Episode 2: Eric Topol, multimodal AI models in medicine, and a glass of Merlot

Send us a textAndy and JC explore the murky world of cyberthreats to biopharma and biomanufacturing with Charles Fracchia, CEO of a Boston startup Black Mesa, currently in stealth mode and co-founder of BIO-ISAC, a BIO-Information Sharing and Analysis Center to educate about threat intelligence, vulnerability identification and mitigation strategies. Charles was previously CEO of BioBright, one of the first life science companies providing end-to-end encrypted data collection and analysis in the cloud.  The Spritz Veneziano (aka Aperol Spritz)Ingredients:2 Oz Aperol 3 Oz sparkling wine 1 Oz club soda. Directions: Add the ingredients to a large wine glass with plenty of ice, mix gently, and garnish with an orange wedge.  Amari that can replace the aperol:CampariAmaro noninoAmaro montenegroAvernaCheck out the resources on BIO-ISAC here: https://www.isac.bio/The Mixer music “Pour Me Another” courtesy of Smooth Moves!

Send us a texthttps://bit.ly/3YxRltJ. Andrew Lo, Charles E. & Susan T. Harris Professor of Finance and director of the Laboratory for Financial Engineering at the MIT Sloan School of Management, gives JC and Andy the skinny on his progress in finding new commercialization models for rare diseases. He also reveals plans on implementing his debt securitization megafund model, first described over a decade ago. Finally, he gives us some tips on how to prepare a delicious refreshing sparkling sake:1) Mio sparkling sake 1 bottle Mio sake1 freezerDIRECTIONS:From Andrew: "Store bottle of Mio at 58ºF (the recommended temperature of typical wine cellar). Move bottle to the freezer section of your refrigerator for about two hours before you're ready to consume it. The time is approximate, and depends on how cold your freezer is, so you may need to play around with this key parameter. After two hours, remove the bottle from the freezer; it should still be completely liquid inside (if it's partially frozen, you've kept it in too long and need to thaw it before opening). Assuming that the sake is completely liquid, twist open the bottle and QUICKLY POUR OUT A SERVING INTO YOUR GLASS. The reason you have to pour quickly is that the sake is sparkling, which means the carbonation creates pressure in the bottle. Once this pressure is released, the liquid starts to foam and the foam will freeze, clogging the bottle and making it impossible to pour out any liquid. By pouring it quickly, the foam forms in the class, yielding the desired frozen treat. The remaining liquid in the bottle is blocked by the frozen foam in the neck, but this will melt while you enjoy the first pour, and should be ready to be poured out in just a few minutes (though the foam won't be quite as thick in the second glass).This works best with Mio's individual 375ml bottles. It can be done with full 750ml bottles but it's hard to pour multiple glasses fast enough before the foam freezes in the neck (you have to line up your glasses and pour quickly in a straight line)." Sources mentioned in the podcast:Andrews new book:Andrew W Lo and Shomesh E Chaudhuri. Healthcare Finance (Princeton University Press, Princeton, 2023) Original paper describing megafund/securitization:Fernandez, JM et al. Commercializing biomedical research through securitization techniques. Nat Biotechnol 30, 964–975 (2012). https://doi.org/10.1038/nbt.2374 Paper describing methodology for assessing risk (likelihood of approval) of biomedical assets:Siah, KW et al. Predicting drug approvals: The Novartis data science and artificial intelligence challenge. Patterns 2, 100312 (August 13, 2021). EU approval of Agilis Biotherapeutics/PTC’s Upstaza AAV2 gene therapy for delivering dopa decarboxylase to patients with aromatic L-amino acid decarboxylase (AADC) deficiency. As AAAC deficiency has an incidence of about 1 per 1,000,000 live newborns (332 potential US patients every year), a billion dollar return could theoretically be obtained in three years...in practice though the challenge for PTC is to find those patients! The Mixer music “Pour Me Another” courtesy of Smooth Moves!

Send us a textAnne Wyllie, principal investigator at the Yale School of Public Health and pioneer of the Saliva Direct initiative, talks to JC and Andy about the potential of open and collaborative models to transform infectious disease diagnostics and pandemic preparedness.1) The Gin & Tonic 1 cup ice cubes2 Oz gin~4 Oz Schweppes Tonic Water1 slice Lime/lemonDIRECTIONS:Pour 2 Oz gin into your favorite glass, ideally a large goblet full of ice, as shown. Top with ~4 Oz tonic water, mix gently, and garnish with lime or lemon. 2) The Mediterranean Gin & Tonic1 cup ice cubes1.5 Oz Gin Mare (Spanish Gin)0.5 Oz Dry Vermouth0.5 Oz Sweet Vermouth~4 Oz Fever Tree Tonic water1 sprig Thyme1 slice Lime/lemon Fill your favorite glass with ice. Pour 1.5 Oz Gin Mare (Spanish gin), 0.5 Oz dry vermouth, 0.5 Oz sweet vermouth. Top with ~4 Oz Fever Tree Mediterranean Tonic and mix gently. Garnish with thyme and lime/lemon. Sources mentioned in the podcast:Paper comparing saliva test to nasal/nasopharyngeal test: Overmeire, Y et al. Equivalence of Saliva RT-qPCR Testing to Nasal-throat/Nasopharyngeal Swab Testing in the General Practitioner’s Setting to Detect SARS-CoV-2. J. Pediatr, Perinatol. Child Health 6, 042-053 (2022). doi: 10.26502/jppch.74050089 CDC COVID-19 testing guidelines (now including saliva) The COVID-19 testing debacle Nat Biotechnol 38 653 (2020) Saliva Direct and its test Emergency Use Authorization BBC News story on kids adding soda to get false positives in COVID-19 tests The Mixer music “Pour Me Another” courtesy of Smooth Moves!

Send us a textVeronique  Kiermer,  Chief Scientific Officer and Executive  Editor  at  the  Public  Library  of  Science, talks about the myriad ways in which open science is changing the face of research and some of the challenges it poses for AI and the translational arena.  01:55 What is open science?03:55 What are barriers to openness?07:28 Early adopters10:30 Open challenges for AI11:35 Registered reports and publication bias14:20 PLOS’ priorities for open science18:40 The Open Science Village beyond data access and sharing24:25 Reproducibility and reuse in drug research27:30 Can biotech companies be as open as pharma?29:44 Pre-competitive consortia for rare disease  32:14 Moving the needle38:00 Professional data curators?39:53 Opening science around the world41:05 COVID-19, infectious disease and open science45:34 Veronique’s favorite tippleThe White Negroni1 Oz gin1 Oz Lillet Blanc1 Oz SuzeDIRECTIONS:Add ingredients to a mixing glass and stir over ice for 45 seconds. Strain over fresh ice in a rocks glass and garnish with a lemon peel.Sources mentioned in the podcastMehra, MR et al. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet (May 22, 2020) https://doi.org/10.1016/S0140-6736(20)31180-6).AlphaFold3—why did Nature publish it without its code? Nature 629, 728 (2024). Good question!Abramson J et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature (8 May 2024). Promoting reproducibility with registered reports. Nat Hum Behav 1, 0034 (2017). https://doi.org/10.1038/s41562-016-0034The Yale University Open Data Access (YODA) Project at the Center for Outcomes Research and Evaluation advocates for the responsible sharing of clinical research dataAll Trials  (https://www.alltrials.net/news/)Gordon, D.E., Jang, G.M., Bouhaddou, M. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583, 459–468 (2020).Nature’s podcast on Registered Reports: Nature's Take: Can Registered Reports help tackle publication bias?The Mixer music “Pour Me Another” courtesy of Smooth Moves!

Send us a textNathan Price, currently on leave from the Institute for Systems Biology in Seattle and Chief Scientific Officer at Thorne HealthTech, talks to JC and Andy about his data-driven approach to understanding health and predicting personal trajectories into disease as we age.03:24 What is scientific wellness?06:53 Correlates of scientific wellness15:45. Generating hypotheses18:40 Multimodal over unimodal data22:04. Biomarkers and individual disease trajectories28:00 How to intervene to maintain wellness?30:01 A new era for supplements?32:26 Single interventions versus combinations37:59 Racial background and lifestyle41:00 Digital twins, trial design and recruitment43:30 Mocktails and mojitosThe Mojito10–12 mint leaves and mint sprig 1 Oz simple syrup (50% sugar solution)2 Oz white rum 0.75 Oz freshly squeezed lime juice. ~1–2 Oz club sodaDIRECTIONS: Place the mint leaves in a shaker tin, add the syrup and gently muddle the leaves 10–12 times. Add the rum and freshly squeezed lime juice. Shake over ice for 15 seconds and double strain over fresh ice into a Collins glass. Top up with the club soda and mix gently. Slap a mint sprig to release the aromatic oils and add it as garnish. Sources mentioned in the podcastThe supposed Native American 'diabetes gene'. Newman, AS. Peace Rev. 12, 517-524 (2010)Todd Rose. The End of Average (HarperCollins, 2016). Can a biologist fix a radio? Lazebnik, Y. Cancer Cell 2, 172-182 (2002) https://www.cell.com/cancer-cell/pdf/S1535-6108(02)00133-2.pdfLancet Commission on risk factors for dementia: Livingston, G et al. Lancet 396, 413-446 (2020) https://www.thelancet.com/article/S0140-6736(20)30367-6/fulltextPrecision Medicine Approaches for Developing Combination Therapies for the Treatment and Prevention of Alzheimer's Disease (AD) and AD-Related Dementia, National Institute of Aging, December 4-5, 2023. Khullar, D How to die in good health. New Yorker (April 15, 2024)The Mixer music “Pour Me Another” courtesy of Smooth Moves!

Send us a textUCSD's  Dan Kaufman, an innovator in the field of induced pluripotent cell (iPSC)-derived natural killer cell therapies, talks to Andy and JC about the latest in allogeneic and autologous immune and regenerative cell therapies at the 2024 Keystone symposium on Emerging Cell Therapies.   02:55 Sourcing and expanding NK cells 05:59 Off-the-shelf versus self09:26. Clinical trials and manufacturing13:40. Stealth, immune cloaking and protein manufacture16:51. Safety, cost, availability and standardization  22:00. Stampede into autoimmune disease28:59. Neurological cell therapies and beyond33:30. Off the shelf and in vivo engineering 38:13. Commercialization headaches39:51. Dan’s drink The Manhattan:2 Oz rye whiskey, 1 Oz sweet vermouth, 2 dashes aromatic bitters. DIRECTIONS: Stir on ice for 45 sec and strain over a coupe glass. Garnish with a maraschino cherry.The Mixer music “Pour Me Another” courtesy of Smooth Moves!

Send us a textUPenn's  Kiran Musunuru, a human geneticist and practicing cardiologist who has pioneered the translation of gene- and base-editing approaches, talks to JC and Andy about the latest clinical results and modalities discussed at the 2024 Keystone symposium on Precision Genome Engineering.   4:07 Impacting patients6:44 In vivo editing in different liver diseases11:37 The FDA stance on programmable therapy19:41 Base-editors march into the clinic25:54 Multiplexing with base editors28:57 Reaching broader patient populations33:32 Investigator-initiated trials39:27 Prime and epigenetic editing44:34 Excitement around Bridge RNAs 47:15 Kiran’s mocktailBloody Mary 3 Ways4oz (120 ml) tomato juice1/2oz (15 ml) fresh lemon juice1/4oz (7 ml) Worcestershire sauce1/2 barspoon (3 ml) prepared horseradish, or to taste2 dashes Tabasco, or to tasteCelery stick, for garnishSalt and freshly ground pepperYour choice of pickled vegetables, skewered on a cocktail pick, for garnishDIRECTIONS: Add the tomato juice, lemon juice, Worcestershire, horseradish, and Tabasco to a shaker tin with ice and gently shake for 5 seconds.  Strain into a chilled double rocks glass over a large ice cube. Garnish with the celery stick, salt, pepper, and pickled vegetables and serve. For alcoholophiles, add 2oz (60 ml) vodka to the tomato juice, lemon, Worcestershire, horseradish and Tabasco. Enjoy!Refs:Gilmore et al. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N Engl J Med 385, 493-502 (2021) DOI: 10.1056/NEJMoa2107454Chiesa et al . Base-edited CAR7 T cells for relapsed T-cell acute lymphoblastic leukemia.  N Engl J Med 389, 899-910 (2023) DOI: 10.1056/NEJMoa2300709 Longhurst et al. CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema N Engl J Med 390, 432-441 (2024) DOI: 10.1056/NEJMoa2309149Durrant et al. Bridge RNAs direct modular and programmable recombination of target and donor DNA.  https://www.biorxiv.org/content/10.1101/2024.01.24.577089v1Keystone Meeting on Precision Genome EngineeringSomatic Cell Genome Editing ConsortiumThe Mixer music “Pour Me Another” courtesy of Smooth Moves!

Send us a textScripps' Eric Topol is a visionary in the application of artificial intelligence to medicine.  He has a wide-ranging conversation with JC and Andy about : 02:52 Multimodal AI is coming06:44 FDA-approved AI software10:02 How to validate AI models?12:50 Synthetic doctor’s notes and other early applications15:38 Thinking about the model and its training19:28 Dealing with hallucination and GPT524:13 Low-to-middle income countries 27:40 Uptake by the medical community29:15 Open or proprietary?35:46 What to do with the data?39:46 Eric’s elixir1) His September 2023 Science editorial,2) Derma Sensor.  3) Wowser package AMIE (Articulate Medical Intelligence Explorer) a descendant of MedPalm 2 4) A recent Science essay on diagnoses. Eric’s Elixir: Pinot Noir!Marimar Mas Cavalls Pinot Noir 2018 from Russian River Valley, CA, USA.Cristom Marjorie Vineyard Pinot Noir 2021 from Villamette Valley, OR, USARacines Pinot Noir Santa Rita Hills 2017 from Santa Rita Hills, CA, USAThe Mixer music “Pour Me Another” courtesy of Smooth Moves!

Send us a textPete Kirkpatrick,  Chief  Editor of  Nature  Reviews  Drug  Discovery, gives Andy and JC the lowdown on a  Nature Conference  on RNA  therapeutics and what innovations he is seeing in the field of mRNA therapies.01:44 Nature conference on RNA therapies08:11 Differences between mRNA therapeutics and mRNA vaccines14:24 mRNA chemistries18:08 mRNA manufacturing22:05 mRNA delivery27:21 Delivering LNPs to organs other than liver34:25 Targeting RNA with small molecules39:35  RNA-guided CRISPR, base and prime editing therapies48:35 Pete’s tipplePete's tipple of choice: Expresso Martini1.5 Oz vodka, 1 Oz coffee liqueur, 1.5 Oz espresso.Shake over large ice cubes for 10-12 sec and strain into a Martini glass. Garnish with roasted coffee beans.(N.B. Ideally, 1.5 Oz of espresso should come from ~20 g of ground coffee.)The Mixer music “Pour Me Another” courtesy of Smooth Moves!