “Even in an extreme scenario where the share price fell to zero, we can observe that Folksam Life and Folksam Sak would remain financially stable and not have any need to change their investment policies.”Swedbank shares are currently trading at around SEK130, having fallen some 26% from around SEK175 at the beginning of this week.Kjeller added that Folksam – the second-largest shareholder in the bank with a 7% stake – had secured a total return of almost SEK18bn from its investment in Swedbank since it became a major shareholder in 2008. Of this, about SEK7bn was realised profits passed on to its customers.At the AGM, the bank elected Kerstin Hermansson as a new supervisory board member. Hermansson has previously worked as managing director at the Swedish Securities Dealers’ Association, a trade body.Alecta’s Billing said: “It is good that the nomination committee continues to work on strengthening the board. The election of Kerstin Hermansson today was a first step.” Meanwhile, fellow pension provider Folksam attempted to reassure its customers that the rapid fall in the bank’s share price would not affect the fund’s stability. Sweden’s biggest pension fund could call for a completely new supervisory board to be appointed for troubled financial services group Swedbank to help deal with recent money-laundering allegations.The SEK878bn (€84.4bn) Alecta which holds around 5% of Swedbank’s shares, said it was dissatisfied with the action taken by the bank’s existing supervisory board in response to reports that billions of krona were laundered through branches of Swedbank and Danske Bank.Commenting after Swedbank’s annual general meeting (AGM) yesterday, in which shareholders discussed the bank’s handling of the money-laundering scandal, Alecta’s chief executive Magnus Billing said: “I do not rule out calling an extraordinary meeting in the near future to get a new board in place.”Just hours before yesterday’s AGM, the Swedbank supervisory board sacked chief executive Birgitte Bonnesen and appointed current chief financial officer Anders Karlsson as acting president and chief executive until a permanent replacement was found.
A few short years ago they were among the NBA’s most promising and exciting teams. By this season, the calls to disassemble the Clippers began well before they spectacularly bombed out of the postseason“We’ve been reading about our obituary for about three months now,” Doc Rivers said Sunday afternoon.The Clippers, despite their eyebrow-raising optimism, were not going to win a championship this season, not with the Warriors ruling the West and especially not after Blake Griffin went down with a toe injury in Game 3 of the first-round series with the Jazz.Chris Paul & Co. would have been beaten badly in a best-of-7 series against Golden State, maybe even swept. But the failure to even get to that round, losing to a Jazz team that was viewed as too green to pose a threat to the top-heavy Clippers, makes the sudden arrival of the offseason all the more bitter. “I’m sure everyone will have their own suggestions,” Rivers said.Even Rivers, the coach and president of the team, the “one voice” of the franchise, is not immune from speculation. An ESPN report this spring linked him to the front office opening in Orlando, and it’s hard to imagine Ballmer hasn’t at least entertained the possibility of asking Rivers to give up his personnel power and just focus on coaching after several lackluster attempts at upgrading the roster.It’s a lot of moving pieces, but just how many of them will be moving on?“I think it’s a great conversation for everybody outside our locker room,” Rivers said. “I don’t think it’s a conversation we’re having in our locker room, I can say that.”There is a line between confidence and believing your own hype. The Clippers often treaded on the wrong side of that marker, doubling down year after year on a model that had not worked. Having balked at reasonable trade offers for Griffin in the past – a reported deal proposal with Denver a year ago now looks like a no-brainer – they now face the prospect of Griffin exercising his early termination option, the presumed and logical move, and losing him for nothing.Or worse: Re-signing Griffin for five years at the maximum $175 million only for him to keep getting hurt and further limiting the Clippers’ options.Paul, meanwhile, can sign a five-year deal with the Clippers for $205 million or take less money and fewer years to chase a ring elsewhere.The Clippers are no longer a young team. Paul will be 32 when he signs his next contract. Griffin is 28 with the battered body of a player with far more games under his belt than the 471 he has actually played.On Sunday, the emotion of the 104-91 loss to the Jazz left the Clippers too raw to delve into the future of the core. At least, the humiliation of becoming the first team in NBA history to blow series leads in five consecutive postseasons provided a convenient excuse to clam up.“Luckily that’s not my job,” Paul said. “My job is to come in, try to make sure I’m in the best shape possible, try to lead our team and stuff like that. That’s not my job to maneuver who’s here and who’s there.”Griffin has surgeryTen days after yet another postseason injury ended Blake Griffin’s season prematurely, the Clippers’ star power forward underwent surgery to repair the plantar plate of his right big toe.The surgery was performed Monday by foot at ankle specialist Dr. Robert Anderson in Charlotte, N.C.Griffin limped off the court in the second quarter of the Clippers’ Game 3 victory over the Utah Jazz on April 21 in Salt Lake City. Initially diagnosed as a sore big toe, an MRI later revealed cartilage damage. The surgery is not expected to sideline Griffin beyond the summer. Newsroom GuidelinesNews TipsContact UsReport an Error The Clippers acted on Sunday like they would solve their problems by just getting back in the gym; by working harder, being better.“You just sort of fall in love with the process,” Paul said. “At the end of the day, it’s a game, and we all love it, know what I mean? You just keep pushing until it happens. It’s not going to change. Keep working, keep playing, keep training, doing all the different stuff until you break through.”Unfortunately, there is far too much paperwork pending for that to be the case. Paul, Griffin and J.J. Redick can be or are free agents. The Clippers, well over the salary cap, could consider a sign-and-trade for any of those stars, but Griffin and Redick might have seen their value diminish in the playoffs.Griffin’s reputation has gone from a case of bad luck to downright brittle; Redick could scarcely make a shot in seven games against the Jazz.Owner Steve Ballmer seems to have two options. Whip out the checkbook to retain a roster likely to be mired in the middle of the Western Conference or start over. The Clippers can’t rebuild through the draft, they don’t have a first-round pick this summer or in 2019.