Motorsports Etc.

first_imgNASCAR driver Kasey Kahne, a Washington native, was rooting for the Seattle Seahawks to make it to the Super Bowl. He was even at Soldier Field to see the Chicago Bears beat his Seahawks. As a result, he will begrudingly be rooting for the Bears to win the Super Bowl. “I really don’t want to see it,” Kahne said. “The only reason why is because I went to Soldier Field and cheered them on and they played great, the Bears played great and the Bears beat them. I feel like the Seahawks may be in the Super Bowl if the Bears didn’t take them out. But it should be a good game. I feel like Peyton Manning, it’s his time. He’s been so good, so clutch, so on top of it for a long time; he’s going to be tough to beat in the Super Bowl.” … Sarah Fisher and Buddy Rice will be drivers for Dreyer & Reinbold Racing in the Indy Racing League, the team’s owners announced Tuesday. Rice won the Indianapolis 500 while driving for Rahal Letterman Racing in 2004. “I’m looking forward to being back in competitive race cars and at the Indy 500,” Rice said. “It’s the biggest race in the world, and I was fortunate to win it before, and I’d like to do it again.” Fisher, who began her career in 1999, has started 50 IndyCar Series races, including two for Dreyer & Reinbold last year. She won a pole position at Kentucky Speedway and has three top-five finishes in her IRL career. Her deal with Dreyer & Reinbold is not presently full-time. 160Want local news?Sign up for the Localist and stay informed Something went wrong. Please try again.subscribeCongratulations! You’re all set!last_img read more

Holiday Food and Beverage Options for Disneyland

first_imgShare This!Today is the official kick-off of the holiday season at the Disneyland Resort. And of course, there are a number of great food and beverage options that are being rolled out for the occasion. Here are the yummy goodies you’ll be able to enjoy while traversing Disneyland Park.Holiday ChurrosCaramel and Coconut Churro (Town Square Churro Cart and Churros Near Sleeping Beauty Castle)Santa’s Cookies and Milk Churro (Churros Near Casey Jr.) – Artisan churro rolled in cookie butter sugar and served with sweet milk dipped sauceToffee-Flavored Churro (Tomorrowland Churro Cart) – add-on chocolate-almond or chocolate dipping sauces availableTurtle Churro (Frontierland Churro Cart) – Artisan churro rolled in chocolate sugar and served with caramel pecan dipping sauceSugar Plum Candy Churro (New Orleans Churro Cart) – Sweet and tart churroOutdoor Vending Carts at DisneylandPink, Blue, and Candy Apple Cotton CandyPeppermint-Caramel Corn©DisneyCarnation CaféFried Bolonga Sandwich – Pullman bread, mayo, fried bologna, lettuce, tomato, and pickle stackers served with friesPork Chop TV Dinner – Pork chop with seasoned apples, mashed potatoes, peas and carrots, and a cheddar and chive scone served with caramel bread puddingGibson Girl Ice Cream ParlorPeppermint Holiday Sundae – Peppermint ice cream topped with chocolate sauce and crushed peppermintRefreshment CornerFrench Dip Sandwich – Roast beef, spicy mustard, and au jus served on a crunchy French roll with chips©DisneyJolly Holiday Bakery CaféThanks-Mas Sandwich – Oven-roasted turkey, stuffing, gravy, and cranberry sauce on rustic breadButternut Squash SoupSnowman Shortbread CookieSanta Hat Macaron – with white mint filling and chocolate ganachePumpkin Muffin (available through Dec. 1)Dutch Apple Cinnamon Muffin (available Dec. 1)Eggnog Latte Cheesecake – with white chocolate mousse foam and a sprinkling of nutmegHoliday Cupcake – Vanilla bean cupcake filled with red and green chocolate pieces, finished with green and white-swirled white chocolate mousse, and chocolate swirl candy piecesHoliday Brownie – topped with white chocolate mousse and sprinkles and finished with chocolate presents and a Christmas treeMickey Gingerbread Man©DisneyMarket HouseHoliday Strawberry Linzer CookieSnowman Shortbread CookieMickey Gingerbread ManPlaza InnRaspberry Mascarpone Yule Log – Vanilla sponge wrapped with raspberry marmalade and mascarpone filling topped with buttercream ganache and chocolate curlsChristmas Cake – Chocolate sponge cake with red, green, and white swirled chocolate mousse filling topped with buttercream and finished with sprinklesChristmas Bundt Cake (available Dec. 1)Red Rose TaverneBeast’s Forbidden Pastrami Burger – Angus beef patty, uncured wagyu pastrami, Swiss-American cheese, spicy mustard aïoli, and a skewered accompanimentPumpkin Spice ShakeMickey Gingerbread Man©DisneyGalactic GrillCaramel Pecan Brownie ParfaitSteakhouse Burger – Angus beef patty, provolone, onion strings, and sweet spiced bacon on a toasted bun served with choice of yogurt or french friesApple Pie SlushNova Coffee Slush – Chocolate-mint-flavored coffee slush©DisneyAlien Pizza PlanetBruschetta Poultrium Pizza – Tender chunks of chicken, house-made bruschetta, and assorted cheeses with spiced marinara sauceGreen Alien Holiday Macaron – with lemon fillingAlpha Broccolius Parfait – Layers of soft mint ganache, green cake, white chocolate mousse, cookies and cream streusel, and whipped topping©DisneyRancho del ZocaloPan Dulce Ice Cream Sandwich – Colorful shell-like Mexican sweet bread with dulce de leche ice cream, cajeta, and churro streuselChampurrado with Churro Bites – Rich, traditional-style Mexican hot chocolate served with cinnamon-sugar churrosChicken Mole – Seasoned half chicken topped with mole, drizzled with sour cream, sprinkled with toasted sesame seeds, and served with Mexican rice and refried beansCaldo de Pollo – Hearty soup of chicken, vegetables, and rice served with onions, cilantro, and limeFrozen Abuelita Hot Chocolate – Layered with frozen horchata and topped with spiced whipped cream©DisneyGolden HorseshoeHoliday Ice Cream SandwichStage Door CaféApple Pie Funnel Cake – House-made funnel cake with cajeta, whipped cream, and streuselHungry Bear RestaurantSnickerdoodle Cold BrewPumpkin Spice Cheesecake Funnel CakeBlue Bayou RestaurantGingerbread Crème Brûlée – with Chantilly cream and a mini chocolate gingerbread man©DisneyCafé OrleansHot Chocolate Beignets – Served with hot chocolate sauce and whipped creamHarbour GalleyHoliday Pozole – plant-based pozole with slow-roasted tomatillos, hominy, and serrano chiles and served with limes, radishes, and shredded cabbagePumpkin Spice Cold Brew CoffeeFrench MarketSmothered Beef – Braised beef with mashed potatoes, seasonal vegetables, roasted garlic, and caramelized onion jusThe Wedding Cake – Buttercream frosting, cherries, and cream cheese filling finished with a splatter of cherry sauceBlue Velvet Cake – With blueberry purée, rice croquette brittle, and a vanilla-blueberry crisp©DisneyMint Julep BarCandy Cane BeignetsChocolate Dipping Sauce Add-OnCranberry Julep – Cranberry-infused mint julepRoyal Street VerandaBlue Lump Crab Fritters – Blue lump crab, cream cheese, herbs, citrus, and herb seasoning with cocktail sauceRiver Belle TerraceBurnt Ends Grilled Cheese Sandwich – Kansas City-style brisket ends tossed in barbecue sauce with pickle and pepperoncini relish and melted cheddar served on Texas toast©DisneyBengal BarbecueYellow Curry Rice Plate – Outback vegetable skewer and herb-marinated tofu served on a bed of jasmine rice with peas, green onions, and a side of citrus-miso slaw These items are only available throughout the holiday season at Disneyland Park, from now until January 6, 2020. In addition, keep in mind that many of these seasonal items are available for mobile ordering through the Disneyland App.last_img read more

SA woman to head World Editors Forum

first_img“Our interest must be in helping editors of news organisations lead change that builds loyal readership, strengthens titles and news brands. A unique annual occasion Ireton is the first woman to head the World Editors Forum, which was created in 1994 as a unique global network for exchanging ideas on newsroom management, editorial quality, online strategies and press freedom issues. Cherilyn Ireton, a South African editor and successful senior manager at some of the country’s top newspapers, has been appointed executive director of the World Editors Forum, the global organisation for editors within the World Association of Newspapers and News Publishers (WAN-IFRA). For the past six years she has been based in London, consulting on media matters to a variety of international organisations and governments. SAinfo reporterWould you like to use this article in your publication or on your website? See: Using SAinfo material “While attention to content delivery channels is vital to the future of newspapers, our focus must equally be on ensuring that high editorial standards and ethics are upheld and that young readers are introduced to the joy and power that news and information can bring,” she said. Ireton is a seasoned newspaper professional with more than 20 years’ experience on South Africa’s top newspapers, including the Sunday Times and Business Day, where she worked as a journalist, editorial manager and chief operations officer.center_img The World Editors Forum conference is held annually alongside the World Newspaper Congress. Together the meetings are the global annual summit meetings of the world’s press. The Forum runs the Editors Weblog and organises several conferences and study tours, including an annual Newsroom Summit and its flagship event: the World Editors Forum Conference, intended for chief editors and other senior executives, a unique annual occasion for dialogue, debate and idea-exchange on the changing business of editing newspapers. “The World Editors Forum needs to build on its role as the leadership hub for editors by providing meaningful spaces, both physical and virtual, for editors to share intelligence, innovative ideas and their experiences with their peers,” Ireton said in a statement this week. It represents more than 18 000 publications, 15 000 online sites and over 3 000 companies in more than 120 countries. 26 January 2012 WAN-IFRA, based in Paris, France, and Darmstadt, Germany, with subsidiaries in Singapore, India, Spain, France and Sweden, is the global organisation of the world’s newspapers and news publishers.last_img read more

Missouri poised to require expanded insurance for children with disabilities

first_img(Missourinet) In 2010, the Missouri Legislature passed a bill requiring insurance companies to cover therapies for the state’s autistic children. A measure passed this year expands that policy by mandating insurers to include physical, occupational and speech therapies for Missouri’s physically and developmentally disabled kids up to age 18. The move will make the Show-Me State among three states in the nation to have a therapy requirement for all children with such challenges.The Schelps pictured with Gov. Mike Parson during bill signingThe bipartisan bill, sponsored by State Representative Chuck Basye, R-Rocheport, was attached to a healthcare bill with several other components. It was signed into law this month by Gov. Mike Parson, a Republican, and takes effect with 2020 insurance plans.Robyn Schelp, of central Missouri’s Columbia, has been a leading advocate of the law because her 11-year-old son, Nathan, is developmentally challenged.“It’s not going to impact him that much anymore like it would have ten years ago, but it needs to be done for all kiddos,” says Schelp. “This is not about Nathan. It’s not about Will. It’s not about the kids that are walking the halls. It’s about all of Missouri’s children.”Schelp’s pursuit for the law included leaving the language broad for all disabilities to get equal treatment.“It is so important that all disabilities be included to do with anything in the disability world,” she says. “This (bill) includes disabilities like Down syndrome, which is pretty common, cerebral palsy, multiple sclerosis, to the really rare genetic disorders. Or like my son, who has a genetic disorder that they can’t even figure out what it is.”In the provision of Senate Bill 514, it says that insurance companies must be limited to a number of visits per calendar year, provided that additional visits shall be covered if approved and deemed medically necessary by the health benefit plan. Schelp is hopeful that more therapy providers will surface in Missouri, especially in schools and in rural areas where healthcare resources are especially limited.“It (the law) impacts their families. It’s impacts their neighbors. It impacts their classrooms – their classmates. It impacts the community. When we start to get beyond ourselves, we can realize when everybody’s needs are met, everybody benefits,” Schelp says.Now that Missouri will soon become the third state to expand coverage, Schelp does not plan to stop advocating for the cause.“Our goal is to see nationwide change. We want this (requirement) to happen everywhere,” says Schelp. “It should have already happened everywhere, but now it’s time to make sure it happens everywhere throughout the country.”last_img read more

This mysterious $2 billion biotech is revealing the secrets behind its new drugs and vaccines

first_img By Kelly ServickFeb. 1, 2017 , 2:30 PM Mind-blowing dataModerna now has more money to throw at those molecules than most biotechs can dream of, though it’s far from the only group chasing mRNA drugs. The German biotech CureVac, for example, has brought mRNA-based vaccines for rabies and cancer to clinical trials, and Karikó now heads a research team at BioNTech in Mainz, Germany, that focuses on mRNA-based drugs.But few companies have delved into nucleoside engineering the way Moderna has, or pursued such a broad range of diseases from the start. Beyond its $100-millionper-year platform research, Moderna runs four wholly owned ventures focused on drugs for infectious diseases, rare diseases, immuno-oncology, and personalized cancer vaccines. It has about 430 full-time employees, spilling across three buildings around biotech-dense Kendall Square. Higher-ups are identified by black-and-white headshots hanging at their office doors.Lavish funding has allowed Moderna to set up production facilities that can manufacture more than 1000 new, made-to-order mRNA a month. (“Moderna has probably made more RNA by in vitro transcription than all of humankind ever,” quips Edward Miracco, a senior scientist on its process innovation team.) And it has allowed for many parallel animal experiments to characterize different mRNA and select the most promising. “If you need to run a 25-arm experiment, just do it,” Bancel recalls telling his team. “We have the money, we have the infrastructure. Just do the right science.” V. Altounian/Science Hacking the kingdom of lifeThe vision of an mRNA drug has beguiled scientists for decades. “It’s a huge idea,” says Michael Heartlein, who heads mRNA research at a competing biotech called RaNA Therapeutics just a few blocks away. “Any protein target [where] you can think of a potential therapeutic, you can approach that with mRNA.” The single-stranded molecule sets up a temporary protein factory outside a cell’s nucleus and attaches to ribosomes. This cellular machinery translates its sequence of four kinds of nucleosides—adenosine, cytidine, uridine, and guanosine—into a protein. Then it degrades within a day.Assembling these chemical instructions could be a faster and more adaptable way to make drugs than manufacturing the individual proteins themselves in large bioreactors. And it would allow scientists to deliver proteins that act inside cells or span their membranes, which are a challenge to introduce from the outside. An mRNA drug would also be easier to control than traditional gene therapy. Like mRNA, gene therapy can induce cells to make therapeutic proteins, but it typically introduces DNA that can integrate unpredictably into the genome.If you can hack the rules of mRNA, “essentially the entire kingdom of life is available for you to play with,” says Hoge, a physician by training who left a position as a health care analyst to become Moderna’s president in 2012. Adjusting mRNA translation to fight disease “isn’t actually super high-risk biology,” he adds. “It’s what your genes would do if they were rational actors.”One key problem, however, is that our bodies would normally destroy incoming mRNA before it could get cranking. It’s a relatively large molecule that is prone to degradation, and as far as our cells are concerned, it’s supposed to come from the nucleus, where it’s transcribed from DNA. RNA invading from outside the cell is the hallmark of a virus, and our immune system has evolved ways to recognize and destroy it. CAMBRIDGE, MASSACHUSETTS—In a recent morning meeting of scientific leaders at Moderna Therapeutics, conversation swerved toward the philosophical. Biochemist Melissa Moore, recently hired to head RNA research at the Boston-area biotech, had something on her mind: hype.Specifically, she was thinking about Gartner’s hype cycle, a glib model cooked up by an IT research firm, in which every new technology ascends a “peak of inflated expectations,” sinks into a “trough of disillusionment,” then climbs the “slope of enlightenment” to reach a “plateau of productivity.” Where on this curve, she wondered to Moderna’s president, Stephen Hoge, was their technology?The question is apt. Moderna was founded on the idea that messenger RNA (mRNA), the molecule that relays genetic instructions from DNA to the cell’s proteinmaking machinery, could be re-engineered into a versatile set of drugs and vaccines. These strands of instructions could teach our cells to make whatever was needed to treat or prevent disease—virus-slaying antibodies, wastegobbling enzymes, heart-mending growth factors. The willingness of pharmaceutical giants and investors to bet on that premise to the tune of nearly $2 billion has unleashed waves of both hype and skepticism.Sign up for our daily newsletterGet more great content like this delivered right to you!Country *AfghanistanAland IslandsAlbaniaAlgeriaAndorraAngolaAnguillaAntarcticaAntigua and BarbudaArgentinaArmeniaArubaAustraliaAustriaAzerbaijanBahamasBahrainBangladeshBarbadosBelarusBelgiumBelizeBeninBermudaBhutanBolivia, Plurinational State ofBonaire, Sint Eustatius and SabaBosnia and HerzegovinaBotswanaBouvet IslandBrazilBritish Indian Ocean TerritoryBrunei DarussalamBulgariaBurkina FasoBurundiCambodiaCameroonCanadaCape VerdeCayman IslandsCentral African RepublicChadChileChinaChristmas IslandCocos (Keeling) IslandsColombiaComorosCongoCongo, The Democratic Republic of theCook IslandsCosta RicaCote D’IvoireCroatiaCubaCuraçaoCyprusCzech RepublicDenmarkDjiboutiDominicaDominican RepublicEcuadorEgyptEl SalvadorEquatorial GuineaEritreaEstoniaEthiopiaFalkland Islands (Malvinas)Faroe IslandsFijiFinlandFranceFrench GuianaFrench PolynesiaFrench Southern TerritoriesGabonGambiaGeorgiaGermanyGhanaGibraltarGreeceGreenlandGrenadaGuadeloupeGuatemalaGuernseyGuineaGuinea-BissauGuyanaHaitiHeard Island and Mcdonald IslandsHoly See (Vatican City State)HondurasHong KongHungaryIcelandIndiaIndonesiaIran, Islamic Republic ofIraqIrelandIsle of ManIsraelItalyJamaicaJapanJerseyJordanKazakhstanKenyaKiribatiKorea, Democratic People’s Republic ofKorea, Republic ofKuwaitKyrgyzstanLao People’s Democratic RepublicLatviaLebanonLesothoLiberiaLibyan Arab JamahiriyaLiechtensteinLithuaniaLuxembourgMacaoMacedonia, The Former Yugoslav Republic ofMadagascarMalawiMalaysiaMaldivesMaliMaltaMartiniqueMauritaniaMauritiusMayotteMexicoMoldova, Republic ofMonacoMongoliaMontenegroMontserratMoroccoMozambiqueMyanmarNamibiaNauruNepalNetherlandsNew CaledoniaNew ZealandNicaraguaNigerNigeriaNiueNorfolk IslandNorwayOmanPakistanPalestinianPanamaPapua New GuineaParaguayPeruPhilippinesPitcairnPolandPortugalQatarReunionRomaniaRussian FederationRWANDASaint Barthélemy Saint Helena, Ascension and Tristan da CunhaSaint Kitts and NevisSaint LuciaSaint Martin (French part)Saint Pierre and MiquelonSaint Vincent and the GrenadinesSamoaSan MarinoSao Tome and PrincipeSaudi ArabiaSenegalSerbiaSeychellesSierra LeoneSingaporeSint Maarten (Dutch part)SlovakiaSloveniaSolomon IslandsSomaliaSouth AfricaSouth Georgia and the South Sandwich IslandsSouth SudanSpainSri LankaSudanSurinameSvalbard and Jan MayenSwazilandSwedenSwitzerlandSyrian Arab RepublicTaiwanTajikistanTanzania, United Republic ofThailandTimor-LesteTogoTokelauTongaTrinidad and TobagoTunisiaTurkeyTurkmenistanTurks and Caicos IslandsTuvaluUgandaUkraineUnited Arab EmiratesUnited KingdomUnited StatesUruguayUzbekistanVanuatuVenezuela, Bolivarian Republic ofVietnamVirgin Islands, BritishWallis and FutunaWestern SaharaYemenZambiaZimbabweI also wish to receive emails from AAAS/Science and Science advertisers, including information on products, services and special offers which may include but are not limited to news, careers information & upcoming events.Required fields are included by an asterisk(*)Moderna has shared little detail in published papers about the technology it’s developing, though there are clues in its abundant patent filings. Until recently, even the targets of drugs already in clinical trials weren’t publicized. We’ve had failures. We’ve gone down blind alleys. But because we’ve been quiet about it, nobody’s seen that. Moderna’s President Stephen Hoge (left), RNA research director Melissa Moore, and CEO Stéphane Bancel aim to transform messenger RNA into drugs and vaccines. Melissa Moore, Moderna Therapeutics But as more trials get underway, Moderna is gingerly opening up. The company agreed to Science’s request for access to some of its researchers and labs over the past few months. And last month, at the annual J.P. Morgan Healthcare Conference in San Francisco, California, CEO Stéphane Bancel unveiled Moderna’s first round of drug candidates, which include vaccines for Zika and flu, and a therapy for heart failure.Expectations are high. Being a startup valued at more than a billion dollars—an anomaly that venture capitalists dub a unicorn—comes with scrutiny, and many wonder whether Moderna’s pipeline, consisting mostly of vaccines for now, will expand to match the company’s original vision of mRNA as a broad treatment platform. “There were a lot of really big promises made,” says Jason Schrum, a biotechnology consultant in San Francisco and a former Moderna employee. “That’s what people latched onto; they want the promises to be true, and they want to see the investment really turn it into something meaningful.”In other words, the trough of disillusionment, if it’s still ahead, threatens to be deep. Biochemist Katalin Karikó heard this argument over and over as she tinkered with mRNA in her University of Pennsylvania (UPenn) biochemistry lab in the early 2000s. But she and her UPenn colleague Drew Weissman found a way to tame cells’ typical inflammatory response by modifying one of mRNA’s four building blocks, uridine. Assembling mRNA using pseudouridine, a nucleoside variant that occurs naturally in the body, greatly reduced the tendency of immune sentinels called dendritic cells to shoot out inflammatory molecules in response, they reported in 2005.In mouse studies, this mRNA proved stable enough to stick around in the body and make proteins. Karikó and Weissman founded a company hoping to develop drugs from the discovery, and won nearly a million dollars in small business grants from the U.S. government for animal studies. But shortly after the money came through, Karikó says, the university sold the intellectual property license, and the effort never reached clinical trials. “I could not find any ear,” she recalls, “someone that would say, ‘Oh, let’s try it.’”But when stem cell biologist Derrick Rossi’s team at Boston Children’s Hospital used pseudouridine-containing mRNA to encode proteins that transformed mature cells into stem cells, he found quite a few ears. Serial entrepreneur Robert Langer of the Massachusetts Institute of Technology (MIT) and Noubar Afeyan, CEO of the venture capital firm Flagship Pioneering, both in Cambridge, saw the makings of a whole new class of drugs—and the idea of Moderna was born.The company, which launched operations in 2011 with Flagship funding, quickly set its sights on new (and patentable) nucleoside modifications that would provoke an even smaller immune response than pseudouridine. “This stuff was working a little bit,” says Hoge, “so why not make it work a lot?”Initially operating in “stealth mode”—without announcement of its existence—Moderna’s team screened mRNA assembled from various modified nucleosides and hit on one called 1-methylpseudouridine. It bore a chemical “bump” that the team suspected kept it from locking into key receptors on the surface of immune cells.As the data flowed in during 2011 and 2012, Bancel, who had come to Moderna from the French diagnostics company bioMérieux, began to work up a pitch. He was catching potential investors at an inauspicious time: Many were smarting from disappointing trials of RNA interference therapies, which use short, double-stranded RNA to disrupt the production of disease-causing proteins. “No one had cracked how to make RNA stable enough to be a therapeutic,” says Mene Pangalos, who heads the Innovative Medicines and Early Development Biotech Unit at AstraZeneca in Cambridge, U.K.Bancel showed Pangalos and his team two studies in which an injection of modified mRNA containing pseudouridine prompted nonhuman primates to express two human proteins. Among dozens of mouse studies, he presented work led by Moderna Co-Founder Kenneth Chien, then at Harvard Medical School in Boston, showing that mice recovering from induced heart attacks survived longer and had stronger hearts when injected with mRNA encoding a protein that drives blood vessel formation—vascular endothelial growth factor (VEGF).”That got us excited,” says Pangalos, who was eager to build up AstraZeneca’s pipeline of cardiovascular drugs. “It was incredibly high risk. It was untried and untested.” But if it could work for one disease, it would likely work for many. Changing the disease target didn’t require developing or identifying a whole new drug, just altering the mRNA sequence. And although many of the initial animal studies used mRNAs with pseudouridine, Moderna’s new chemistry was already starting to outperform that first generation in rodent studies. “I don’t think it was such a stretch to imagine the technology would continue to improve, given what they were doing,” Pangalos says. In March 2013, a few months after Moderna announced itself to the world, AstraZeneca put an up-front $240 million into a partnership to pursue up to 40 drug candidates using Moderna’s technology.Schrum, who led early chemistry research at Moderna and made some of the discoveries behind its initial patents, had left the company by the time the AstraZeneca deal was sealed. To him, the sum was astonishing, given the preliminary findings he had seen. “There was a lot of excitement that this [technology] can be applied to anything, and that this is a panacea,” he says. Before meetings with potential investors and partners, he remembers the Moderna team being “frantic to get some sort of data, just general data, without a whole lot of specifics attached.” Winning those early investments, by his estimate, “comes down to salesmanship.”Moderna’s bold premise inspired headlines comparing it to a young Genentech, the most famously successful of all biotechs. Bancel, meanwhile, insists that he never hyped the company. “We never said, ‘Oh look at mRNA; we’re going to cure 2 million diseases.’ No, we said, ‘What if? What if this could work?’” But as more cash poured in—$100 million from Alexion Pharmaceuticals to pursue rare diseases, $100 million from Merck for a set of antiviral drugs—the image of Bancel as a brash newcomer with a crisp suit and an audacious pitch became part of the company’s mystique.Afeyan at Flagship, who recruited Bancel, calls such a portrayal irrelevant “social science” that gives Moderna’s technology short shrift. “There is real science here,” he says. “There’s real data, there’s real molecules.” Engineering the messenger Moderna aims to design messenger RNA (mRNA) that directs cells to make a protein that works as a drug or vaccine. To succeed, the mRNA has to enter the cell, avoid degradation, and be translated efficiently.center_img This mysterious $2 billion biotech is revealing the secrets behind its new drugs and vaccines The biotech Moderna delivers messenger RNA (blue) into cells to be translated into proteins by ribosomes. © Ken Richardson J. You/ Science It has taken a lot of science to make mRNA act like a drug. Some of Moderna’s most promising early candidates, although they could tiptoe past the immune system, produced underwhelming amounts of protein in animal studies. The same nucleoside modifications that made mRNA more stealthy also made it less recognizable to the ribosome. “If you’re trying to sneak in there and make a thing, you have to look pretty darn natural,” Hoge says. Moderna needed to figure out what features of naturally occurring mRNA were most important for translation, and how to restore them.By the summer of 2013, word of the company’s ambitions was wafting through academic labs, including Melissa Moore’s at the University of Massachusetts Medical School in Worcester. Moore had spent her career studying the intricacies of how nascent mRNA gets spliced in the nucleus and loaded with proteins to become a complex known as a messenger ribonucleoprotein (mRNP). Over those years, she had also grown frustrated by how many more male than female scientists held consulting roles at biotech companies. When a colleague told her about Moderna, she decided to go out on a limb.”Although we have many common connections, I don’t believe you and I have ever met,” she wrote in an email to Tony de Fougerolles, who was then Moderna’s chief scientific officer. “I am arguably the world’s expert on how the synthetic history and protein complements of mRNPs contribute to gene expression.” Maybe, Moore suggested, her knowledge could improve Moderna’s product. “I remember going home and being emotionally depleted, because I had completely just put myself out there,” she says. “I had never done anything like that before, but I knew I had to do it.”De Fougerolles invited Moore to give a seminar, which led to a sponsored research agreement, and, eventually, a position on the scientific advisory board. Last year, Moore left her tenured position to become chief scientific officer of Moderna’s research platform. “I could have spent the next 15 years turning the crank, putting out more papers, training more students,” she says, “but when I’m 80 or 90 and I look back at my life, I would regret that decision.”Moore’s academic work has advanced a counterintuitive theory about mRNA. It might seem that secondary structure—the folds and loops caused by bonding between nucleosides in the strand—should hinder protein production. Too much structure could force the ribosome to do extra work untangling the strand or even stall translation altogether. But findings in Moore’s lab supported the view that mRNA strands with more of the nucleosides that tend to form tight bonds are, in fact, easier for ribosomes to translate.The bioinformatics team at Moderna was making parallel discoveries. Even between mRNAs with the same sequence, they were finding that different modified nucleosides produced different amounts of protein. And nucleosides with a tendency to form tighter structures were more productive. The team knew that the frequency and placement of the modified nucleosides in the strand changed how it folded, and hence how it interacted with the ribosome. And because trillions upon trillions of different nucleoside sequences can code for the same protein, there were plenty of ways to engineer more efficient ones—providing they could be predicted.Doing so took the Moderna team deep into the structure of mRNA. To model how single-atom changes affected bonding between nucleosides, they enlisted a quantum chemistry expert, Michelle Hall. “When I started looking for industry jobs, people were like, ‘Oh that’s adorable. Nobody does that in industry,’” Hall remembers. “Turns out, not true.”Her calculations informed an algorithm that predicts, for a given protein, what mRNA sequence would produce the structure most appealing to a ribosome. Across many drug candidates, the team saw a several-fold increase in protein production using the new designs. Bancel recalls the meeting when they described this breakthrough: “They blew my brain on the walls.” Avoiding the hype curveOutside researchers can’t yet weigh in on how mind-blowing Moderna’s fundamental research might be. “It would be stupendous to see the data out of Moderna,” says Paul Agris, an analytical biochemist at the State University of New York in Albany’s RNA Institute who has spent decades studying the consequences of modifying RNA nucleosides.But for now, the company’s only published paper is the one from Chien’s group on producing VEGF in mice. It hasn’t revealed which modified nucleoside is in its newest generation of drug candidates. And it launched its first two phase I trials without announcing what diseases they targeted—a decision Bancel attributes to fears that financial markets would prematurely pigeonhole the company into a particular field. (Investigators are not required to register phase I trials with ClinicalTrials.gov.)Moderna’s leaders argue that they’ve disclosed research the way most private companies do—by detailing it in patent filings. “It wasn’t a deliberate effort to be secretive,” Hoge says. “The act of publication was not, in and of itself, a focus for us. In fact, it wasn’t even clear that it was anywhere on our priority list.”For many researchers who have worked with companies, that isn’t surprising. “It’s a highly competitive field, and they’ve made the decision that they don’t want to publish a bunch of papers. That makes sense,” says Daniel Anderson, a molecular geneticist who develops drug delivery systems at MIT. “Publishing papers can generate excitement. … But if you have a whole lot of people and a whole lot of money, it may be smart just to stay quiet and develop your technology and patent the heck out of it.” Votes of confidence Venture capitalists, pharmaceutical companies, and others have invested heavily in Moderna’s vision of mRNA-based drugs. V. Altounian/Science Holding its data close doesn’t seem to have hurt Moderna’s ability to raise money and advance its drugs. But now that treatments are being injected into people, “there’s a certain obligation to patients to start to tell that story,” Hoge says. The company has submitted several manuscripts to journals, and last month described the collection of drugs in its pipeline.Human safety trials have already begun for vaccines against two flu strains and the Zika virus, and for a fourth undisclosed viral vaccine developed in collaboration with Merck. In each case, the mRNA encodes viral proteins that infected cells would normally present to activate the immune system and beat back an infection. Last month, Moderna also began trials of its VEGF drug, developed with AstraZeneca. Intended to treat cardiovascular diseases as well as slow wound healing in diabetes, the growth factor-encoding mRNA is first being injected under the skin of trial participants to evaluate safety.Moderna is also doing animal safety tests of a personalized cancer vaccine that would code for immune-activating proteins unique to a person’s cancer cells, based on genetic sequencing of their tumor. Another possible cancer drug, awaiting regulatory approval for a clinical trial, consists of mRNA for a surface protein called OX40L that would, when injected into a tumor, prompt T cells to proliferate and attack.Last month’s presentation also got attention for what it didn’t describe—trials of drugs that replace missing or deficient proteins to treat chronic diseases. Most of Moderna’s advanced candidates are vaccines, which require just a low dose of mRNA that makes enough protein to kick the immune system into gear. And all of them are administered locally, under the skin or into a muscle or tumor. To tackle lifelong diseases where patients are missing a key protein, such as an enzyme that removes toxic compounds from the body, mRNA drugs will likely have to be delivered intravenously for decades. That makes even mild toxicity or subtle immune reactions a potential deal-breaker.Much of the risk comes down to formulation—the molecular packaging that ferries mRNA into cells and protects it from being hacked apart by enzymes along the way. “That’s where the breakthroughs are really needed,” says RaNA’s Heartlein. Many RNA drugs to date have encapsulated the nucleic acid in nanoparticles made of lipids. But because mRNA is so large—roughly 100 times the length of the RNA used for interference therapies—it’s harder to stabilize and to encapsulate. And many lipid nanoparticles are not easily degraded in the body, so they can cause toxic buildup in the liver. “We’re going to find applications [for mRNA drugs],” Heartlein says, but “it may not be as broadly applicable at the end of the day as people are thinking.”Hoge acknowledges that some conditions may be off limits to mRNA drugs simply because they require higher levels of protein than the mRNA can make at a safe dose. Muscular dystrophies or skin disorders where patients lack a key structural protein, for example, are a long shot. “A lot of people think that gene therapy might be the only solution for some of these diseases. And certainly for some of them, it might be,” he says.Moderna is developing delivery systems that may limit toxicity. Among its proprietary nanoparticles is a family of engineered lipids that its scientists have found to be more biodegradable—and thus more tolerable at higher doses—than existing formulations. A separate “delivery innovation” team is developing nonlipid formulations, such as polymers that form solid, porous structures interspersed with mRNA.AstraZeneca’s Pangalos says his group has its sights set firmly on mRNA drugs for chronic use, and expects a drug intended for repeated dosing to enter trials in the next 18 months. But Moderna has had to retreat from optimistic predictions about a partnership with Alexion to treat a rare disease called Crigler-Najjar syndrome. The mRNA treatment would code for an enzyme that breaks down bilirubin, a toxic substance that builds up in patients’ blood. Before it can enter human testing, the companies must be sure the dose needed to impact the disease is many-fold lower than the dose that causes toxicity.In 2015, Moderna and Alexion predicted that the drug would advance to clinical trials in 2016, but late last year they informed investors that the trials would be delayed, so that the formulation could be optimized. “Lavishly funded Moderna hits safety problems,” announced an article published by STAT after Bancel left the drug out of last month’s presentation.A missed milestone, particularly in preclinical studies, hardly signals a catastrophe, says Eric Schmidt, a biotech analyst at Cowen Group in New York City. “I’m just surprised at the drama around the situation,” he says. “Why, just because this company has been successful at raising money, is it being treated differently in the popular press?” That may be the price of Moderna’s unicorn status: The higher the hopes are for a new treatment approach, the more consequential its warts and blunders become.But wealth and secrecy may also be protective. Maybe, as Moore and Hoge concluded from their morning meeting, you don’t have to ride up and down Gartner’s hype curve if you can work through the biggest setbacks before the public ever sees them.Most small biotechs have to publicize every step of their early research in a scramble to raise money, Moore notes. “Then people get to see all the failures. We’ve had failures. We’ve gone down blind alleys. But because we’ve been quiet about it, nobody’s seen that,” she says. “That’s why I think we’re going to end up on the slope of enlightenment without passing the trough of disillusionment.”last_img read more