Podcasts about caribou

Bowhunting Around the Country with Bill Vanderheyden   Show Notes:   Bill Vanderheyden from Iron Will joins me today. He's the owner, founder, and lead engineer for Iron Will Broadheads. Bill's been bow hunting for 50 years, a mechanical engineer for 30, and designing broadheads for 17. Bow hunting is his passion – he goes out and tests his products and is always asking how he can apply science to make the best models. His new single bevel is something I've been using, and it's been great.   Bill's had some good hunts this year and went to Hawaii in June. A friend took him out on the Big Island, to hunt some sheep in the mountains. The terrain was mostly lava rocks and thick trees which made things tough, but he wound up getting a good shot on a ram. He also hunted areas off the coast in some hills where he spotted more rams, goats, and pigs. The older sheep were pretty wise and were onto him, but he shot a big wild hog in that spot.    In mid-August, Bill went Caribou hunting in Alaska, going after northwest Arctic herd. They flew out 160 miles from the nearest village, where the true wilderness is. Last year, him and his crew got their bulls early and were pulled out. This year, he took his time so he could spend the whole ten days. Bill also drew a tag in Wyoming. When he went, conditions weren't great, it was crazy warm. On his seventh day out, he found out where a bunch of elk were and got right in on first light. He wasn't confident and the herd split, but then he worked his way back around them. He waited until the thermals were right and then a bull walked out about 30 yards in front, and he smoked it. Bill used a broadhead and got a double lung hit in the mid-body.    In North Texas, Bill's friend has a ranch, and he spent some time elk hunting there. He also shot an 8-point in Indiana in November with his 4 brothers, sister-in-law, and son. They put down 5 bucks in 4 days! He also hunted in his hometown in Wisconsin and shot a nice heavy buck with good antler mass. Finally, he came back to Colorado for a mule deer tag. It's possible to have great success with bow hunting, but no matter how many times you do it, you never feel like an expert. Sometimes it feels impossible and other times it seems easy. You always get a reality check when you expect to fill all your tags and wind up getting humbled. Make sure to check out Bill's products on his website below. What's Inside: My experience using Bill's new single bevel. Hunting stories from Bill's trips to Hawaii and Alaska. Bill's elk hunt in Wyoming. Bill's trips shooting deer in North Texas, Indiana, and Colorado. How Bill tested some of his products on wild hogs. Mentioned in this episode: Phoenix Shooting Bags save 20% with code johnstallone Days In The Wild JohnStallone.me Iron Will Outfitters   Short Description:. Bill “Iron Will” Vanderheyden is the founder of Iron Will Broadheads. He makes a great single bevel that I've been using. He's got a ton of stories from hunts this year from Alaska to Hawaii and everywhere in between. He's had some solid opportunities to test and develop his products and got some decent shots along the way.   Tags: big game hunting, hunting tips, hunting guide, big buck hunting, hunting stories, elk hunting, archery hunting, broadheads, sheep hunting, single bevel

CRISPR is an exciting space, with a number of companies finally sharing early clinical data in 2021. NTLA benefitted the most from this by doubling in valuation after data release, while the other CRISPR companies continue to trend lower in the XBI bear market. Caribou Biosciences is one of the smaller EV CRISPR companies with their first clinical readout coming up in 2022. In this episode, I go through a short primer on all the CRISPR companies and discuss why I think Caribou will have a great year. 2022 is on track for another exciting year in biotech - despite the early sell off in the XBI. In this episode, I cover the trends to watch including a number of targets in oncology. As well, Curis reported a data update in their two programs: CA-4948 and CI-8993. The stock sold off by 25% but I explain why I plan on continuing to hold the stock. Thank you to InfoPathways for being a sponsor on the show! Check them out for all your biotech IT needs at infopathways.com or call 410-751-9929. Help out the show (or join the discord) by becoming a patron at: https://www.patreon.com/breakingbiotech Follow me on twitter @matthewlepoire Send me an email matthewlepoire@gmail.com www.breakingbiotech.com #breakingbiotech Disclaimer: All opinions expressed by Matt (or his guests) in this podcast are solely his (their) opinions. You should not treat any opinion expressed by Matt in this podcast as a specific inducement to make a particular investment or follow a particular strategy, but only as an expression of his opinion. Matt's opinions are based upon information he considers reliable, but Matt cannot warrant its completeness or accuracy, and it should not be relied upon as such. Matt is not under any obligation to update or correct any information provided in this podcast. Past performance is not indicative of future results. Matt does not guarantee any specific outcome or profit. You should be aware of the real risk of loss in following any strategy or investment discussed in this podcast. #biotech

First show of the year. Pete talks board games, the gansta bins have a special helper & Little Simz releases yet another track. Tracks offa: Janet Jackson, SiR, Arlo Parks, Biig Piig, Church & AP, El Michels Affair, Loyal Carner, Latto, Kairo, Simz, Mouse Outfit, Christopher The Grey, Nas & A$AP, ZHU, Roddy Ricch, Portishead, Joyo Valarde, SAULT, Caribou, Kings, Bonobo, Ta-Ku, Mylo + MORE. ❤️

In the winter, caribou paw the ground to get at their favorite dish. See acast.com/privacy for privacy and opt-out information.

This week is no MINUSCULE episode! To end the year right, we answer listener scenarios to perfection, we're hiring Liam Neeson to rescue a girl from Caribou, and Clark WANTS to be slapped apparently.Follow us on twitter and insta: @TOTIPodhttps://linktr.ee/TOTIPodEmail us: tipoftheiceberg.pod@gmail.comBusiness Inquiries: tipoftheiceberg.pod@gmail.com1-V-1 Inquiries: topoftheiceborg.pog@gmail.com

Omicron in the U.S.; House Doctor Bhardwaj; Language and belonging; B.C. Snowmobile Federation reacts to newly announced caribou closures in the Peace; Prince George RCMP budget questions; Provincial Health Officer Dr. Bonnie Henry on new COVID restrictions; Year-end interview with B.C. Liberal Interim Leader Shirley Bond; B.C. Nurses' Union on burnout and shortages; Using Scrabble to improve English in Prince Rupert.

With no warning, the province announced substantial areas in the Peace are no longer open to snowmobilers. It's part of the government's efforts to save endangered caribou. However, the snowmobile community is frustrated by the way decisions are being made. We talk to Donegal Wilson of the B.C. Snowmobile Federation.

BenGreenfieldFitness.com/comfortcrisis In many ways, we're more comfortable than ever before. But could our sheltered, temperature-controlled, overfed, under-challenged lives actually be the leading cause of many of our most urgent physical and mental health issues? In the book The Comfort Crisis: Embrace Discomfort to Reclaim Your Wild, Healthy, Happy Self, award-winning journalist Michael Easter, my guest on this podcast, seeks out off-the-grid visionaries, disruptive genius researchers, and mind-body conditioning trailblazers who are unlocking the life-enhancing secrets of a counterintuitive solution: discomfort. In this podcast, we take a deep dive into Michael's book, and you'll discover the mind and body benefits of living at the edges of your comfort zone and reconnecting with the wild. Michael is a leading voice on how humans can integrate modern science and evolutionary wisdom for improved health, meaning, and performance in life and at work. During our discussion, you'll discover: -How perspectives change when exposed to raw nature and discomfort... -The ancient Japanese practice to build championship athletes... -A nutrition expert who challenges conventional thinking about food... -How a trip to Bhutan changed Michael's view of death... -Why we've tipped too far into the realm of comfort... -And much more... Episode sponsors: -Kion Flex -JOOVV -Paleo Valley Beef Sticks -Thrive Market Do you have questions, comments or feedback for Michael Easter or me? Leave your thoughts at https://bengreenfieldfitness.com/comfortcrisis

Rauhnächte, Keanu Reeves, Hundemantel, Pulp, Caribou, Bioladen Sprezzatura - der Podcast aus dem schönsten Café des Internets. Über Stilfragen, Popkultur, Gestern und Heute plaudern unsere beiden Lieblings-Podcaster André Georg Haase und Jasmin Klein. Eine Musikliste zum Podcast bringt den Sprezzatura-Lifestyle zum Klingen und wird jede Woche von den Beiden mit Songs angereichert. Alle Filme, die die Beiden in den Moviespecial-Folgen besprochen haben, sind in einer Liste bei Letterboxd zu finden, die wöchentlich erweitert wird. Alle Links findet Ihr hier: https://linktr.ee/sprezzatura_podcast Statt vieler eigener Worte hier Feedback aus dem Internet: "Jasmin Klein spricht mit André Georg Haase. Beides belesene Paradiesvögel im besten Alter, aber keinen von beiden kennt man jetzt aus großen Produktionen. Daher umso wichtiger, dass Ihr hier über diesen Podcast stolpert. Er ist nämlich, wie man sich Laberpodcasts wünscht und so selten bekommt: sprudelnd, konzentriert, üppig. Klein und Haase wissen zu Allem was: ob Spülmittel, Ritter Sport, getragenen Höschen oder Kaffeeautomaten. „Sprezzatura“ betrachte ich als echten Lieblingsort!" - Linus Volkmann, Musikexpress "Ein Podcast wie ein Aperitif in einem Pariser Straßencafé." - Matthias En "Die extrem sympathischen und angenehm klingenden André Georg Haase und Jasmin Klein sprechen über die schönen, sprich: die wichtigen Dinge des Lebens. Ob es sich um Konzertbesuche, Urlaubsberichte oder das perfekte Getränk handelt. im Grunde geht es immer um eins: Lebensart. Der Limoncello der Podcasts." - Felix Neugebauer "Kenne diese unaufgeregte und trotzdem nicht langweilige Art sonst aus keinem anderen Podcast. Außerdem gelingt es Euch, tatsächlich positive Vibes auszustrahlen, ohne cheesy zu sein. Fühle mich nach dem Hören gut gelaunt und nehme immer noch etwas mit." - okapitapir "Allwöchentliche Plaudereien zweier eloquenter und kulturell bewanderter Personen über kleine Alltäglichkeiten und Beobachtungen." - Hichs "Geeignet zur Untermalung aller möglichen Tätigkeiten und vor allem für positive Vibes. Die Playlist zum Podcast ist außerdem eine super Ergänzung für meine Spotify-Heavy-Rotation. Danke, und weiter so!" - Eintiefesrot

Caribou or reindeer?  Reindeer or caribou?  These animals are amazing critters that are adapted to the most unforgiving, inhospitable, and frigid environments.  Marvin and Gabrielle talk about these adaptations, unique and fascinating facts, as well as the relationship between reindeer and Santa, of course!Reindeer and Caribou Websites to Visit:https://blog.nwf.org/2010/12/reindeer-twelve-fascinating-facts-about-these-amazing-creatures/https://www.fda.gov/animal-veterinary/animal-health-literacy/fun-facts-about-reindeer-and-caribouhttps://www.treehugger.com/things-you-didnt-know-about-reindeer-4864068Santa, Reindeer, and Rudolph:https://a-z-animals.com/blog/christmas-reindeer-whats-the-story-behind-santa-and-reindeer/https://www.si.edu/newsdesk/snapshot/rudolph-red-nosed-reindeerYou can follow us on Facebook at Nature Nook PhotographyEmail us at www.walkingonthewildside21@gmail.comYou can also listen to us on our new Facebook Podcast Page - Walkin' on the Wild SideOr listen directly from our website at https://walkinonthewildside.buzzsprout.com*Gabrielle, our co-host, is actively fundraising for Make-A-Wish and finished her 3rd 28.3 mile hike.  Please help her meet her fundraising goal:- Gabrielle Bouknight Trailblaze Challenge - Donate Now!- Make-A-Wish HomepageAs always, we hope you enjoy listening to our podcast and welcome your emails, comments, and feedback.   Subscribe to our podcasts and leave us a review on Apple Podcasts, Google Podcasts, Audible, Spotify, iHeart Radio, TuneIn, Stitcher, and more!  So get out there and start "Walkin' on the Wild Side"!

We meet some preschoolers at the Wildflowers Child Care Centre in Gander who showed their kindness by giving up their play time to collect for the food bank. Ever wonder about what people were tuning into before CBC started broadcasting in Upper Lake Melville? We speak with Chris Charland about the history of VOUG: Voice of the Wilderness. Have legal questions and not sure where to turn? There's a free legal clinic tonight with one-on-one consultations with a lawyer. Shirley White of the Public Legal Information Association of Newfoundland and Labrador joins us. Diem Saunders is being honoured posthumously as one of the 2021 Human Rights Award recipients of Newfoundland and Labrador. We hear some archival tape from 2017 after they were named one of Amnesty International's Ambassadors of Conscience. A team from Memorial University hopes to improve the research culture of academics working in indigenous communities. We hear from Violet Ford, MUN's VP for Indigenous Research, and VP of Research Neil Bose. It's Day 4 of our 12 Days of Christmas giveaway. Today we hear about the book Caribou and You by Sara McCarthy and Jessica Dahn. Finally, Heather Scoffield of the Toronto Star joins us to break down the political action in Ottawa as the House of Commons winds up it's last week before the holiday break.

Alaska, not for the faint of heart.

Today, in the Hot Notes: John Eastman is the latest seditionist to indicate he will be pleading the fifth in front of the 1/6 Committee; legal experts claim that Meadows has waived any claim to executive privilege over subjects he wrote about in his book; metadata in Clark's draft letter to Georgia asking them to overturn the election indicates some White House involvement in drafting it; two Georgia election workers are suing gateway pundit for defamation; plus Allison and Dana deliver your Good News. Our Guest: Glenn Kirschner https://twitter.com/glennkirschner2 https://www.youtube.com/glennkirschner2 Follow AG and Dana on Twitter: Dr. Allison Gill  https://twitter.com/allisongill https://twitter.com/MuellerSheWrote https://twitter.com/dailybeanspod Dana Goldberg https://twitter.com/DGComedy Follow Aimee on Instagram: Aimee Carrero (@aimeecarrero) Listener Survey: http://survey.podtrac.com/start-survey.aspx?pubid=BffJOlI7qQcF&ver=short Have some good news, a confession, a correction, or a case for Beans Court? https://www.dailybeanspod.com/confessional/ Want to support the show and get it ad-free and early? https://dailybeans.supercast.tech/ Or https://patreon.com/thedailybeans Ca adoption: https://www.facebook.com/photo?fbid=265226552312449&set=a.225487579619680 Promo Codes Best Fiends! Download Best Fiends FREE today on the App Store or Google Play. Turn your least active times into your most productive opportunities to stay healthy with Cubii! Visit https://Cubii.com/BEANS to find the Cubii elliptical model that's right for you! ChiliSleep makes customizable, hydro-powered, temperature-controlled mattress toppers that fit over your existing mattress to provide your ideal sleep temperature.  Head over to chilisleep.com/BEANS  to check out a special offer, available exclusively for The Daily Beans listeners. Helix is offering up to 200 dollars off all mattress orders AND two free pillows for our listeners at HelixSleep.com/dailybeans Get a smarter design guide with fresh takes, creative ideas & smart solutions for dressing your windows. Go to HunterDouglas.com/DAILYBEANS for your free design guide. Your weight doesn't reflect your willpower. Get back in control with Calibrate. Get $50 off the one-year metabolic reset when you use promo code DAILYBEANS at JoinCalibrate.com Learn more about your ad choices. Visit megaphone.fm/adchoices

The web of life is sometimes freezing. Take, for instance, what's happening in the Alaska Arctic. In one of the largest remaining wilderness ecosystems on the planet, the frigid place is home to the Western Arctic Caribou Herd, and is also a hotspot to study the effects of climate change. What becomes of the caribou if climate change continues unabated? Further, what becomes of those that live, and depend, on the caribou, like the indigenous Iñupiat people, if the caribou disappear? The interconnectedness of us all is hanging by a thread. Seth Kantner was born and raised in northern Alaska and has worked as a trapper, wilderness guide, wildlife photographer, gardening teacher, and adjunct professor. His writing has appeared in The New York Times, Outside, Orion, and Smithsonian. Kantner is the author of the award-winning novel Ordinary Wolves, memoir Shopping for Porcupine, and collection of essays Swallowed by the Great Land: And Other Dispatches from Alaska's Frontier. He has been a commercial fisherman in Kotzebue Sound for more than four decades and lives in the Northwest Arctic. Bellamy Pailthorp covers the environment beat from the Seattle offices of KNKX Public Radio News, where she has worked since 1999. She also has a deep interest in indigenous affairs and the Salish Sea. Buy the Book: A Thousand Trails Home: Living with Caribou [Hardcover] from Mountaineers Books Presented by Town Hall Seattle. To become a member or make a donation click here. 

SHOW NOTES Intro: For all you hunters sniffing around the 6.8 Western, here's an in-depth look at the cartridge with A Man Who Knows: Browning's own Rafe Nielson.  6.8 Western cartridge discussion: Genesis of the 6.8 Western Significant differences from the .270 WSM Short shots & long shots with the 6.8 Western Hunt stories: Caribou, whitetails, and Roosevelt elk  Cartridge comparisons: 6.8 Western vs. 7mm Rem. Mag., 6.5 PRC, and .280 Ackley Improved High-performance 6.8 Western loads in detail:  175-grain Long Range Pro bullet 165-grain AccuBond Long Range bullet 162-grain Copper Impact bullet Rifles chambered in 6.8 Western Browning's standard-line X-Bolt versions Browning's Pro series X-Bolts Browning's base model X-Bolts Winchester's Model 70  Winchester's XPR Here to stay: Current sales and future promise of the 6.8 Western Wrap: Is the 6.8 Western a candidate for an ultimate Western rifle for the one-gun hunter?    FRIENDS, PLEASE SUPPORT THE PODCAST!  Join the Backcountry Hunting Podcast tribe and access all our patron-only bonus episodes, gear tips, and gear reviews on www.patreon.com/backcountry Contribute via PayPal using joseph@backcountrypodcast.com Contribute via VENMO: @Joseph-vonBenedikt VISIT OUR SPONSORS HERE:  www.browning.com www.silencercentral.com www.timneytriggers.com www.siembidacustomknives.com

Keep Crisis in Christmas. The New Klux Klan. Dogs having a great time until not. Scaffold harvesting with Charlie Sheen. The stories behind Rudolph the Red Nosed Reindeer, Clive the Club-footed Caribou and Benny the Rump-Stabbing Elf. Jack tries to land audiobooks: Getting to Mars, A History of Microsoft, Truman: A History. Sponsor: www.manscaped.com Use checkout code QM to get 20% off your order, and free shipping.

Artemis is doing a deep-dive into climate science. In our opening episode we talk with Maddison Easley, a California biologist who straddles the divide between the conservation world and agency life. Much of Maddison's work is aimed at rangeland conservation. We talk about how birds, vegetation and soils are all indicators of ecosystem health - and what's changing with grasslands as the climate changes. 4:00 Point Blue Conservation Science 5:00 Growing up a rancher, becoming a biologist, returning to the ranch 7:00 Alaska caribou hunt & helping a nephew harvest his first turkey for Thanksgiving dinner 10:00 Caribou... the move FAST + a first-timer's take on a new species 14:00 #gohunterhippies 15:00 Rangeland Monitoring Network -  "The primary goal is to preserve the ecological value of rangelands"  17:00 Birds, soil, vegetation... all indicators of ecosystem health 20:00 Soil carbon monitoring 22:00 About half of California is rangeland, and about half of those lands are privately owned 23:00 Grazing management tactics to put more carbon in the soil 25:00 Carbon sequestration 101 29:00 Not all soils are created equal for sequestration + ecological site descriptions 31:00 Drought affects carbon sequestration in soil 35:00 Co-operating with private landowners 36:00 EQIP program - Environmental Quality Incentive Program; California Department of Ag Healthy Soils program 41:00 Birds as an indicator species 43:00 White-breasted nuthatch 44:00 Changes in the last decade; wetland and grassland birds in decline 50:00 Tips to minimize the spread of invasive species... "Humans are the primary vector of invasive species" 56:00 Eradication isn't a reality for many invasive species... "but we can reduce the frequency and abundance in places, and increase diversity" 57:00 North American Grasslands Act - modeled after the North American Wetlands Conservation Act to conserve grasslands  1:02 Citizen science through apps like iNaturalist and eBird contributes to the massive data sets increasingly useful to scientists  1:08 Join the Artemis community -- we have a Facebook group, a killer book club, and programs/events for female hunters. If Artemis has meant something to you, please consider sharing it with a friend or making a donation.   1:09 The Hunter and Angler's Guide to Climate Change

Just Mustard - "I Am You," a 2021 single on Partisan. Irish quintet Just Mustard caught our ears with their powerful noise rock debut Wednesday, an album that earned them a Choice Music Prize nomination for Album of the Year in 2018. Since then, they've signed to Partisan Records and have shared a first look at a sophomore release (projected released: 2022) with today's Song of the Day. The moody, shoegaze-tinged track was produced by the band and mixed by David Wrench (FKA twigs, The xx, Caribou). The accompanying video, directed by Dylan Friese-Greene, captures the song's eerie vibe, with vocals from Katie Ball reminiscent of Alison Shaw of Cranes.  Read the full post on KEXP.org Support the show: https://www.kexp.org/donate See omnystudio.com/listener for privacy information.

Walking mile upon mile upon mile with herds of iconic Woodland Caribou, a story about Moose silhouettes, a stunning cross fox, and the ongoing challenges of the ever-changing weather along the northern Atlantic, highlights Mark's recap of this true wilderness therapy voyage!

On the 213th episode of Audioface:REVIEWS: "Juno" by remi wolf, "Valentine" by Snail Mail, and "Sympathy For Life" by Parquet CourtsDan dishes details on Syndicate 23: the exciting all-in-one membership platform for Audioface content and more. Dan and Sean react to Grammys 2022 Nominations category-by-category. The Juno review. Did Kanye just pop back into reality for a moment? BTS continues to make history for the influence of Asian musicians in America, and Four Tet battles his former record label Domino after his albums disappear from streaming services.  The Valentine review.  A rapper is charged with being behind a horrific parade car attack, and a Queen member is upset about a BRIT awards change. The Sympathy For Life review. Jonny Greenwood and Paul Thomas Anderson collaborate yet again, and someone made a toilet that looks like Metallica's guitarist. ---GET MORE AUDIOFACE WITH SYNDICATE 23 MEMBERSHIPMore info at join.syndicate23.coSUPPORT AUDIOFACE!Subscribe to this podcast (or Follow on Spotify) so you don't miss new episodes every week. Tell some friends about this show to keep it growing! We appreciate it, and you.Keep up with Audioface's 2021 Playlist:https://open.spotify.com/playlist/5Gm0rc9gByK4idEhZw6oRu?si=a28c212ddf014641Reach out to us: https://twitter.com/audiofacepod/https://intsagram.com/audiofacepod/https://www.youtube.com/audiofacepod?sub_confirmation=1For advertising opportunities, email info (at) syndicate23 (dot) co

Interview with Matt Black, co-founder of Ninja Tune and one half of Coldcut. We explore his relationship with ambient music via some song selections that have signposted his life and also play music from and speak about the @0 ambient compilation he put together in aid of the charities Calm, Mind and Black Minds Matter. We discuss and play music from Ryuichi Sakamoto, Irresistible Force, Specimens, Coldcut, Steve Reich, Steve Roach and many more and get into the mind of this fascinating artist. This show originally aired as a Moving Sounds interview on Soho Radio.

In this episode, Aaron takes control of the hosting chair while Steve nurses a wicked hangover. We've also got French comic book creator David Foissard in the rotating chair to talk about saucy daddies, superheroes, and how he's single-handedly responsible for Aaron getting back into comics.Books: Elvira Meets Vincent Price #3, Wasp: Darkhold #1, Nubia & and the Amazons #2, Wonder Woman: Evolution #1, Fantastic Four Anniversary Tribute, Static Season One #4, Icon and Rocket #4, Excalibur #25, Hellions #17, X-Force #25, Marauders #25, S.W.O.R.D. #10, Superman: Son of Kal-El #5, Batman Secret Files: The Gardener #1, Batman #117, Nightwing #86, The Nice House on the Lake #1-6, Savage Dragon #260, Defenders #1-3, Shazam #4, Showcase Presents: The Elongated Man Vol. 1Other Stuff: Last Night in Soho (movie), Caribou, Kara Lis Coverdale (live performance)The Comic Book Podcast is brought to you by Talking Comics (www.talkingcomicbooks.com) The podcast is hosted by Steve Seigh, Bob Reyer, Joey Braccino, Aaron Amos, and John Burkle, who weekly dissect everything comics-related, from breaking news to new releases. Our Twitter handle is @TalkingComics

About MatthewMatthew Prince is co-founder and CEO of Cloudflare. Cloudflare's mission is to help build a better Internet. Today the company runs one of the world's largest networks, which spans more than 200 cities in over 100 countries. Matthew is a World Economic Forum Technology Pioneer, a member of the Council on Foreign Relations, winner of the 2011 Tech Fellow Award, and serves on the Board of Advisors for the Center for Information Technology and Privacy Law. Matthew holds an MBA from Harvard Business School where he was a George F. Baker Scholar and awarded the Dubilier Prize for Entrepreneurship. He is a member of the Illinois Bar, and earned his J.D. from the University of Chicago and B.A. in English Literature and Computer Science from Trinity College. He's also the co-creator of Project Honey Pot, the largest community of webmasters tracking online fraud and abuse.Links: Cloudflare: https://www.cloudflare.com Blog post: https://blog.cloudflare.com/aws-egregious-egress/ Bandwidth Alliance: https://www.cloudflare.com/bandwidth-alliance/ Announcement of R2: https://blog.cloudflare.com/introducing-r2-object-storage/ Blog.cloudflare.com: https://blog.cloudflare.com Duckbillgroup.com: https://duckbillgroup.com TranscriptAnnouncer: Hello, and welcome to Screaming in the Cloud with your host, Chief Cloud Economist at The Duckbill Group, Corey Quinn. This weekly show features conversations with people doing interesting work in the world of cloud, thoughtful commentary on the state of the technical world, and ridiculous titles for which Corey refuses to apologize. This is Screaming in the Cloud.Corey: Writing ad copy to fit into a 30 second slot is hard, but if anyone can do it the folks at Quali can. Just like their Torque infrastructure automation platform can deliver complex application environments anytime, anywhere, in just seconds instead of hours, days or weeks. Visit Qtorque.io today and learn how you can spin up application environments in about the same amount of time it took you to listen to this ad.Corey: This episode is sponsored in part by Honeycomb. When production is running slow, it's hard to know where problems originate: is it your application code, users, or the underlying systems? I've got five bucks on DNS, personally. Why scroll through endless dashboards, while dealing with alert floods, going from tool to tool to tool that you employ, guessing at which puzzle pieces matter? Context switching and tool sprawl are slowly killing both your team and your business. You should care more about one of those than the other, which one is up to you. Drop the separate pillars and enter a world of getting one unified understanding of the one thing driving your business: production. With Honeycomb, you guess less and know more. Try it for free at Honeycomb.io/screaminginthecloud. Observability, it's more than just hipster monitoring.Corey: Welcome to Screaming in the Cloud, I'm Corey Quinn. Today, my guest is someone I feel a certain kinship with, if for no other reason than I spend the bulk of my time antagonizing AWS incredibly publicly. And my guest periodically descends into the gutter with me to do the same sort of things. The difference is that I'm a loudmouth with a Twitter account and Matthew Prince is the co-founder and CEO of Cloudflare, which is, of course, publicly traded. Matthew, thank you for deigning to speak with me today. I really appreciate it.Matthew: Corey, it's my pleasure, and appreciate you having me on.Corey: So, I'm mostly being facetious here, but not entirely, in that you have very publicly and repeatedly called out some of the same things I love calling out, which is AWS's frankly egregious egress pricing. In fact, that was a title of a blog post that you folks put out, and it was so well done I'm ashamed I didn't come up with it myself years ago. But it's something that is resonating with a large number of people in very specific circumstances as far as what their company does. Talk to me a little bit about that. Cloudflare is a CDN company and increasingly looking like something beyond that. Where do you stand on this? What got you on this path?Matthew: I was actually searching through really old emails to find something the other day, and I found a message from all the way back in 2009, so actually even before Michelle and I had come up with a name for Cloudflare. We were really just trying to understand the pricing on public clouds and breaking it all down. How much does the compute cost? How much does storage cost? How much does bandwidth cost?And we kept running the numbers over and over and over again, and the storage and compute costs actually seemed relatively reasonable and you could understand it, but the economics behind the bandwidth just made no sense. It was clear that as bandwidth usage grew and you got scale that your costs eventually effectively went to zero. And I think it was that insight that led to us starting Cloudflare. And the self-service plans at Cloudflare have always been unlimited bandwidth, and from the beginning, we didn't charge for bandwidth. People told us at the time we were crazy to not do that, but I think that that realization, that over time and at scale, bandwidth costs do go to zero is really core to who Cloudflare is.Cloudflare launched a little over 11 years ago now, and as we've watched the various public clouds and AWS in particular just really over that same 11 years not only not follow the natural price of bandwidth down, but really hold their costs steady. At some point, we've got a lot of mutual customers and it's a complaint that we hear from our mutual customers all the time, and we decided that we should do something about it. And so that started four years ago, when we launched the Bandwidth Alliance, and worked with almost all the major public clouds with the exception of Amazon, to say that if someone is sending traffic from a public cloud network to Cloudflare's network, we're not going to charge them for the bandwidth. It's going across a piece of fiber optic cable that yeah, there's some cost to put it in place and maybe there's some maintenance costs associated with it, but there's not—Corey: And the equipment at the end costs money, but it's not cloud cost; it just cost on a per second, every hour of your lifetime basis. It's a capital expense that is amortized across a number of years et cetera, et cetera.Matthew: And it's a fixed cost. It's not a variable cost. You put that fiber optic cable and you use a port on a router on each side. There's cost associated with that, but it's relatively de minimis. And so we said, “If it's not costing us anything and it's not costing a cloud provider anything, why are we charging customers for that?”And I think it's an argument that resonated with almost every other provider that was out there. And so Google discounts traffic when it's sent to us, Microsoft discounts traffic when it's sent to us, and we just announced that Oracle has joined this discounting their traffic, which was already some of the most cost-effective bandwidth from any cloud provider.Corey: Oh, yeah. Oracle's fantastic. As you were announced, I believe today, the fact that they're joining the Bandwidth Alliance is both fascinating and also, on some level, “Okay. It doesn't matter as much because their retail starting cost is 10% of Amazon's.” You have to start pushing an awful lot of traffic relative to what you would do AWS before it starts to show up. It's great to see.Matthew: And the fact that they're taking that down to effectively zero if you're using us is even better, right? And I think it again just illustrates how Amazon's really alone in this at being so egregious in how they do that. And it's, when we've done the math to calculate what their markups are, it's almost 80 times what reasonable assumptions on what their wholesale costs are. And so we really do believe in fighting for our customers and being customer-centric, and this seems like a place where—again, Amazon provides an incredible service and so many things, but the data transfer costs are just completely outrageous. And I'm glad that you're calling them out on it, and I'm glad we're calling them out on it and I think increasingly they look isolated and very anti-customer.Corey: What's interesting to me is that ingress to AWS at all the large public tier-one cloud providers is free. Which has led, I think, to the assumption—real or not—that bandwidth doesn't actually cost anything, whereas going outbound, all I can assume is that one day, some Amazon VP was watching a rerun of Meet the Parents and they got to the line where Ben Stiller says, “Oh, you can milk anything with nipples,” and said, “Holy crap. Our customers all have nipples; we can milk them with egress charges.” And here we are. As much as I think the cloud empowers some amazing stuff, the egress charges are very much an Achilles heel to a point where it starts to look like people won't even consider public cloud for certain workloads based upon that.People talk about how Netflix is a great representation of the ideal AWS customers. Yeah, but they don't stream a single byte to customers from AWS. They have their own CDN called Open Connect that they put all around the internet, specifically for that use case because it would bankrupt them otherwise.Matthew: If you're a small customer, bandwidth does cost something because you have to pay someone to do the work of interconnecting with all of the various networks that are out there. If you start to be, though, a large customer—like a Cloudflare, like an AWS, like an Azure—that is sending serious traffic to the internet, then it starts to actually be in the interest of ISPs to directly interconnect with you, and the costs of your bandwidth over time will approach zero. And that's the just economic reality of how bandwidth pricing works. I think that the confusion, to some extent, comes from all of us having bought our own home internet connection. And I think that the fact that you get more bandwidth up in most internet connections, and you get down, people think that there's some physics, which is associated with that.And there are; that turns out just to be the legacy of the cable system that was really designed to send pictures down to your—Corey: It wasn't really a listening post. Yeah.Matthew: Right. And so they have dedicated less capacity for up and again, in-home network connections, that makes a ton of sense, but that's not how internet connections work globally. In fact, you pay—you get a symmetric connection. And so if they can demonstrate that it's free to take the traffic in, we can't figure out any reason that's not simply about customer lock-in; why you would charge to take data out, but you wouldn't charge to put it in. Because actually cost more from writing data to a disk, it costs more than reading it from a disk.And so by all reasonable accounts, if they were actually charging based on what their costs were, they would charge for ingress but they want to charge for egress. But the approach that we've taken is to say, “For standard bandwidth, we just aren't going to charge for it.” And we do charge for if you use our premium routing services, which is something called Argo, but even then it's relatively cheap compared with what is just standard kind of internet connectivity that's out there. And as we see more of the clouds like Microsoft and Google and Oracle show that this is a place where they can be much more customer-centric and customer-friendly, over time I'm hopeful that will put pressure on Amazon and they will eliminate their egress fees.Corey: People also tend to assume that when I talk about this, that I'm somehow complaining about the level of discounting or whatnot, and they yell at me and say, “Oh, well, you should know by now, Corey, that no one at significant scale pays retail pricing.” “Thanks, professor. I appreciate that, but four years ago, or so I sat down with a startup founder who was sketching out the idea for a live video streaming service and said, ‘There's something wrong with my math because if I built this on AWS—which he knew very well, incidentally—it looks like it would cost me at our scale of where we're hoping to hit $65,000 a minute.'” And I checked and yep, sure enough, his math was not wrong, so he obviously did not build his proof of concept on top of AWS. And the last time I checked, they had raised several 100 million dollars in a bunch of different funding rounds.That is a company now that will not be on AWS because it was never an option. I want to talk as well about your announcement of R2, which is just spectacular. It is—please correct me if I get any of this wrong—it's an object store that lives in your existing distributed-points-of-presence-slash-data-centers-slash-colo-slash-a-bunch-of-computers-in-fancy-warehouse-rooms-with-the-lights-are-always-on-And-it's-always-cold-and-noisy. And people can store data there—Matthew: [crosstalk 00:10:23] aisles it's cold; in the other aisles, it's hot. But yes.Corey: Exactly. But it turns out when you lurk around to the hot aisle, that's not where all the buttons are and the things you're able to plug into, so it's freeze or sweat, and there's never a good answer. But it's an object store that costs a fair bit less than retail pricing for Amazon S3, or most other object stores out there. Which, okay, great. That's always good to see competition in the storage space, but specifically, you're not charging any data transfer costs whatsoever for doing this. First, where did this come from?Matthew: So, we needed it ourselves. I think all of the great products at Cloudflare start with an internal need. If you look at why do we build our zero-trust solutions? It's because we said we needed a security solution that was fast and reliable and secure to protect our employees as they were going out and using the internet.Why did we build Cloudflare Workers? Because we needed a very flexible compute platform where we could build systems ourselves. And that's not unique to us. I mean, why did Amazon build AWS? They built it because they needed those tools in order to continue to grow and expand as quickly as possible.And in fact, I think if you look at the products that Google makes that are really great, it ends up being the ones that Google's employees use themselves. Gmail started as Caribou once upon a time, which was their internal email system. And so we needed an object store and the sometimes belligerent CEO of Cloudflare insisted that our team couldn't use any of the public cloud object stores. And so we had to build it.That was the start of it and we've been using it internally for products over time. It powers, for example, Cloudflare Images, it powers a lot of our streaming video services, and it works great. And at some point, we said, “Can we take this and make it available to everyone?” The question that you've asked on Twitter, and I think a lot of people reasonably ask us, “What's the catch?”Corey: Well, in my defense, I think it's fair. There was an example that I gave of, “Okay, I'm going to go ahead and keep—because it's new, I don't trust new object stores. Great. I'm going to do the same experiment twice, keep one the pure AWS story and the other, I'm just going to add Cloudflare R2 to the mix so that I have to transfer out of AWS once.” For a one gigabyte file that gets shared out for a petabyte's worth of bandwidth, on AWS it costs roughly $52,000 to do that. If I go with the R2 solution, it cost me 13 cents, all of which except for a penny-and-a-half are AWS charges. And that just feels—when you're looking at that big of a gap, it's easy to look at that and think, “Okay, someone is trying to swindle me somewhere. And when you can't spot the sucker, it's probably me. What's the catch?”Matthew: I guess it's not really a catch; it's an explanation. We have been able to drive our bandwidth costs down low enough that in that particular use case, we have to store the file, and that, again, that—there's a hard disk in there and we replicate it to make sure that it's available so it's not just one hard disk, but it's multiple hard disks in various places, but that amortized over time, isn't that big a cost. And then bandwidth is effectively zero. And so if we can do that, then that's great.Maybe a different way of framing the question is like, “Why would we do that?” And I think what we see is that there is an opportunity for customers to be able to use the best of various cloud providers and hook the different parts together. So, people talk about multi-cloud all the time, and for a while, the way that I think people thought about that was you take the exact same workload and you run it in Azure and AWS. That turns out not to be—I mean, maybe some people do that, but it's super rare and it's incredibly hard.Corey: It has been a recurring theme of most things I say where, by default, that is one of the dumbest things I can imagine.Matthew: Yeah, that isn't good. But what people do want to do is they want to say, “Listen, there's some really great services that Amazon provides; we want to use those. And there's some really great services that Azure provides, and we want to use those. And Google's got some great machine learning, and so does IBM. And I want to sort of mix and match the various pieces together.”And the challenge in doing that is the egress fees. If everyone just had a detente and said there's going to be no egress fees for us to be able to hook these various [pits 00:14:48] together, then you would be able to take advantage of a lot of the different technologies and we would actually get stronger applications. And so the vision of what we're trying to build is how can we be the fabric that can stitch the various cloud providers together so that you can do that. And when we looked at that, and we said, “Okay, what's the path to getting there?” The big place where there's the just meatiest cost on egress fees is object stores.And so if you could have a centralized object store, and you can say then from that object go use whatever the best service is at Amazon, go use whatever the best service is at Google, go use whatever the best service is at Azure, that then allows, I think, actually people to take advantage of the cloud in a way which is what people really should mean when they talk about multi-cloud. Which is, there should be competition on the various features themselves, and you should be able to pick and choose the best of all of the different bits. And I think we as consumers then benefit from that. And so when we're looking at how we can strategically enable that future, building an object store was a real key part of that, and that's part of what we're doing. Now, how do we make money off of that? Well, there's a little bit off the storage, and again, even [laugh]—Corey: Well, that is the Amazonian answer there. It's like, “Your margin is my opportunity,” is a famous Bezos quote, and I figure you're sitting there saying, “Ah, it would cost $52,000 to do that in Amazon. Ah, we can make a penny-and-a-half.” That's very Amazonian, you could probably get hired over there with that philosophy.Matthew: Yeah. And this is a commodity service, just [laugh] storing data. If you look across the history of what Cloudflare has done, in 2014, we made encryption free because it's absurd to pay for math, right? I mean, it's just crazy right?Corey: Or to pay for security as a value-add. No, that should be baked into whatever you're doing, in an ideal world.Matthew: Domain registration. Like, it's writing something down in a ledger. It's a commodity; of course it should go to whatever the absolute cost is. On the other hand, there are things that we do that aren't commodities where we are able to better protect people because we see so much traffic, and we've built the machine learning models, and we've done those things, and so we charge for those things. So commodities, we think over time, go to effectively, whatever their cost is, and then the value is in the actual intelligent services that are on top of it.But an object store is a commodity and so we should be trying to drive that pricing down. And in the case of bandwidth, it's effectively free for us. And so if we can be that fabric that connects the different class together, I think that makes sense is a strategy for us and that's why R2 made a ton of sense for us to build and to launch.Corey: There seems to be a lack of ability for lots of folks, at least on the internet to imagine a use case other than theirs. I cheated by being a consultant, I get to borrow other people's use cases at a high degree of turnover. But the question I saw raised was, “Well, how many workloads really do that much egress from static objects that don't change? Doesn't sound like there'd be a whole lot of them.” And it's, “Oh, my sweet summer child. Sure, your app doesn't do a lot of that, but let me introduce it to my friends who are hosting videos on their website, for example, or large images that get accessed a whole bunch of times; things that are written once and then read forever by the internet.”Matthew: And we sit in a position where because of the role that Cloudflare plays where we sit in front of a number of these different cloud providers, we could actually look at the use cases and the data, and then build products in order to solve that. And that's why we started with Workers; that's why we then built the KV store that was on top of that; we built object-store next. And so you can see as we're sort of marching through these things, it is very much being informed by the data that we actually see from real customers. And one of the things that I really like about R2 is in exactly the example that you gave where you can keep everything in S3; you can set R2 in front of it and put it in slurp mode, and effectively it just—as those objects get pulled out, it starts storing them there. And so the migration path is super easy; you don't have to actually change anything about your application and will cut your bills substantially.And so I think that's the right thing to enable a multi-cloud world where, again, it's not you're running the exact same workload in different places, but you get to take advantage of the really great tack that all of these companies are building and use that. And then the companies will compete on building that tech well. So, it's not just about how do I get the data in and then kind of underinvest in all of the different services that I provide. It's how can we make sure that on a service-by-service basis, you actually are having real competition over time. And again, I think that's the right thing for customers, and absolutely R2 might not be the right thing for every use case that's out there, but I think that it wi—enabling more competition is going to make the cloud better for everyone.Corey: Oh, yeah. It's always fun hearing it from Amazonians. It's, “You have a service that talks to satellites in orbit. You really think that's a general-purpose thing that every company out there has to deal with?” No. Well, not yet, anyway.It also just feels to me like their transfer approach is antithetical to almost every other aspect of how they have built their cloud. Amazonians have told me repeatedly—I believe them—that their network is effectively magic. The fact that you can get near line rate between any two points without melting various [unintelligible 00:20:14], which shows that there was significant thought, work, effort, planning, technology, et cetera, put into the network. And I don't dispute that. But if I'm trying to build a workload and put it inside of AWS, I can control how it performs tied to budget; I can have a lot of RAM for things that are memory intensive, or I can have a little RAM; I can have great CPU performance or terrible CPU performance.The challenge with data transfer is it is uniformly great. “I want to get that data over there super quickly.” Yeah, awesome. I'm fine paying a premium for that. But I have this pile of data right here. I want to get it over there, ideally by Tuesday. There's no good way to do that, even with their Snowball—or Snow Family devices—when you fill them with data and send them into AWS, yeah, that's great. Then you just pay for the use of the device.Use them to send data out of AWS, they tack on an additional per-gigabyte fee for getting the data out. You're training as a lawyer, you went to the same law school that my wife did, the University of Chicago, which, oh, interesting stories down that path. But if we look at this, my argument is that the way to do an end-run around this is to sue Amazon for something, and then demand access to the data you have living in their environment during discovery. Make them give it to you for free, though, they'd probably find a way to charge it there, too. It's just a complete lack of vision and lack of awareness because it feels like they're milking a cash cow until it dies.Matthew: Yeah, they probably would charge for it and you'd also have to pay a lot of lawyers. So, I'm not sure that's the cost [crosstalk 00:21:44]—Corey: Its only works above certain volumes, I figure.Matthew: I do think that if your pricing strategy is designed to lock people in to prevent competition, then that does create other challenges. And there are certainly some University of Chicago law professors out there that have spent their careers arguing why antitrust laws don't make any sense, but I think that this is definitely one of those areas where you can see very clearly that customers are actually being harmed by the pricing strategy that's there. And the pricing strategy is not tied in any way to the underlying costs which are associated with that. And so I do think that, especially as you see other providers in the space—like Oracle—taking their bandwidth costs to effectively zero, that's the sort of thing that I think will have regulators start to scratch their heads. If tomorrow, AWS took egress costs to zero, and as a result, R2 was not as advantaged as it is today against them, you know, I think there are a lot of people who would say, “Oh, they showed Cloudflare.” I would do a happy dance because that's the best thing [thing they can do 00:22:52] for our customers.Corey: Our long-term goals, it sounds like, are relatively aligned. People think that I want to see AWS reign ascendant; people also say I want to see them burning and crashing into the sea, and neither one of those are true. What I want is, I want someone in a few years from now to be doing a startup and trying to figure out which cloud provider they should pick, and I want that to be a hard decision. Ideally, if you wind up reducing data transfer fees enough, it doesn't even have to be only one. There are stories that starts to turn into an actual realistic multi-cloud story that isn't, at its face, ridiculous. But right now, you have to pick a horse and ride it, for a variety of reasons. And I don't like that.Matthew: It's entirely egress-based. And again, I think that customers are better off if they are able to pick who is the best service at any time. And that is what encourages innovation. And over time, that's even what's good for the various cloud providers because it's what keeps them being valuable and keeps their customers thinking that they're building something which is magical and that they aren't trapped in the decision that they made, which is when we talk to a lot of the customers today, they feel that way. And it's I think part of why something like R2 and something like the Bandwidth Alliance has gotten so much attention because it really touches a nerve on what's frustrating customers today. And if tomorrow Amazon announced that they were eliminating egress fees and going head-to-head with R2, again, I think that's a wonderful outcome. And one that I think is unlikely, but I would celebrate it if it happened.Corey: This episode is sponsored by our friends at Oracle Cloud. Counting the pennies, but still dreaming of deploying apps instead of "Hello, World" demos? Allow me to introduce you to Oracle's Always Free tier. It provides over 20 free services and infrastructure, networking databases, observability, management, and security.And - let me be clear here - it's actually free. There's no surprise billing until you intentionally and proactively upgrade your account. This means you can provision a virtual machine instance or spin up an autonomous database that manages itself all while gaining the networking load, balancing and storage resources that somehow never quite make it into most free tiers needed to support the application that you want to build.With Always Free you can do things like run small scale applications, or do proof of concept testing without spending a dime. You know that I always like to put asterisks next to the word free. This is actually free. No asterisk. Start now. Visit https://snark.cloud/oci-free that's https://snark.cloud/oci-free.Corey: My favorite is people who don't do research on this stuff. They wind up saying, “Oh, yeah. Cloudflare is saying that bandwidth is a fixed cost. Of course not. They must be losing their shirt on this.”You are a publicly-traded company. Your gross margins are 76% or 77%, depending upon whether we're talking about GAAP or non-GAAP. Point being, you are clearly not selling this at a loss and hoping to make it up in volume. That's what a VC-backed company does. Is something that is real and as accurate.I want to, on some level, I guess, low-key apologize because I keep viewing Cloudflare through a lens that is increasingly inaccurate, which is as a CDN. But you've had Cloudflare Workers for a while, effectively Functions as a Service that run at the edge, which has this magic aura around it, that do various things, which is fascinating to me. You're launching R2; it feels like you are in some ways aiming at becoming a cloud provider, but instead of taking the traditional approach of building it from the region's outward, you're building it from the outward in. Is that a fair characterization?Matthew: I think that's right. I think fundamentally what Cloudflare is, is a network. And I remember early on in the pandemic, we did a series of fireside chats with people we thought we could learn from. And so was everyone from Andre Iguodala, the basketball player, to Mark Cuban, the entrepreneur, to we had a [unintelligible 00:25:56] governor and all kinds of things. And we these were just internal on off the record.And I got to do one with Eric Schmidt, the former CEO of Google. And I said, “You know, Eric, one of the things that we struggle with is describing what is Cloudflare.” And without hesitation, he said, “Oh, that's easy. You're the network I plug into and don't have to worry about anything else.” And I think that's better than I could say it, myself, and I think that's what it is that we fundamentally are: we're the network that fits together.Now, it turns out that in the process of being that network and enabling that network, we are going to build things like R2, which start to be an object store and starts to sort of step into some of the cloud provider space. And Workers is really just a way of programming that network in order to do that, but it turns out that there are a bunch of workloads that if you move them into the network itself, make sense—not going to be every workload, but a lot of workloads that makes sense there. And again, I think that you can actually be very bullish on all of the big public cloud providers and bullish on Cloudflare at the same time because what we want to do is enable the ability for people to mix and match, and change, and be the fabric that connects all of those things together. And so over time, if Amazon says, “We're going to drop egress fees,” it may be that R2 isn't a product that exists—I don't think they're going to do that, so I think it's something that is going to be successful for us and get a lot of new users to us—but fundamentally, I think that where the traditional public clouds think of themselves as the place you put data and you process data, I think we think of ourselves as the place you move data. And that's somewhat different.That then translates into it as we're building out the different pieces, where it does feel like we're building from the outside in. And it may be that over time, that put versus move distinction becomes narrower and narrower as we build more and more services like R2, and durable objects, and KV, and we're working on a database, and all those things. And it could be that we converge in a similar place.Corey: One thing I really appreciate about your vision because it is so atypical these days, is that you aren't trying to build the multifunction printer of companies. You are not trying to be all things to all people in every scenario. Which is impossible to do, but companies are still trying their level best to do it. You are staking out the bounds of where you were willing to start and where you're willing to stop, in a variety of different ways. I would be—how do I put it?—surprised if you at some point in the next five years come out with, “And this is our own database that we have built out that directly competes with the following open-source project that we basically have implemented their API and gone down that particular path.” It does not sound like it is in your core wheelhouse at that point. You don't need—to my understanding—to write your own database engine in order to do what you do.Matthew: Maybe. I mean, we actually are kind of working on a database because—Corey: Oh, no, here we go again.Matthew: [laugh]—and yeah—in a couple of different ways. So, the first way is, we want to make sure that if you're using Workers, you can connect to whatever database you want to use anywhere in the world. And that's something that's coming and we'll be there. At the same time, the challenge of distributed computing turns out not to be the computing, it turns out to be the data and figuring out how to—CAP theorem is real, right? Consistency, Availability, and Partition tolerance; you can pick any two out of the three, but you can't get all three.And so you there's always going to be some trade-off that's there. And so we don't see a lot of good examples. There's some really cool companies that are working on things in the space, but we don't see a lot of really good examples of who has built a database that can be run on a distributed workload system, like Cloudflare to it do well. And so our team internally needs that, and so we're trying to figure out how to build it for ourselves, and I would imagine that after we build it for ourselves—if it works the way we expect it will—that that will then be something that we open up.Our motivation and the way we think about products is we need to build the tools for our own team. Our team itself is customer zero, and then some of those things are very specific to us, but every once in a while, when there are functions that makes sense for others, then we'll build them as well. And that does maybe risk being the multifunction printer, but again, I think that because the customer for that starts with ourselves, that's how we think about it. And if there's someone else's making a great tool, we'll use that. But in this case, we don't see anyone that's built a multi-tenant, globally-distributed, ACID-compliant relational database.Corey: I can't let it pass on challenge. Sure they have, and you're running it yourself. DNS: the finest database in the world. You stuff whatever you want to text records, and now you have taken a finely crafted wrench and turned it into a barely acceptable hammer, which is what I love about doing that terrible approach. Yeah, relational is not going to quite work that way. But—Matthew: Yes. That's a fancy key-value store, right? So—and we've had that for a long time. As we're trying to build those things up, the good news is that, again, we've run data at scale for quite some time and proven that we can do it efficiently and reliably.Corey: There's a lot that can be said about building the things you need to deliver your product to customers. And maybe a database is a poor example here, but I don't see that your motivation in this space is to step into something completely outside your areas of expertise solely because there's money to be made over there. Well, yeah, fortune passes everywhere. The question is, which are you best positioned to wind up delivering an actual transformative solution to that space, and what parts of it are just rent-seeking where it's okay, we're going to go and wherever the money is, we're chasing that down.Matthew: Yeah, we're still a for-profit business, and we've been able to grow revenue well, but I think it is that what motivates us and what drives us comes back to our mission, which is how do you help build a better internet? And you can look at every single thing that we've done, and we try to be very long-term-oriented. So, for instance, when we in 2014 made encryption free, the number one reason at the time, when people upgraded for the free version of our service, the paid version of our service is they got encryption for that. And so it was super scary to say, “Hey, we're going to take the biggest feature and give it away for free,” but it was clearly the direction of history and we wanted to be on the right side of history. And we considered it a bug that the internet wasn't built in an encrypted way from the beginning.So, of course, that was going to head that direction. And so I think that we and then subsequently Let's Encrypt, and a bunch of others have said, it's absurd that you're charging for math. And again, I think that's a good example of how we think about products. And we want to continue to disrupt ourselves and take the things that once upon a time were reserved for our customers that spend $10 million-plus with us, and we want to keep pushing those things down because, over time, the real opportunity is if you do right by customers, there will be plenty of ways that you can earn some of their budget. And again, we think that is the long-term winning strategy.Corey: I would agree with this. You're not out there making sneakers and selling them because you see people spend a lot of money on that; you're delivering value for customers. I say this as one of your paying customers. I have zero problem paying you every month like clockwork, and it is the least cloud-like experience because I know exactly what the bill is going to be in advance, which is apparently not how things should be done in this industry, yadda, yadda, yadda. It is a refreshingly delightful experience every time.The few times I've had challenges with the service, it has almost always been a—I'll call it a documentation gap, where the way it was explained in the formal documentation was not how I conceptualize things, which, again, explaining what these complex things are to folks who are not steeped in certain areas of them is always going to be a challenge. But I cannot think back to a single customer service failure I've had with you folks. I can't look back at any point where you have failed me as a customer, which is a strange thing to say, given how incredibly efficient I am at stumbling over weird bugs.Matthew: Terrific to have you as a customer. We are hardly perfect and we make mistakes, but one of the things I think that we try to do and one of the core values of Cloudflare is transparency. If I think about, like, the original sins of tech, a lot of it is this bizarre secrecy which pervades the entire industry. When we make mistakes, we talk about them, and we explain them. When there's an error, we don't throw up a white page; we put up a page that has our logo on it because we want to own it.And that sometimes gets blowback because you're in front of it, but again, I think it's the right thing to do for customers. And it's and I think it's incredibly important. One of the things that's interesting is you mentioned that you know what your bill is going to be. If you go back and look at the history of hosting on the internet, in the early days of internet hosting, it looks a lot like AWS.Corey: Oh, 95th percentile transit billing; go for one five minutes segment over and boom, your bill explodes. Oh, I remember those days. Unkindly.Matthew: And it was super complicated. And then what happened is the hosting world switched from this incredibly complicated billing to much more simplified, predictable, unlimited bandwidth with maybe some asterisks, but largely that was in place. And then it's strange that Amazon came along and then has brought us back to the more complicated world that's out there. I would have predicted that that's a sine wave—Corey: It has to be. I mean—Matthew: —and it's going to go back and forth over time. But I would have predicted that we would be more in the direction of coming back toward simplify, everything included. And again, I think that's how we've priced our things from the beginning. I'm surprised that it has held on as long as it has, but I do think that there's going to be an opportunity for—and I don't think Amazon will be the leader here, but I think there will be an opportunity for one of the big clouds.And again, I think Oracle is probably doing this the best of any of them right now—to say, “How can we go away from that complexity? How can we make bills predictable? How can we not nickel and dime everything, but allow you to actually forecast and budget?” And it just seems like that's the natural arc of history, and we will head back toward that. And, again, I think we've done our part to push that along. And I'm excited that other cloud providers seem to be thinking about that now as well.Corey: Oh, yeah. What I do with fixing AWS bills is the same thing folks were doing in the 70s and 80s with long-distance bills for companies. We're definitely hitting that sine wave. I know that if I were at AWS in a leadership role, I would be actively embarrassed that the company that is delivering a better customer experience around financial things is Oracle of all companies, given their history of audits and surprising people and the rest. It is ridiculous to me.One last topic that I want to cover with you before we call it an episode is, back in college, you had a thesis that you have done an excellent job of effectively eliminating from the internet. And the theme of this, to my understanding, was that the internet is a fad. And I am so aligned with that because I'm someone who has said for years that emerging technologies are fads. I've said it about cloud, about virtualization, about containers. And I just skipped Kubernetes. And now I'm all-in on serverless, which means, of course it's going to fail because I'm always wrong on these things. But tell me about that.Matthew: When I was seven years old in 1980, my grandmother gave me an Apple ][+ computer for Christmas. And I took to it like a just absolute duck to water and did things that made me very popular in junior high school, like going to computer camp. And my mom used to sign up for continuing education classes at the local university in computer science, and basically sneak me in, and I'd do all the homework and all that. And I remember when I got to college, there was a small group of students that would come around and help other students set their computer up, and I had it all set up and was involved. And so, got pretty deeply involved in the computer science program at college.And then I remember there was a group of three other students—so they were four of us—and they wanted to start an online digital magazine. And at the time, this was pre-web, or right in the early days of the web; it was sort of nineteen… ninety-three. And we built it originally on old Apple technology called HyperCard. And we used to email out the old HyperCard stacks. And the HyperCard stacks kept getting bigger and bigger and bigger, and we'd send them out to the school so [laugh] that we—so we kept crashing the mail servers.But the college loved this, so they kept buying bigger and bigger mail servers. But they were—at some point, they said, “This won't scale. You got to switch technologies.” And they introduced us to two different groups. One was a printer company based out in San Francisco that had this technology called PDF. And I was a really big fan of PDF. I thought PDF was the future, it was definitely going to be how everything got published.And then the other was this group of dorky graduate students at the University of Illinois that had this thing called a browser, which was super flaky, and crashed all the time, and didn't work. And so of the four of us, I was the one who voted for PDF and the other three were like, “Actually, I think this HTML thing is going to be a hit.” And we built this. We won an award from Wired—which was only a print magazine at the time—that called us the first online-only weekly publication. And it was such a struggle to get anyone to write for it because browsers sucked and, you know, trying to get students on campus, but no one on campus cared.We would get these emails from the other side of the world, where I remember really clearly is this—in broken English—email from Japan saying, “I love the magazine. Please keep writing more for the magazine.” And I remember thinking at the time, “Why do I care if someone in Japan is reading this if the girl down the hall who I have a crush on isn't?” Which is obviously what motivates dorky college students like myself. And at that same time, you saw all of this internet explosion.I remember the moment when Netscape went public and just blew through all the expectations. And it was right around the time I was getting ready to graduate for college, and I was kind of just burned out on the entire thing. And I thought, “If I can't even get anyone to write for this dopey magazine and yet we're winning awards, like, this stuff has to all just be complete garbage.” And so wrote a thesis on—ehh, it was not a very good [laugh] thesis. It's—but one of the things I said was that largely the internet was a fad, and that if it wasn't, that it had some real risks because if you enabled everyone to connect with whatever their weird interests and hobbies were, that you would very quickly fall to the lowest common denominator. And predicted some things that haven't come true. I thought for sure that you would have both a liberal and conservative search engine. And it's a miracle to this day, I think that doesn't exist.Corey: Now, that you said it, of course, it's going to.Matthew: Well, I don't know I've… [sigh] we'll see. But it is pretty amazing that Google has been able to, again, thread that line and stay largely apolitical. I'm surprised there aren't more national search engines; the fact that it only Russia and China have national search engines and France and Germany don't is just strange to me. It seems like if you're controlling the source of truth and how people find it, that seems like something that governments would try and take over. There are some things that in retrospect, look pretty wise, but there were a lot more things that looked really, really stupid. And so I think at some level, I had to build Cloudflare to atone for that stupidity all those years ago.Corey: There's something to be said for looking back and saying, “Yeah, I had an opinion, and with the light of new information, I am changing my opinion.” For some reason, in some circles, it feels like that gets interpreted as a sign of weakness, but I couldn't disagree more, it's, “Well, I had an opinion based upon what I saw at the time. Turns out, I was wrong, and here we are.” I really wish more people were capable of doing that.Matthew: It's one of the things we test for in hiring. And I think the characteristic that describes people who can do that well is really empathy. The understanding that the experiences that you have lead you to have a unique set of insights, but they also create a unique set of blind spots. And it's rare that you find people that are able to do that. And whenever you do—whenever we do we hire them.Corey: To that end, as far as hiring and similar topics go, if people want to learn more about how you view things, and how you see the world, and what you're releasing—maybe even potentially work with you—where can they find you?Matthew: [laugh]. So, the joke, sometimes, internal at Cloudflare is that Cloudflare is a blogging company that runs this global network just to have something to write about. So, I think we're unlike most corporate blogs, which are—if our corporate blog were typical, we'd have articles on, like, “Here are the top six reasons you need a fast website,” which would just be, you know, shoot me. But instead, I think we write about the things that are going on online and our unique view into them. And we have a core value of transparency, so we talk about that. So, if you're interested in Cloudflare, I'd encourage you to—especially if you're of the sort of geekier variety—to check out blog.cloudflare.com, and I think that's a good place to learn about us. And I still write for that occasionally.Corey: You're one of the only non-AWS corporate blogs that I pay attention to, for that exact reason. It is not, “Oh, yay. More content marketing by folks who just feel the need to hit a quota as opposed to talking about something valuable and interesting.” So, it's appreciated.Matthew: The secret to it was we realized at some point that the purpose of the blog wasn't to attract customers, it was to attract potential employees. And it turns out, if you sort of change that focus, then you talk to people like their peers, and it turns out then that the content that you create is much more authentic. And that turns out to be a great way to attract customers as well.Corey: I want to thank you for taking so much time out of your day to speak with me. I really appreciate it.Matthew: Thanks for all you're doing. And we're very aligned, and keep fighting the good fight. And someday, again, we'll eliminate cloud egress fees, and we can share a beer when we do.Corey: I will absolutely be there for it. Matthew, Prince, CEO, and co-founder of Cloudflare. I'm Cloud Economist Corey Quinn, and this is Screaming in the Cloud. If you've enjoyed this podcast, please leave a five-star review on your podcast platform of choice, whereas if you've hated this podcast, please leave a five-star review on your podcast platform of choice along with a rambling comment explaining that while data packets into a cloud provider are cheap and crappy, the ones being sent to the internet are beautiful, bespoke, unicorn snowflakes, so of course they cost money.Corey: If your AWS bill keeps rising and your blood pressure is doing the same, then you need The Duckbill Group. We help companies fix their AWS bill by making it smaller and less horrifying. The Duckbill Group works for you, not AWS. We tailor recommendations to your business and we get to the point. Visit duckbillgroup.com to get started.Announcer: This has been a HumblePod production. Stay humble.

The guys sit down for a final recap of Franks trip up to Alaska to hunt for Caribou. Bill Vanderheyden, co-founder and lead engineer of Ironwill Broadheads joins in with Aron, Isaac Aleman, and Frank to add his recount of the story. They touch on the highlights of the trip up to the barren ground of Alaska, and the details of getting a caribou on the ground. Bill was the only guy to gut it out the whole time with a bow in his hands. He talks about the struggles of getting close to the animals.   Did you like this episode? If you like what you hear go over to our Patreon and check out our levels of support, it helps up keep the lights on.

On todays episode I spoke with Travis Will about his recent Alaska Caribou hunt!  Not only was it a success for the whole crew, but Travis was able to get it done with his bow!  Travis is always looking for a challenge and find ways to push himself to be a better hunter which is something I respect a ton.  I enjoyed the conversation and I think you will too.  Go check out his IG page @travis_will_hunt  Also, if you are looking for backcountry meals for the season, go to www.alpenfuel.com and use discount code WELCOME10 for 10% off of your first order.  This code works for anything on their entire site.

Original Air Date: December 05, 1949 Host: Andrew Rhynes Show: Challenge of the Yukon Phone: (707) 98 OTRDW (6-8739) Stars: • Paul Sutton (Sgt. Preston) Writer: • Fran Striker Producer: • George W. Trendle Exit music from: Roundup on the Prairie by Aaron Kenny https://bit.ly/3kTj0kK

Original Air Date: December 05, 1949 Host: Andrew Rhynes Show: Challenge of the Yukon Phone: (707) 98 OTRDW (6-8739) Stars: • Paul Sutton (Sgt. Preston) Writer: • Fran Striker Producer: • George W. Trendle Exit music from: Roundup on the Prairie by Aaron Kenny https://bit.ly/3kTj0kK

link Трек-лист: The Yardbirds — For Your Love Slaves — Cheer Up London Miles Kane — Come Closer Anacondaz — Круглый год Kid Loco — Suspicious Minds Заточка — Белый London Grammar — How Does It Feel СБПЧ — Вечный взрыв Caribou — Sunny's Time (Logic1000 remix) Parov Stelar — All Night Long They Might … Продолжить чтение Lofstrom loop 260

link Трек-лист: The Yardbirds — For Your Love Slaves — Cheer Up London Miles Kane — Come Closer Anacondaz — Круглый год Kid Loco — Suspicious Minds Заточка — Белый London Grammar — How Does It Feel СБПЧ — Вечный взрыв Caribou — Sunny's Time (Logic1000 remix) Parov Stelar — All Night Long They Might … Продолжить чтение Lofstrom loop 260

A group of buffet concepts is accused of misusing PPP funds. Caribou Coffee wants to go national. And Toppers Pizza sets its sights on growth.

This week Chad talks with Brad Brooks from Argali about his “Working Mans Triple Crown” hunting trip in Alaska.  Brad set out to hunt Sitka Blacktail, Caribou and Moose.  These are the three species that don't require a guide in Alaska.  On this podcast Brad talks about his 5 weeks of hunting and fishing.  Sounds like an amazing trip.  Enjoy the show! BRAD BROOKS - ARGALIInstagram - @argali_officialWebsite – https://argalioutdoors.comBACKCOUNTRY ROOKIESWebsite - https://backcountryrookies.comInstagram - @backcountryrookiesFacebook - Backcountry Rookies      Group - Backcountry Rookies NationgoHUNT InsiderReceive a $50 Credit to the goHUNT Gear Shop when you purchase the Insider Program and use the code ROOKIESwww.gohunt.com/insiderElk101 University of Elk HuntingSave 20% by using the code ROOKIEShttps://www.elk101.com/product/university-of-elk-hunting-online-course/Vortex OpticsUse the code ROOKIES and save 20% on apparel at the Vortex Optics Websitehttps://vortexoptics.com Backcountry Rookies is powered by Simple Cast.

This week Chad talks with Brad Brooks from Argali about his “Working Mans Triple Crown” hunting trip in Alaska.  Brad set out to hunt Sitka Blacktail, Caribou and Moose.  These are the three species that don't require a guide in Alaska.  On this podcast Brad talks about his 5 weeks of hunting and fishing.  Sounds like an amazing trip.  Enjoy the show! BRAD BROOKS - ARGALIInstagram - @argali_officialWebsite – https://argalioutdoors.comBACKCOUNTRY ROOKIESWebsite - https://backcountryrookies.comInstagram - @backcountryrookiesFacebook - Backcountry Rookies      Group - Backcountry Rookies NationgoHUNT InsiderReceive a $50 Credit to the goHUNT Gear Shop when you purchase the Insider Program and use the code ROOKIESwww.gohunt.com/insiderElk101 University of Elk HuntingSave 20% by using the code ROOKIEShttps://www.elk101.com/product/university-of-elk-hunting-online-course/Vortex OpticsUse the code ROOKIES and save 20% on apparel at the Vortex Optics Websitehttps://vortexoptics.com Backcountry Rookies is powered by Simple Cast.

There's a big Animal Crossing update coming soon; will it bring Jason and Dawn back to the yard? Caribou is out of pumpkin already for the rest of the season? Joanna Gaines shared her secret to her delicious pecan pie. Adele's "Easy On Me" beat BTS' "Butter" for most downloads in a day. A longer "The Batman" trailer with Robert Pattinson and Zoey Kravitz dropped; are we excited to see it?

La drogue n'a pas des effets que sur les humains. Les animaux aussi peuvent devenir accro, que cela soit votre chat, le caribou et même la truite.Texte et présentation : Julia Mothu - NEONMontage et production : Julien Louët / Lucas WyboSee Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Associate Pastor Jonathon VanGilst tells us about his experience as a child, pastor, and even Caribou barista! Hear how he's grown in faith, and followed Gods calling to him.

In this episode, I'm joined by Tyler and Jordan Wagner, who I met on the Haul road, and we recap our action-packed hunts! comments or questions? email podcast@tundratalkak.com

Across Canada, climate change is exacerbating challenges caribou herds already face. But research shows protecting caribou habitat could have other benefits for climate.

Frank, David, and Aron are joined by Issac Aleman today and give a recount of an unexpected and unforgettable adventure in the tundra of the Alaska. Between bear sightings and encounters and the gastro-intestinal interruptions this trip had it all, including huge bull caribou. To hear the full story give this one a listen and look out for the first full-length Kifaru film of the year in Barren Ground. Go check out the trailer for the new Kifaru film Barren Ground and keep an eye out for the premiere dropping soon!   Did you like this episode? If you like what you hear go over to our Patreon and check out our levels of support, it helps up keep the lights on.

Support Penny's work by becoming a Patreon! https://www.patreon.com/pennykelly/me...Penny's website: https://www.pennykelly.com OR  https://www.consciousnessonfire.comFollow Penny on ODYSEE! https://odysee.com/@pennykelly:aBITCHUTE!  https://www.bitchute.com/channel/pennykelly/YOUTUBE channel: https://www.youtube.com/channel/UCgzsPCyTYGwnkkz8gFzZ0jA/videosDISCLAIMER:The information, procedures, suggestions and forecasts contained in all Penny Kelly podcasts or videos are not meant to take the place of a diagnosis, physician, financial advisor or professional advice. They are for educational purposes only. All use of the information presented is at your own discretion. Neither Penny Kelly, Kelly Networks LLC or any of her associates will be held liable for any injury, damage, or loss (financial or otherwise) as a result of the information contained in all Penny Kelly podcasts or videos.ALL RIGHTS RESERVED: No part of this video or publication may be reproduced, transmitted, or stored in any form or by any means, whether handwritten, printed, electronic, or otherwise, other than Fair Use as permitted by U.S. Copyright Law, without the prior written permission of Kelly Networks LLC info@kellynetworks.com

John Schmersal is a songwriter, singer and producer. For the past 20 years he has recorded and toured as the guitarist and/or keyboardist for bands Brainiac, Enon and most recently, Caribou.  In this episode John shares his stories of a pantsless show and impromptu tailoring,   broken bass strings and how he pulled off an entire festival show without monitors.  Joe and John discuss the virtues of preparedness, the rules of shorts in rock n roll,  and whether people really care if you're nude anymore. Music by Enon and Joe Plummer Use Code Fret10 for a free month of Music Production Suite Pro and a 10% discount on all other software. Visit Izotope.com

Episode 536: September 19, 2021 playlist: Caribou, "You Can Do It" (You Can Do It) 2021 Merge Mary Lattimore, "Mary, You Were Wrong" (Collected Pieces II) 2018 Ghostly Jeffrey Alexander and the Heavy Lidders, "Audubon Trooper" (Jeffrey Alexander and the Heavy Lidders) 2021 Arrowhawk Porter Ricks, "Spoil" (Porter Ricks) 1997/2021 Force Inc. / Mille Plateaux Catherine Graindorge, "Lockdown" (Eldorado) 2021 Glitterbeat Nurse With Wound, "Optical Illusion Pad (alternative version)" (Second Pirate Session LP) 1998 United Dairies GCOM, "XO 4 (Wolf 1061c)" (E2-XO) 2021 !K7 Hugo Randulv, "1" (Radio Arktis (samlade ljud fran den norra polcirkeln)) 2021 Discreet Music Can, "Your Friendly Neighbourhood Whore" (The Lost Tapes) 2012 Spoon Bob Mould, "The Ocean" (Blue Hearts) 2020 Merge Email podcast at brainwashed dot com to say who you are; what you like; what you want to hear; share pictures for the podcast of where you're from, your computer or MP3 player with or without the Brainwashed Podcast Playing; and win free music! We have no tracking information, no idea who's listening to these things so the more feedback that comes in, the more frequent podcasts will come. You will not be put on any spam list and your information will remain completely private and not farmed out to a third party. Thanks for your attention and thanks for listening.

This was probably one of the top 3 hunts I've done. I absolutely love the challenge of going to a new place and trying to figure it out. The Haul Rd is the ultimate DIY figure it out hunt. I had been planning to do a fly out caribou hunt, I was headed out solo […]

On this episode of The Federalist Radio Hour, Federalist Western Correspondent Tristan Justice joins Culture Editor Emily Jashinsky to discuss his recent reporting trip to Alaska where natural resource conflicts have taken over the state’s politics. Justice visited oil drilling sites and a remote southwest Alaskan village that is effectively banned from harvesting their massive deposits of copper, gold, porphyry, and molydenum.

On this episode of The Federalist Radio Hour, Federalist Western Correspondent Tristan Justice joins Culture Editor Emily Jashinsky to discuss his recent reporting trip to Alaska where natural resource conflicts have taken over the state’s politics. Justice visited oil drilling sites and a remote southwest Alaskan village that is effectively banned from harvesting their massive […]

Pokedads Rick and Aaron and Pokedad Intern Drew are joined by Special Conditions Hosts Ken and Pokedad Adam, Jackal, Samantha Chalk and Frosted Caribou. We go over ideas what we think the V-Star Mechanic will be like. POG 2021 drama and how we should handle it in the future. We all pick 1 card we dont want to see go and 1 we cant wait to say goodbye. Is that you ADP packing their bags? Text Us! Pokedads has a Phone Number! Call us for questions or fun Pokedad Stories! 815-782-0202 Help us keep the lights on and the wives from yelling at us! Visit our Patreon. https://www.paperorplastic.net https://kollectiblekings.com https://www.nestcollectibles.com/ https://www.patreon.com/Pokedadstcg https://twitter.com/PokeDadsTCG https://www.youtube.com/channel/UCBM1si3nlZjzwq75MJwpFig https://www.instagram.com/pokedadstcg/ Pokémon And All Respective Names are Trademark and © of Nintendo 1996-2021 Pokémon GO is Trademark and © of Niantic, Inc. PokéDads are not affiliated with Niantic Inc., The Pokémon Company, Game Freak or Nintendo #pokemon #pokemontcg #pokemonpodcast --- Send in a voice message: https://anchor.fm/pokedads/message

Cassius, Caribou, Earth Wind and Fire, Flying Lotus : leurs favoris. Josh Lloyd-Watson et Tom McFarland les deux producteurs derrière Jungle sont nos invités du Nova Club. Sophie Marchand et David Blot reviennent avec eux sur leur parcours, leurs influences musicales (fortement marquées par la French Touch) mais aussi leur dernier album "Loving In Stereo".Le groupe nous a aussi balancé une exclu : le remix de "Keep Moving" par Gaspard Augé ! Seuls les auditeurs en direct ont pu écouter cette exclu, alors comme David Blot le dit souvent : "Ecoutez le direct !".TRACKLISTTHE ISLEY BROTHERS - WORK TO DO (MR.K EDIT)PARCELS - COMINGBACK JOHN GLACIER - BOOZYEQUIKNOXX -- WAS NOT INITIALLY CALLED MAKE IT STOP TOKISCHA - LINDA (FEAT. ROSALIA)JUNGLE - ROMEO (FEAT. BAS)JUNGLE - DRY YOUR TEARSCASSIUS - CASSIUS 1999DAFT PUNK - AERODYNAMICCARIBOU - HOME OUTKAST - Ms. JACKSONMARTHA REEVES & THE VANDELLAS - NOWHERE TO RUNFLYING LOTUS - MASSAGE SITUATIONGASPARD AUGE & JUSTICE- FORCE MAJEURETHUNDERCAT - THEM CHANGESPRIYA RAGU - KAMALITHE PHARCYDE - PASSIN' ME BY ESG - DANCEHOT CHIP - BOY FROM SCHOOLEARTH, WIND & FIRE - LET'S GROOVE See acast.com/privacy for privacy and opt-out information.

Mark and Brendan are back with your weekly dose of indie goodness! This week, we start off with a new track from Ontario's Caribou, and then shift to an indie rock track from New York City's Lightning Bug. Then, off we go to Chicago for a new song from Circuit des Yeux, and our last new tune of the week comes from Ibiza-based Nightmares on Wax. And as usual, we are keeping it tight. Running time this week is a compact 14:34. That's right, you get bits of ten new songs plus a dab of music history in a package that doesn't even take up fifteen minutes of your time. How cool is that?! Fully half that number of new songs qualify as bonus tracks, but you will have to sign up for our email newsletter to get those gems. If you want to do that now, please take a second to sign up for that newsletter right here. Lastly, don't miss our fabulous Spotify playlists. We make one for each episode of the show, so grab the latest if you are up to date, and dig into previous episodes if you are new here, or just curious. Have a great week! (And Happy Labor Day weekend to all of our American listeners.) 

This week Harry is joined by Kevin Davies, author of the 2020 book Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing. CRISPR—an acronym for Clustered Regularly Interspaced Short Palindromic Repeats—consists of DNA sequences that evolved to help bacteria recognize and defend against viral invaders, as a kind of primitive immune system. Thanks to its ability to precisely detect and cut other DNA sequences, CRISPR has spread to labs across the world in the nine years since Jennifer Doudna and Emmanuel Charpentier published a groundbreaking 2012 Science paper describing how the process works. The Nobel Prize committee recognized the two scientists for the achievement in 2020, one day after Davies' book came out. The book explains how CRISPR was discovered, how it was turned into an easily programmable tool for cutting and pasting stretches of DNA, how most of the early pioneers in the field have now formed competing biotech companies, and how the technology is being used to help patients today—and in at least one famous case, misused. Today's interview covers all of that ground and more.Davies is a PhD geneticist who has spent most of his career in life sciences publishing. After his postdoc with Harvey Lodish at the Whitehead Institute, Davies worked as an assistant editor at Nature, the founding editor of Nature Genetics (Nature's first spinoff journal), editor-in-chief at Cell Press, founding editor-in-chief of the Boston-based publication Bio-IT World, and publisher of Chemical & Engineering News. In 2018 he helped to launch The CRISPR Journal, where he is the executive editor. Davies' previous books include Breakthrough (1995) about the race to understand the BRCA1 breast cancer gene, Cracking the Genome (2001) about the Human Genome Project, The $1,000 Genome (2010) about next-generation sequencing companies, and DNA (2017), an updated version of James Watson's 2004 book, co-authored with Watson and Andrew Berry.Please rate and review MoneyBall Medicine on Apple Podcasts! Here's how to do that from an iPhone, iPad, or iPod touch:1. Open the Podcasts app on your iPhone, iPad, or Mac. 2. Navigate to the page of the MoneyBall Medicine podcast. You can find it by searching for it or selecting it from your library. Just note that you'll have to go to the series page which shows all the episodes, not just the page for a single episode.3.Scroll down to find the subhead titled "Ratings & Reviews."4.Under one of the highlighted reviews, select "Write a Review."5.Next, select a star rating at the top — you have the option of choosing between one and five stars. 6.Using the text box at the top, write a title for your review. Then, in the lower text box, write your review. Your review can be up to 300 words long.7.Once you've finished, select "Send" or "Save" in the top-right corner. 8.If you've never left a podcast review before, enter a nickname. Your nickname will be displayed next to any reviews you leave from here on out. 9.After selecting a nickname, tap OK. Your review may not be immediately visible.Full TranscriptHarry Glorikian: I'm Harry Glorikian, and this is MoneyBall Medicine, the interview podcast where we meet researchers, entrepreneurs, and physicians who are using the power of data to improve patient health and make healthcare delivery more efficient. You can think of each episode as a new chapter in the never-ending audio version of my 2017 book, “MoneyBall Medicine: Thriving in the New Data-Driven Healthcare Market.” If you like the show, please do us a favor and leave a rating and review at Apple Podcasts.Harry Glorikian: We talk a lot on the show about how computation and data are changing the way we develop new medicines and the way we deliver healthcare. Some executives in the drug discovery business speak of the computing and software side of the business as the “dry lab” —to set it apart from the “wet labs” where scientists get their hands dirty working with actual cells, tissues, and reagents.But the thing is, recent progress on the wet lab side of biotech has been just as amazing as progress in areas like machine learning. And this week, my friend Kevin Davies is here to talk about the most powerful tool to come along in the last decade, namely, precise gene editing using CRISPR.Of course, CRISPR-based gene editing has been all over the news since Jennifer Doudna and Emmanuel Charpentier published a groundbreaking Science paper in 2012 describing how the process works in the lab. That work earned them a Nobel Prize in medicine just eight years later, in 2020.But what's not as well-known is the story of how CRISPR was discovered, how it was turned into an easily programmable tool for cutting and pasting stretches of DNA, how most of the early pioneers in the field have now formed competing biotech companies, and how the technology is being used to help patients today—and in at least one famous case, misused.Kevin put that whole fascinating story together in his 2020 book Editing Humanity. And as the executive editor of The CRISPR Journal, the former editor-in-chief of Bio-IT World, the founding editor at Nature Genetics, and the author of several other important books about genomics, Kevin is one of the best-placed people in the world to tell that story. Here's our conversation.Harry Glorikian: Kevin, welcome to the show. Kevin Davies: Great to see you again, Harry. Thanks for having me on.Harry Glorikian: Yeah, no, I mean, I seem to be saying this a lot lately, it's been such a long time since, because of this whole pandemic, nobody's really seeing anybody on a regular basis. I want to give everybody a chance to hear about, you had written this book called Editing Humanity, which is, you know, beautifully placed behind you for, for product placement here. But I want to hear, can you give everybody sort of an overview of the book and why you feel that this fairly technical laboratory tool called CRISPR is so important that you needed to write a book about it?Kevin Davies: Thank you. Yes. As you may know, from some of my previous “bestsellers” or not, I've written about big stories in genetics because that's the only thing I'm remotely qualified to write about. I trained as a human geneticist in London and came over to do actually a pair of post-docs in the Boston area before realizing my talents, whatever they might be, certainly weren't as a bench researcher. So I had to find another way to stay in science but get away from the bench and hang up the lab coats.So moving into science publishing and getting a job with Nature and then launching Nature Genetics was the route for me. And over the last 30 years, I've written four or five books that have all been about, a) something big happening in genomics, b) something really big that will have both medical and societal significance, like the mapping and discovery of the BRCA1 breast cancer gene in the mid-90s, the Human Genome Project at the turn of the century, and then the birth and the dawn of consumer genetics and personalized medicine with The $1,000 Genome. And the third ingredient I really look for if I'm trying to reach a moderately, significantly large audience is for the human elements. Who are they, the heroes and the anti heroes to propel the story? Where is the human drama? Because, you know, we all love a good juicy, gossipy piece of story and rating the good guys and the bad guys. And CRISPR, when it first really took off in 2012, 2013 as a gene editing tool a lot of scientists knew about this. I mean, these papers are being published in Science in particular, not exactly a specialized journal, but I was off doing other things and really missed the initial excitement, I'm embarrassed to say. It was only a couple of years later, working on a sequel to Jim Watson's DNA, where I was tasked with trying to find and summarize the big advances in genomic technology over the previous decade or whatever, that I thought, well, this CRISPR thing seems to be taking off and the Doudnas and the Charpentiers are, you know, winning Breakthrough Prizes and being feted by celebrities. And it's going on 60 Minutes. They're going to make a film with the Rock, Dwayne Johnson. What the heck is going on. And it took very little time after that, for me to think, you know, this is such an exciting, game-changing disruptive technology that I've got to do two things. I've gotta, a) write a book and b) launch a journal, and that's what I did. And started planning at any rate in sort of 2016 and 17. We launched the CRISPR Journal at the beginning of 2018. And the book Editing Humanity came out towards the end of 2020. So 2020, literally one day before the Nobel Prize—how about that for timing?—for Doudna and Charpentier for chemistry last year. Harry Glorikian: When I think about it, I remember working with different companies that had different types of gene editing technology you know, working with some particularly in the sort of agriculture space, cause it a little bit easier to run faster than in the human space. And you could see what was happening, but CRISPR now is still very new. But from the news and different advances that are happening, especially here in the Boston area, you know, it's having some real world impacts. If you had to point to the best or the most exciting example of CRISPR technology helping an actual patient, would you say, and I've heard you say it, Victoria Gray, I think, would be the person that comes to mind. I've even, I think in one of your last interviews, you said something about her being, you know, her name will go down in history. Can you explain the technology that is helping her and what some of the similar uses of CRISPR might be?Kevin Davies: So the first half of Editing Humanity is about the heroes of CRISPR, how we, how scientists turned it from this bizarre under-appreciated bacterial antiviral defense system and leveraged it and got to grips with it, and then figured out ways to turn it into a programmable gene editing technology. And within a year or two of that happening that the classic Doudna-Charpentier paper came out in the summer of 2012. Of course the first wave of biotech companies were launched by some of the big names, indeed most of the big names in CRISPR gene editing hierarchies. So Emmanuel Charpentier, Nobel Laureate, launched CRISPR Therapeutics, Jennifer Doudna co-founded Editas Medicine with several other luminaries. That didn't go well for, for reasons of intellectual property. So she withdrew from Editas and became a co-founder of Intellia Therapeutics as well as her own company, Caribou, which just went public, and Feng Zhang and others launched Editas Medicine. So we had this sort of three-way race, if you will, by three CRISPR empowered gene editing companies who all went public within the next two or three years and all set their sights on various different genetic Mendelian disorders with a view to trying to produce clinical success for this very powerful gene editing tool. And so, yes, Victoria Gray is the first patient, the first American patient with sickle cell anemia in a trial that is being run by CRISPR Therapeutics in close association with Vertex Pharmaceuticals. And that breakthrough paper, as I think many of your listeners will know, came out right at the end of 2020 published in the New England Journal of Medicine. Doesn't get much more prestigious than that. And in the first handful of patients that CRISPR Therapeutics have edited with a view to raising the levels of fetal hemoglobin, fetal globin, to compensate for the defective beta globin that these patients have inherited, the results were truly spectacular.And if we fast forward now to about two years after the initial administration, the initial procedures for Victoria Gray and some of her other volunteer patients, the results still look as spectacular. Earlier this year CRISPR Therapeutics put out of sort of an update where they are saying that the first 20 or 24 patients that they have dosed with sickle cell and beta thallasemia are all doing well. There've been little or no adverse events. And the idea of this being a once and done therapy appears very well founded. Now it's not a trivial therapy. This is ex-vivo gene editing as obviously rounds of chemotherapy to provide the room for the gene edited stem cells to be reimplanted into the patient. So this is not an easily scalable or affordable or ideal system, but when did we, when will we ever able to say we've pretty much got a cure for sickle cell disease? This is an absolutely spectacular moment, not just for CRISPR, but for medicine, I think, overall. And Victoria Gray, who's been brilliantly profiled in a long running series on National Public Radio, led by the science broadcaster Rob Stein, she is, you know, we, we can call her Queen Victoria, we can call it many things, but I really hope that ,it's not just my idea, that she will be one of those names like Louise Brown and other heroes of modern medicine, that we look and celebrate for decades to come.So the sickle cell results have been great, and then much more recently, also in the New England Journal, we have work led by Intellia Therapeutics, one of the other three companies that I named, where they've been also using CRISPR gene editing, but they've been looking at a rare liver disease, a form of amyloidosis where a toxic protein builds up and looking to find ways to knock out the production of that abnormal gene.And so they've been doing in vivo gene editing, really using CRISPR for the first time. It's been attempted using other gene editing platforms like zinc fingers, but this is the first time that I think we can really say and the New England Journal results prove it. In the first six patients that have been reported remarkable reductions in the level of this toxic protein far, not far better, but certainly better than any approved drugs that are currently on the market. So again, this is a very, very exciting proof of principle for in vivo gene editing, which is important, not just for patients with this rare liver disorder, but it really gives I think the whole field and the whole industry enormous confidence that CRISPR is safe and can be used for a growing list of Mendelian disorders, it's 6,000 or 7,000 diseases about which we know the root genetic cause, and we're not going to tackle all of them anytime soon, but there's a list of ones that now are within reach. And more and more companies are being launched all the time to try and get at some of these diseases.So as we stand here in the summer of 2021, it's a really exciting time. The future looks very bright, but there's so much more to be done. Harry Glorikian: No, we're just at the beginning. I mean, I remember when I first saw this, my first question was off target effects, right? How are we going to manage that? How are they going to get it to that place that they need to get it to, to have it to that cell at that time, in the right way to get it to do what it needs to do. And you know, all these sorts of technical questions, but at the same time, I remember I'm going to, trying to explain this to my friends. I'm like, “You don't understand, this can change everything.” And now a high school student, I say this to people and they look at me strangely, a high school student can order it and it shows up at your house.Kevin Davies: Yeah, well, this is why I think, and this is why one reason why CRISPR has become such an exciting story and receives the Nobel Prize eight years after the sort of launch publication or the first demonstration of it as a gene editing tool. It is so relatively easy to get to work. It's truly become a democratized or democratizing technology. You don't need a million-dollar Illumina sequencer or anything. And so labs literally all around the world can do basic CRISPR experiments. Not everyone is going to be able to launch a clinical trial. But the technology is so universally used, and that means that advances in our understanding of the mechanisms, new tools for the CRISPR toolbox new pathways, new targets, new oftware, new programs, they're all coming from all corners of the globe to help not just medicine, but many other applications of CRISPR as well.Harry Glorikian: Yeah. I always joke about like, there, there are things going on in high school biology classes now that weren't, available, when I was in college and even when we were in industry and now what used to take an entire room, you can do on a corner of a lab bench.Kevin Davies: Yeah. Yeah. As far as the industry goes we mentioned three companies. But you know, today there's probably a dozen or more CRISPR based or gene editing based biotech companies. More undoubtedly are going to be launched before the end of this year. I'm sure we'll spend a bit of time talking about CRISPR 2.0, it seems too soon to be even thinking about a new and improved version of CRISPR, but I think there's a lot of excitement around also two other Boston-based companies, Beam Therapeutics in Cambridge and Verve Therapeutics both of which are launching or commercializing base editing. So base editing is a tool developed from the lab of David Lu of the Broad Institute [of MIT and Harvard]. And the early signs, again, this technology is only five or six years old, but the early signs of this are incredibly promising. David's team, academic team, had a paper in Nature earlier this year, really reporting successful base editing treatment of sickle cell disease in an animal model, not by raising the fetal globin levels, which was sort of a more indirect method that is working very well in the clinic, but by going right at the point mutation that results in sickle cell disease and using given the chemical repertoire of base editing.Base editing is able to make specific single base changes. It can't do the full repertoire of single base changes. So there are some limitations on researchers' flexibility. So they were unable to flip the sickle cell variant back to the quote unquote wild type variants, but the change they were able to make is one that they can live with, we can live with because it's a known benign variant, a very rare variant that has been observed in other, in rare people around the world. So that's completely fine. It's the next best thing. And so that looks very promising. Beam Therapeutics, which is the company that David founded or co-founded is trying a related approach, also going right at the sickle cell mutation. And there are other companies, including one that Matthew Porteus has recently founded and has gone public called Graphite Bio.So this is an exciting time for a disease sickle cell disease that has been woefully neglected, I think you would agree, both in terms of basic research, funding, medical prioritization, and medical education. Now we have many, many shots on goal and it doesn't really, it's not a matter of one's going to win and the others are going to fall by the wayside. Just like we have many COVID vaccines. We'll hopefully have many strategies for tackling sickle cell disease, but they are going to be expensive. And I think you know the economics better than I do. But I think that is the worry, that by analogy with gene therapies that have been recently approved, it's all, it's really exciting that we can now see the first quote, unquote cures in the clinic. That's amazingly exciting. But if the price tag is going to be $1 million or $2 million when these things are finally approved, if and when, that's going to be a rather deflating moment. But given the extraordinary research resources that the CRISPRs and Intellias and Beams and Graphites are pouring into this research, obviously they've got to get some return back on their investment so that they can plow it back into the company to develop the next wave of of gene editing therapies. So you know, it's a predicament Harry Glorikian: One of these days maybe I have to have a show based on the financial parts of it. Because there's a number of different ways to look at it. But just for the benefit of the listeners, right, who may not be experts, how would you explain CRISPR is different from say traditional gene therapies. And is CRISPR going to replace older methods of, of gene therapy or, or will they both have their place? Kevin Davies: No, I think they'll both have their place. CRISPR and, and these newer gene editing tools, base editing and another one called prime editing, which has a company behind it now called Prime Medicine, are able to affect specific DNA changes in the human genome.So if you can target CRISPR, which is an enzyme that cuts DNA together with a little program, the GPS signal is provided in the form of a short RNA molecule that tells the enzyme where to go, where to go in the genome. And then you have a couple of strategies. You can either cut the DNA at the appropriate target site, because you want to inactivate that gene, or you just want to scramble the sequence because you want to completely squash the expression of that gene. Or particularly using the newer forms of gene editing, like base editing, you can make a specific, a more nuanced, specific precision edit without, with one big potential advantage in the safety profile, which is, you're not completely cutting the DNA, you're just making a nick and then coaxing the cell's natural repair systems to make the change that you sort of you're able to prime.So there are many diseases where this is the way you want to go, but that does not in any way invalidate the great progress that we're making in traditional gene therapy. So for example today earlier today I was recording an interview or for one of my own programs with Laurence Reid, the CEO of Decibel Therapeutics, which is looking at therapies for hearing loss both genetic and other, other types of hearing disorders.And I pushed him on this. Aren't you actually joinomg with the gene editing wave? And he was very circumspect and said, no, we're very pleased, very happy with the results that we're getting using old fashioned gene replacement therapy. These are recessive loss of function disorders. And all we need to do is get the expression of some of the gene back. So you don't necessarily need the fancy gene editing tools. If you can just use a an AAV vector and put the healthy gene back into the key cells in the inner ear. So they're complimentary approaches which is great.Harry Glorikian: So, you know, in, in this podcast, I try to have a central theme when I'm talking to people. The relationships of big data, computation, advances in new drugs, and other ways to keep people healthy. So, you know, like question-wise, there's no question in my mind that the whole genomics revolution that started in the ‘90s, and I was happy to be at Applied Biosystems when we were doing that, would have been impossible in the absence of the advances in computing speed and storage in the last three decades. I think computing was the thing that held up the whole human genome, which gave us the book of life that CRISPR is now allowing us to really edit. But I wonder if you could bring us sort of up-to-date and talk about the way CRISPR and computation are intertwined. What happens when you combine precision of an editing tool like CRISPR with the power of machine learning and AI tools to find meaning and patterns in that huge genetic ball? Kevin Davies: Yeah. Well, yeah. I'm got to tread carefully here, but I think we are seeing papers from some really brilliant labs that are using some of the tools that you mentioned. AI and machine learning with a view to better understanding and characterizing some of the properties and selection criteria of some of these gene editing tools. So you mentioned earlier Harry, the need to look out for safety and minimize the concern of off-target effects. So I think by using some of these some algorithms and AI tools, researchers have made enormous strides in being able to design the programmable parts of the gene editing constructs in such a way that you increase the chances that they're going to go to the site that you want them to go to, and nnot get hung up latching onto a very similar sequence that's just randomly cropped up on the dark side of the genome, across the nucleus over there. You don't want that to happen. And I don't know that anybody would claim that they have a failsafe way to guarantee that that could never happen. But the you know, the clinical results that we've seen and all the preclinical results are showing in more and more diseases that we've got the tools and learned enough now to almost completely minimize these safety concerns. But I think everyone, I think while they're excited and they're moving as fast as they can, they're also doing this responsibly. I mean, they, they have to because no field, gene therapy or gene editing really wants to revisit the Jesse Gelsinger tragedy in 1999, when a teenage volunteer died in volunteering for a gene therapy trial at Penn of, with somebody with a rare liver disease. And of course that, that setback set back the, entire field of gene therapy for a decade. And it's really remarkable that you know, many of the sort of pioneers in the field refuse to throw in the towel, they realized that they had to kind of go back to the drawing board, look at the vectors again, and throw it out. Not completely but most, a lot of the work with adenoviruses has now gone by the wayside. AAV is the new virus that we hear about. It's got a much better safety profile. It's got a smaller cargo hold, so that's one drawback, but there are ways around that. And the, the explosion of gene therapy trials that we're seeing now largely on the back of AAV and now increasingly with, with non-viral delivery systems as well is, is very, very gratifying. And it's really delivery. I think that is now the pain point. Digressing from your question a little bit, but delivery, I think is now the big challenge. It's one thing to contemplate a gene therapy for the eye for rare hereditary form of blindness or the ear. Indeed those are very attractive sites and targets for some of these early trials because of the quantities that you need to produce. And the localization, the, the physical localization, those are good things. Those help you hit the target that you want to. But if you're contemplating trying something for Duchenne muscular dystrophy or spinal muscular atrophy, or some of the diseases of the brain, then you're going to need much higher quantities particularly for muscular disorders where, you run into now other challenges, including, production and manufacturing, challenges, and potentially safeguarding and making sure that there isn't an immune response as well. That's another, another issue that is always percolating in the background.But given where we were a few years ago and the clinical progress that we've talked about earlier on in the show it, I think you can safely assume that we've collectively made enormous progress in, in negating most, if not all of these potential safety issues.Harry Glorikian: No, you know, it's funny, I know that people will say like, you know, there was a problem in this and that. And I look at like, we're going into uncharted territories and it has to be expected that you just…you've got people that knew what they were doing. All of these people are new at what they are doing. And so you have to expect that along the way everything's not going to go perfectly. But I don't look at it as a negative. I look at it as, they're the new graduating class that's going to go on and understand what they did right. Or wrong, and then be able to modify it and make an improvement. And, you know, that's what we do in science. Kevin Davies: Well, and forget gene editing—in any area of drug development and, and pharmaceutical delivery, things don't always go according to plan. I'm sure many guests on Moneyball Medicine who have had to deal with clinical trial failures and withdrawing drugs that they had all kinds of high hopes for because we didn't understand the biology or there was some other reaction within, we didn't understand the dosing. You can't just extrapolate from an animal model to humans and on and on and on. And so gene editing, I don't think, necessarily, should be held to any higher standard. I think the CRISPR field has already in terms of the sort of market performance, some of the companies that we've mentioned, oh my God, it's been a real roller coaster surprisingly, because every time there's been a paper published in a prominent journal that says, oh my God, there's, there's a deletion pattern that we're seeing that we didn't anticipate, or we're seeing some immune responses or we're seeing unusual off target effects, or we're seeing P53 activation and you know, those are at least four off the top of my head. I'm sure there've been others. And all had big transient impact on the financial health of these companies. But I think that was to be expected. And the companies knew that this was just an overreaction. They've worked and demonstrated through peer review publications and preclinical and other reports that these challenges have been identified, when known about, pretty much completely have been overcome or are in the process of being overcome.So, you know, and we're still seeing in just traditional gene therapy technologies that have been around for 15, 20 years. We're still seeing reports of adverse events on some of those trials. So for gene editing to have come as far as it's common, to be able to look at these two big New England Journal success stories in sickle cell and ATTR amyloidosis, I don't think any very few, except the most ardent evangelists would have predicted we'd be where we are just a few years ago. [musical transition]Harry Glorikian: I want to pause the conversation for a minute to make a quick request. If you're a fan of MoneyBall Medicine, you know that we've published dozens of interviews with leading scientists and entrepreneurs exploring the boundaries of data-driven healthcare and research. And you can listen to all of those episodes for free at Apple Podcasts, or at my website glorikian.com, or wherever you get your podcasts.There's one small thing you can do in return, and that's to leave a rating and a review of the show on Apple Podcasts. It's one of the best ways to help other listeners find and follow the show.If you've never posted a review or a rating, it's easy. All you have to do is open the Apple Podcasts app on your smartphone, search for MoneyBall Medicine, and scroll down to the Ratings & Reviews section. Tap the stars to rate the show, and then tap the link that says Write a Review to leave your comments. It'll only take a minute, but it'll help us out immensely. Thank you! And now back to the show.[musical transition]Harry Glorikian:One of your previous books was called The $1,000 Genome. And when you published that back in 2010, it was still pretty much science fiction that it might be possible to sequence someone's entire genome for $1,000. But companies like Illumina blew past that barrier pretty quickly, and now people are talking about sequencing individual genome for just a few hundred dollars or less. My question is, how did computing contribute to the exponential trends here. And do you wish you'd called your book The $100 Genome?Kevin Davies: I've thought about putting out a sequel to the book, scratching out the 0's and hoping nobody would notice. Computing was yes, of course, a massive [deal] for the very first human genome. Remember the struggle to put that first assembly together. It's not just about the wet lab and pulling the DNA sequences off the machines, but then you know, the rapid growth of the data exposure and the ability to store and share and send across to collaborators and put the assemblies together has been critical, absolutely critical to the development of genomics.I remember people were expressing shock at the $1,000 genome. I called the book that because I heard Craig Venter use that phrase in public for the first time in 2002. And I had just recently published Cracking the Genome. And we were all still recoiling at the billions of dollars it took to put that first reference genome sequence together. And then here's Craig Venter, chairing a scientific conference in Boston saying what we need is the $1,000 genome. And I almost fell off my chair. “what are you? What are you must you're in, you're on Fantasy Island. This is, there's no way we're going to get, we're still doing automated Sanger sequencing. God bless Fred Sanger. But how on earth are you going to take that technology and go from billions of dollars to a couple of thousand dollars. This is insanity.” And that session we had in 2002 in Boston. He had a local, a little episode of America's Got Talent and he invited half a dozen scientists to come up and show what they had. And George Church was one of them. I think Applied Biosystems may have given some sort of talk during that session. And then a guy, a young British guy from a company we'd never heard of called Celexa showed up and showed a couple of pretty PowerPoint slides with colored beads, representing the budding DNA sequence on some sort of chip. I don't know that he showed any data. It was all very pretty and all very fanciful. Well guess what? They had the last laugh. Illumina bought that company in 2006. And as you said, Harry you know, I think when, when they first professed to have cracked the $1,000 dollar genome barrier, a few people felt they needed a pinch of salt to go along with that. But I think now, yeah, we're, we're, we're well past that. And there are definitely outfits like BGI, the Beijing Genomics Institute being one of them, that are touting new technologies that can get us down to a couple of hundred. And those were such fun times because for a while there Illumina had enormous competition from companies like 454 and Helicose and PacBio. And those were fun heady times with lots and lots of competition. And in a way, Illumina's had it a little easy, I think over the last few years, but with PacBio and Oxford Nanopore gaining maturity both, both in terms of the technology platforms and their business strategy and growth, I think Illumina' gonna start to feel a little bit more competition in the long read sequence space. And one is always hearing whispers of new companies that may potentially disrupt next-gen sequencing. And that would be exciting because then we'd have an excuse to write another book. Harry Glorikian: Well, Kevin, start writing because I actually think we're there. I think there are a number of things there and you're right, I think Illumina has not had to bring the price down as quickly because there hasn't been competition. And you know, when I think about the space is, if you could do a $60 genome, right, it starts to become a rounding error. Like what other business models and opportunities now come alive? And those are the things that excite me. All right. But so, but you have a unique position as editor of the journal of CRISPR and the former editor of a lot of prominent, you know, publications, Nature Genetics, Bio-IT World, Chemical & Engineering News. Do you think that there's adequate coverage of the biological versus the computing side of it? Because I, I have this feeling that the computing side still gets a little overlooked and underappreciated. Kevin Davies: I think you're right. I mean I think at my own company Genetic Engineering News, we still have such deep roots in the wet lab vision and version of biotechnology that it takes a conscious effort to look and say, you know, that's not where all the innovation is happening. Bio-IT World, which you mentioned is interesting because we launched that in 2002. It was launched by the publisher IDG, best-known from MacWorld and ComputerWorld and this, this whole family of high-tech publications.And we launched in 2002 was a very thick glossy print magazine. And ironically, you know, we just couldn't find the advertising to sustain that effort, at least in the way that we'd envisioned it. And in 2006 and 2007, your friend and mine Phillips Kuhl, the proprietor of Cambridge Healthtech Institute, kind of put us out of our misery and said, you know what I'll, take the franchise because IDG just didn't know what to do with it anymore. But what he really wanted was the trade show, the production. And even though at the magazine eventually we fell on our sword and eventually put it out of its misery, the trade show went from strength to strength and it'll be back in Boston very soon because he had the vision to realize there is a big need here as sort of supercomputing for life sciences.And it's not just about the raw high-performance computing, but it's about the software, the software tools and data sharing and management. And it's great to go back to that show and see the, you know, the Googles and Amazons and yeah, all the big household names. They're all looking at this because genome technology, as we've discussed earlier has been one of the big growth boom areas for, for their services and their products.Harry Glorikian: Right. I mean, well, if you look at companies like Tempus, right. When I talked to Joel Dudley over there on the show it's, they want to be the Amazon AWS piping for all things genomic analysis. Right. So instead of creating it on your own and building a, just use their platform, basically, so it's definitely a growth area. And at some point, if you have certain disease states, I don't see how you don't get you know, genomic sequencing done, how a physician even today in oncology, how anybody can truly prescribe with all the drugs that are being approved that have, you know, genomic biomarkers associated with them and not use that data.Kevin Davies: On a much lower, lo-fi scale, as I've been doing a lot of reading about sickle cell disease lately, it's clear that a lot of patients who are, of course, as you, as you know, as your listeners know, are mostly African-American because the disease arose in Africa and the carrier status gives carriers a huge health advantage in warding off malaria. So the gene continues to stay, stay high in in frequency. Many African-American patients would benefit from some generic drugs that are available in this country that provide some relief, but aren't aware of it and maybe their physicians aren't completely aware of it either. Which is very sad. And we've neglected the funding of this disease over many decades, whereas a disease like cystic fibrosis, which affects primarily white people of Northern European descent that receives far more funding per capita, per head, than than a disease like sickle cell does. But hopefully that will begin to change as we see the, the potential of some of these more advanced therapies.I think as far as your previous comment. I think one of the big challenges now is how we tackle common diseases. I think we're making so much progress in treating rare Mendelian diseases and we know thousands of them. But it's mental illness and asthma and diabetes you know, diseases that affect millions of people, which have a much more complicated genetic and in part environmental basis.And what can we learn, to your point about having a full genome sequence, what can we glean from that that will help the medical establishment diagnose and treat much more common diseases, not quite as simple as just treating a rare Mendelian version of those diseases? So that's, I think going to be an important frontier over the next decade.Harry Glorikian: Yeah. It's complicated. I think you're going to see as we get more real-world data that's organized and managed well, along with genomic data, I think you'll be able to make more sense of it. But some of these diseases are quite complicated. It's not going to be find one gene, and it's going to give you that answer.But I want to go back to, you can't really talk about CRISPR without talking about this specter of germline editing. And a big part of your book is about this firestorm of criticism and condemnation around, you know, the 2018 when the Chinese researcher He Jankui, I think I said it correctly.Yep.Kevin Davies: He Jankui is how I say it. Close. Harry Glorikian: He announced that he had created twin baby girls with edits to their genomes that were intended to make them immune to HIV, which sort of like—that already made me go, what? But the experiment was, it seems, unauthorized. It seems that, from what I remember, the edits were sloppy and the case spurred a huge global discussion about the ethics of using CRISPR to make edits that would be inherited by future generations. Now, where are we in that debate now? I mean, I know the National Academy of Sciences published a list of criteria, which said, don't do that. Kevin Davies: It was a little more nuanced than that. It wasn't don't do that. It was, there is a very small window through which we could move through if a whole raft of criteria are met. So they, they refuse to say hereditary genome editing should be banned or there should be a moratorium. But they said it should not proceed until we do many things. One was to make sure it is safe. We can't run before we can walk. And by that, I mean, we've got to first demonstrate—because shockingly, this hasn't been done yet—that genome editing can be done safely in human embryos. And in the last 18 months there've been at least three groups, arguably the three leading groups in terms of looking at genetic changes in early human embryos, Kathy Niakan in London, Shoukhrat Mitalipov in Oregon, and Dieter Egli in New York, who all at roughly the same time published and reports that said, or posted preprints at least that said, when we attempt to do CRISPR editing experiments in very early human embryos, we're seeing a mess. We're seeing a slew of off-target and even on-target undesirable edits.And I think that says to me, we don't completely understand the molecular biology of DNA repair in the early human embryo. It may be that there are other factors that are used in embryogenesis that are not used after we're born. That's speculation on my part. I may be wrong. But the point is we still have a lot to do to understand, even if we wanted to.And even if everybody said, “Here's a good case where we should pursue germline editing,” we've gotta be convinced that we can do it safely. And at the moment, I don't think anybody can say that. So that's a huge red flag.But let's assume, because I believe in the power of research, let's assume that we're going to figure out ways to do this safely, or maybe we say CRISPR isn't the right tool for human embryos, but other tools such as those that we've touched on earlier in the show base editing or prime editing, or maybe CRISPR 3.0 or whatever that is right now to be published somewhere. [Let's say ] those are more safe, more precise tools. Then we've got to figure out well, under what circumstances would we even want to go down this road? And the pushback was quite rightly that, well, we already have technologies that can safeguard against families having children with genetic diseases. It's called IVF and pre-implantation genetic diagnosis. So we can select from a pool of IVF embryos. The embryos that we can see by biopsy are safe and can therefore be transplanted back into the mother, taken to term and you know, a healthy baby will emerge.So why talk about gene editing when we have that proven technology? And I think that's a very strong case, but there are a small number of circumstances in which pre-implantation genetic diagnosis will simply not work. And those are those rare instances where a couple who want to have a biological child, but have both of them have a serious recessive genetic disease. Sickle cell would be an obvious case in point. So two sickle cell patients who by definition carry two copies of the sickle cell gene, once I have a healthy biological child preimplantation genetic diagnosis, it's not going to help them because there are no healthy embryos from whatever pool that they produce that they can select. So gene editing would be their only hope in that circumstance. Now the National Academy's report that you cited, Harry, did say for serious diseases, such as sickle cell and maybe a few others they could down the road potentially see and condone the use of germline gene editing in those rare cases.But they're going to be very rare, I think. It's not impossible that in an authorized approved setting that we will see the return of genome editing, but that's okay. Of course you can can issue no end of blue ribbon reports from all the world's experts, and that's not going to necessarily prevent some entrepreneur whose ethical values don't align with yours or mine to say, “You know what, there's big money to be made here. I'm going offshore and I'm going to launch a CRISPR clinic and you know, who's going to stop me because I'll be out of the clutches of the authorities.” And I think a lot of people are potentially worried that that scenario might happen. Although if anyone did try to do that, the scientific establishment would come down on them like a ton of bricks. And there'll be a lot of pressure brought to bear, I think, to make sure that they didn't cause any harm.Harry Glorikian: Yeah. It's funny. I would like to not call them entrepreneurs. I like entrepreneurs. I'd like to call them a rogue scientist. Kevin Davies: So as you say, there's the third section of four in Editing Humanity was all about the He Jankui debacle or saga. I had flown to Hong Kong. It's a funny story. I had a little bit of money left in my travel budget and there were two conferences, one in Hong Kong and one in China coming up in the last quarter of 2018. So I thought, well, okay, I'll go to one of them. And I just narrowed, almost a flip of a coin, I think. Okay, let's go to the Hong Kong meeting.It's a bioethics conference since I don't expect it to be wildly exciting, but there are some big speakers and this is an important field for the CRISPR Journal to monitor. So I flew there literally, you know, trying to get some sleep on the long flights from New York and then on landing, turn on the phone, wait for the new wireless signal provider to kick in. And then Twitter just explode on my feed as this very, very astute journalists at MIT Technology Review, Antonio Regalado, had really got the scoop of the century by identifying a registration on a Chinese clinical trial website that he and only he had the foresight and intelligence to sort of see. He had met He Jankui in an off the record meeting, as I described in the book, about a month earlier. A spider sense was tingling. He knew something was up and this was the final clue. He didn't know at that time that the Lulu and Nana, the CRISPR babies that you mentioned, had actually been born, but he knew that there was a pregnancy, at least one pregnancy, from some of the records that he'd seen attached to this registration document. So it was a brilliant piece of sleuthing. And what he didn't know is that the Asociated Press chief medical writer Marilynm Marchion had confidentially been alerted to the potential upcoming birth of these twins by an American PR professional who was working with He Jankui in Shenzhen. So she had been working on an embargoed big feature story that He Jankui and his associates hoped would be the definitive story that would tell the world, we did this quote unquote, “responsibly and accurately, and this is the story that you can believe.” So that story was posted within hours.And of course the famous YouTube videos that He Jankui had recorded announcing with some paternal pride that he had ushered into the world these two gene edited, children, screaming and crying into the world as beautiful babies I think was [the phrase]. And he thought that he was going to become famous and celebrated and lauded by not just the Chinese scientific community, but by the world community for having the ability and the bravery to go ahead and do this work after Chinese researchers spent the previous few years editing human embryos. And he was persuaded that he had to present his work in Hong Kong, because he'd set off such a such an extraordinary firestorm. And I think you've all seen now you're the clips of the videos of him nervously walking onto stage the muffled, the silence, or the only sound in the front row, the only sound in the big auditorium at Hong Kong university—[which] was absolutely packed to the rim, one side of the auditorium was packed with press photographers, hundreds of journalists and cameras clicking—and the shutters clattering was the only, that was the applause that he got as he walked on stage.And to his credit, he tried to answer the questions directly in the face of great skepticism from the audience. The first question, which was posed by David Liu, who had traveled all the way there, who just asked him simply, “What was the unmet medical need that you are trying to solve with this reckless experiment? There are medical steps that you can do, even if the couple that you're trying to help has HIV and you're trying to prevent this from being passed on. There are techniques that you can use sperm washing being one of them. That is a key element of the IVF process to ensure that the no HIV is transmitted.”But he was unable to answer the question in terms of I'm trying to help a family. He'd already moved out and was thinking far, far bigger. Right? And his naiveté was shown in the manuscript that he'd written up and by that point submitted to Nature, excerpts of which were leaked out sometime later.So he went back to Shenzhen and he was put under house arrest after he gave that talk in Hong Kong. And about a year later was sentenced to three years in jail. And so he's, to the best of my knowledge that's where he is. But I often get asked what about the children? As far as we know, there was a third child born about six months later, also gene-edited. We don't even know a name for that child, let alone anything about their health. So one hopes that somebody in the Chinese medical establishment is looking after these kids and monitoring them and doing appropriate tests. The editing, as you said, was very shoddily performed. He knocked out the gene in question, but he did not mimic the natural 32-base deletion in this gene CCR5 that exists in many members of the population that confers, essentially, HIV resistance. So Lulu and Nana on the third child are walking human experiments, sad to say. This should never have been done. Never should have been attempted. And so we hope that he hasn't condemned them to a life of, you know, cancer checkups and that there were no off-target effects. They'll be able to live, hopefully, with this inactivated CCR5 gene, but it's been inactivated in a way that I don't think any, no other humans have ever been recorded with such modifications. So we, we really hope and pray that no other damage has been done. Harry Glorikian: So before we end, I'd love to give you the chance to speculate on the future of medicine in light of CRISPR. Easy, fast, inexpensive genome sequencing, give us access to everybody's genetic code, if they so choose. Machine learning and other forms of AI are helping understand the code and trace interactions between our 20,000 genes. And now CRISPR gives us a way to modify it. So, you know, it feels like [we have] almost everything we need to create, you know, precise, targeted, custom cures for people with genetic conditions. What might be possible soon, in your view? What remaining problems need to be solved to get to this new area of medicine? Kevin Davies: If you know the sequence that has been mutated to give rise to a particular disease then in principle, we can devise a, some sort of gene edit to repair that sequence. It may be flipping the actual base or bases directly, or maybe as we saw with the first sickle cell trial, it's because we understand the bigger genetic pathway. We don't have to necessarily go after the gene mutation directly, but there may be other ways that we can compensate boost the level of a compensating gene.But I think we, we should be careful not to get too carried away. As excited as I am—and hopefully my excitement comes through in Editing Humanity—but for every company that we've just mentioned, you know, you can go on their website and look at their pipeline. And so Editas might have maybe 10 diseases in its cross hairs. And CRISPR [Therapeutics] might have 12 diseases. And Intellia might have 14 diseases and Graphite has got maybe a couple. And Beam Therapeutics has got maybe 10 or 12. And Prime Medicine will hasn't listed any yet, but we'll hopefully have a few announced soon. And so I just reeled off 50, 60, less than a hundred. And some of these are gonna work really, really well. And some are going to be either proven, ineffective or unviable economically because the patient pool is too small. And we've got, how many did we say, 6,000 known genetic diseases. So one of the companies that is particularly interesting, although they would admit they're in very early days yet, is Verve Therapeutics. I touched on them earlier because they're looking at to modify a gene called PCSK9 that is relevant to heart disease and could be a gene modification that many people might undergo because the PCSK9 gene may be perfectly fine and the sequence could be perfectly normal, but we know that if we re remove this gene, levels of the bad cholesterol plummet, and that's usually a good thing as far as heart management goes. So that's an interesting, very interesting study case study, I think, to monitor over the coming years, because there's a company looking at a much larger patient pool potentially than just some of these rare syndromes with unpronounceable names. So the future of CRISPR and gene editing is very bright. I think one of the lessons I took away from CRISPR in Editing Humanity is, looking at the full story, is how this technology, this game-changing gene-editing technology, developed because 25 years ago, a handful of European microbiologists got really interested in why certain microbes were thriving in a salt lake in Southeastern Spain. This is not exactly high-profile, NIH-must-fund-this research. There was a biological question that they wanted to answer. And the CRISPR repeats and the function of those repeats fell out of that pure curiosity, just science for science's sake. And so it's the value of basic investigator-driven, hypothesis-driven research that led to CRISPR being described and then the function of the repeats.And then the story shifted to a yogurt company in Europe that was able to experimentally show how having the right sequence within the CRISPR array could safeguard their cultures against viral infection. And then five years of work people in various groups started to see, were drawn to this like moths to a flame. Jennifer Doudna was intrigued by this from a tip-off from a coffee morning discussion with a Berkeley faculty colleagues, Jill Banfield, a brilliant microbiologist in her own. And then she met meets Emmanuelle Charpentier in Puerto Rico at a conference, and they struck up a friendship and collaboration over the course of an afternoon. And that, why should that have worked? Well, it did, because a year later they're publishing in Science. So it's serendipity and basic research. And if that can work for CRISPR, then I know that there's another technology beginning to emerge from somewhere that may, yet trump CRISPR.And I think the beauty of CRISPR is its universal appeal. And the fact is, it's drawn in so many people, it could be in Japan or China or South Korea or parts of Europe or Canada or the U.S. or South America. Somebody is taking the elements of CRISPR and thinking well, how can we improve it? How can we tweak it?And so this CRISPR toolbox is being expanded and modified and updated all the time. So there's a hugely exciting future for genome medicine. And you know, whether it's a new form of sequencing or a new form of synthetic biology, you know, hopefully your show is going to be filled for many years to come with cool, talented, young energetic entrepreneurs who've developed more cool gadgets to work with our genome and other genomes as well. We haven't even had time to talk about what this could do for rescuing the wooly mammoth from extinction. So fun things, but maybe, maybe another time. Harry Glorikian: Excellent. Well, great to have you on the show. Really appreciate the time. I hope everybody got a flavor for the enormous impact this technology can have. Like you said, we talked about human genome, but there's so many other genomic applications of CRISPR that we didn't even touch. Kevin Davies: Yup. Yup. So you have to read the book. Harry Glorikian: Yeah. I will look forward to the next book. So, great. Thank you so much. Kevin Davies: Thanks for having me on the show, Harry. All the best.Harry Glorikian: Take care.Harry Glorikian: That's it for this week's show. You can find past episodes of MoneyBall Medicine at my website, glorikian.com, under the tab “Podcast.” And you can follow me on Twitter at hglorikian.  Thanks for listening, and we'll be back soon with our next interview.

Check out our sponsors: Better Help: Get 10% off your first month at https://betterhelp.com/impacttheory Butcher Box: Go to butcherbox.com/IMPACT Get 2 five-ounce lobster tails and 2 ten-ounce ribeye steaks all FREE in your first box. Upstart: UPSTART.com/IMPACT Magic Mind: Go to Magicmind.co and use promo code IMPACT to get 20% OFF. Ladder: Go to LadderLife.com/impacttheory You are living through exciting and strange times. There are so many technological advances with AI, space travel, NFTs, and a rapidly changing culture with social media, it's near impossible to just turn ‘off'. Let's admit it, FOMO is real and it keeps a lot of people connected when they're not even sure why they're connected. When was the last time you unplugged and took on a challenge you weren't sure you'd complete? How long has it been since you've sat with yourself in total silence or allowed yourself to just be bored out of your mind? Author and journalist, Michael Easter, joins me today to discuss his journey and share the lessons and insights he's gained from spending a month in the Arctic surviving. Hunting his own food, carrying heavy loads, and sitting with absolute boredom are just part of his story. As you listen to his story, it is my hope you will consider ways you step out of your comfort zone. There is something very freeing about being able to shake things up and break your routines and habits to improve the quality of your life in unconventional ways. This episode is about facing discomfort and finding new ways to challenge yourself for the better.   Order Michael Easter's new book, The Comfort Crisis - https://amzn.to/3ihebjB   SHOW NOTES: 0:00 | Introduction to Michael Easter 1:05 | The Comfort Crisis Explained 3:02 | Journey to the Arctic 5:03 | Recovering from Alcohol 7:40 | Outside the Comfort Zone 8:55 | Helicopter Parenting Losing Challenges 12:16 | Touching Controversial Topics 14:53 | Challenges Surviving the Arctic 20:11 | Problem Creep 28:05 | Need for Rite of Passage 35:12 | Metaphorical Lions for Passage 41:19 | Comfort Creep & Habits 44:22 | Breaking Routine to be Present 47:45 | Discomfort and Boredom 50:00 | Benefits of Boredom 57:12 | Daily Routine 1:02:11 | Rucking & Human Design 1:14:05 | Killing His 1st Caribou 1:17:16 | Life Cycle & Mortality 1:27:16 | “This Too Shall Pass” 1:30:31 | Want to Live Forever? 1:39:12 | Assigning Meaning to Life 1:42:20 | Rites of Passage Transformation 1:46:12 | Problem Creep Comparison 1:50:34 | Finding Gratitude   QUOTES: “By never putting yourself in a position where you are uncomfortable, whether that is physically or mentally or with, what you think to be true? You're not gonna, you're not gonna learn anything about yourself.” [7:41]   “As humans face fewer and fewer problems in our lives, we don't actually experience fewer problems. We just redefine what a problem is.” [22:50]   “If we never put ourselves in the position of true challenge, then we don't really learn something about ourselves” [40:26]   “The idea of trying to do new things, learn new things that totally shake up a routine. It's interesting, because now all of a sudden, I can't predict the future, and I've got to learn some new stuff, and this is forcing you into presence and focus,” [45:18]   “When you're bored, your brain actually goes inward, starts to sort of ruminate it, you sort of have these different thoughts that are more inward focus” [50:21]   “We don't realize how freaking amazing daily life is. It is unbelievable all this shit that we take for granted in our life every single day. We become unsatisfied with it, we look for the problems.” [1:50:36]   “If you look for the things that are joyful, and good and wonderful, then you're gonna see that and that frame of reference will color how you approach change.” [1:53:36]   Follow Michael Easter: Website: https://eastermichael.com/ Facebook: https://www.facebook.com/Michael-Easter-225875898170585 Instagram: https://www.instagram.com/michael_easter/?hl=en  

Journalist and author Michael Easter talks about his book The Comfort Crisis with EconTalk host Russ Roberts. Easter thinks modern life is too easy, too comfortable. To be healthy, he says, we need to move out of our comfort zones and every once in a while try to do something, especially something physically demanding, that we didn't think was possible. Easter discusses rising levels of anxiety and depression in the West and why taking on challenges can be part of the solution.