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What are the fundamental principles that govern the physical world around us, and how did we get to them? In this episode, Bio Eats World hosts Hanne Winarsky and Lauren Richardson talk to Nobel prize-winning physicist Frank Wilczek about the essential principles of modern physics that have built our understanding of the world. Wilczek (who won the Nobel in 2004 for the discovery of asymptotic freedom in the theory of the strong interaction) dives into not just the principles of physics themselves—around space, time, fields, energy, and the laws that govern them—but the key intellectual driver that brought us to them, which he calls "radical conservatism", or the idea of pushing every theory to its limit. In this wide-ranging, philosophical conversation, Wilczek tells the stories of how certain key theories moved from ideas to principles, from cosmology to complementarity; how the complexity of biology arises from the simplicity of physics; what lead to the discovery of dark matter and axions; whether time can be reversed; what the future of the universe might look like; but most of all, how we as humans attempt to understand the beautiful, complicated world around us.

David Olson, Ph.D, Assistant Professor at the University of California, Davis, joins host Lauren Richardson to discuss the results and implications of the article "A non-hallucinogenic psychedelic analogue with therapeutic potential" by Lindsay P. Cameron, Robert J. Tombari, Ju Lu, Alexander J. Pell, Zefan Q. Hurley, Yann Ehinger, Maxemiliano V. Vargas, Matthew N. McCarroll, Jack C. Taylor, Douglas Myers-Turnbull, Taohui Liu, Bianca Yaghoobi, Lauren J. Laskowski, Emilie I. Anderson, Guoliang Zhang, Jayashri Viswanathan, Brandon M. Brown, Michelle Tjia, Lee E. Dunlap2, Zachary T. Rabow, Oliver Fiehn, Heike Wulff, John D. McCorvy, Pamela J. Lein, David Kokel, Dorit Ron, Jamie Peters, Yi Zuo & David E. Olson, published in Nature.

Genetic testing is on the cusp of a major revolution, which has the potential to shift not just how we understand our risk for disease, but how we practice healthcare. In the clinic today, genetic testing is used only in cases where we know that mutations have big impact on physiology (BRCA mutations in breast cancer, for example). But our knowledge of how our genetics influences our risk for disease has evolved, and we now know that many (tens of thousands to even millions) small changes in our genes, each of which individually has a tiny effect, combine to influence our risk profile. This new appreciation — coupled with powerful statistical methods and massive datasets — has fueled the creation of a new tool to quantify the risk of a broad range of common diseases: the polygenic risk score. On this episode, host Lauren Richardson (@lr_bio) is joined by Dr. Peter Donnelly, (@genemodeller Professor of Statistical Science at the University of Oxford and the CEO of Genomics PLC,) and Vineeta Agarwala, (@vintweeta physician-scientist and general partner at a16z), to discuss these scores and how they can reshape healthcare, away from a paradigm of treating illness and towards prevention and maintenance of health.

Dr. Willem Mulder is a Professor at the Icahn School of Medicine at Mt. Sinai, Eindhoven University of Technology, and  Radboud University Medical Center and is a co-founder of Trained Therapeutix Discovery. He joins host Lauren Richardson to discuss the results and implications of the article "Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition" by Bram Priem, Mandy M.T. van Leent, Abraham J.P. Teunissen, Alexandros Marios Sofias, Vera P. Mourits, Lisa Willemsen, Emma D. Klein, Roderick S. Oosterwijk, Anu E. Meerwaldt, Jazz Munitz, Geoffrey Pre ́vot, Anna Vera Verschuur, Sheqouia A. Nauta, Esther M. van Leeuwen, Elizabeth L. Fisher, Karen A.M. de Jong, Yiming Zhao, Yohana C. Toner, Georgios Soultanidis, Claudia Calcagno, Paul H.H. Bomans, Heiner Friedrich, Nico Sommerdijk, Thomas Reiner, Raphae ̈l Duivenvoorden, Eva Zupancic, Julie S. Di Martino, Ewelina Kluza, Mohammad Rashidian, Hidde L. Ploegh, Rick M. Dijkhuizen, Sjoerd Hak, Carlos Pe ́ rez-Medina, Jose Javier Bravo-Cordero, Menno P.J. de Winther, Leo A.B. Joosten, Andrea van Elsas, Zahi A. Fayad, Alexander Rialdi, Denis Torre, Ernesto Guccione, Jordi Ochando, Mihai G. Netea, Arjan W. Griffioen, and Willem J.M. Mulder, published in Cell. For more on the innate immune system, also check out "Journal Club: Why do only some people get severe COVID-19?" and "Journal Club: How to Win an Evolutionary Arms Race"

For more on brain organoids and their many applications, check out this episode of Journal Club: "Modeling Mysterious Brain Structures." Host Lauren Richardson talks to Dr. Madeline Lancaster, a Group Leader at the MRC Laboratory of Molecular Biology in Cambridge, about her lab's article in Science describing an organoid model for studying the cerebrospinal fluid and the choroid plexus, and how these organoids can be used to study brain development, evolution, and improve the drug development process.

Dr. Helen Su, Chief of the Human Immunological Diseases Section at the National Institute of Allergy and Infectious Diseases (part of the NIH) and co-leader of the COVID Human Genetic Effort, joins host Lauren Richardson to discuss the results and implications of the articles "Inborn errors of type I IFN immunity in patients with life-threatening COVID-19"  and "Autoantibodies against type I IFNs in patients with life-threatening COVID-19", both published in Science. 

Building a software company in healthcare is hard—and comes along with unique challenges no other entrepreneurs face. In this conversation, a16z bio general partner (and previous founder of genomics company Knome) Jorge Conde; and a16z bio partner and former founder Julie Yoo (of patient provider matching system, Kyruus) share their mistakes and hard earned lessons learned with Bio Eats World host Hanne Winarsky in this now classic episode, first aired on the a16z Podcast. Why is this so damn hard? How should founders think about this space differently? What are the specific things that healthcare founders can do—when, where, and why? You wish you only knew all this when you started your own company.

A year ago, none of us would believe that mRNA vaccines would be a household name. And yet here we are, at the end of 2020, counting the days towards a vaccine that could not just save lives but help bring us back into a world that feels “normal” again. In this special episode, airing the day the FDA authorized the vaccine for emergency use, Moderna CEO Stephane Bancel tells the story of not just the vaccine’s development, but the machine that made the vaccine: the platform, the technology, and the moves behind the vaccine’s development. This episode of Bio Eats World takes us from a world of pipette and lab benches to a world of industrial robots making medicines: We used to grow our vaccines, now we can “print” them, getting them to patients faster and more efficiently than ever before. In conversation with a16z general partner Jorge Conde and Bio Eats World host Hanne Winarsky, Bancel describes the exact moment he realized they might actually be able to make a vaccine for Covid-19; what happened next to go from pathogen to design; how this new technology that uses mRNA works (in a chocolate mousse metaphor!), and what makes it different from “old” vaccines; and how to think about managing both innovation and speed in this world. Why is this such a fundamental shift in the world of drug development? And where will this technology go next?

with @pmarca and @vijaypande How come things like healthcare, education, and housing get more and more expensive, but things like socks, shoes, and electronics all get cheaper and cheaper? In this episode of Bio Eats World, a16z founder and internet pioneer Marc Andreessen, and General Partner Vijay Pande, discuss the lesser known law of economics that explains why healthcare, education and housing is so damn expensive, and getting worse. What’s really at heart is tech’s ability to transform (expensive) services into (affordable) goods: think of the cost of a live string quartet, versus a streamed recorded track; or the cost of a custom-made shoe, versus a factory-made one. Until now, using tech to similarly transform services into goods in healthcare has seemed like an impossible dream — how would you do this for, say, the service of doctors providing care? But in this wide ranging conversation all about technology and society across all industries, Andreessen and Pande talk about the massive new gains recent technologies have begun to make this seem within reach, from eye surgery in malls to using AI in processing medical claims. Is there a future in which what doctors are doing today feels analogous to farmers hand plowing fields 300 years ago? And what would the role of that doctor of the future be?

Harmit Malik, PhD (Professor and Associate Director of the Basic Sciences Division at the Fred Hutchinson Cancer Research Center) joins host Lauren Richardson to discuss the results and implications of the article "Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races", by Jeannette L Tenthorey, Candice Young, Afeez Sodeinde, Michael Emerman, and Harmit S Malik,  published in eLife.

You don't have to build a million planes to test a million aeronautical designs; we have mathematical simulations and models that do that for us. But in biology—once the class you'd take in high school if you loved science, but hated math—that's been impossible... until very recently. In this episode, Markus Covert, Professor of Bioengineering at Stanford, a16z deal partner Judy Savitskaya, and Bio Eats World host Hanne Winarsky, talk all about where we are in our ability to simulate and build models for how biology works. Because biology has been so qualitative in the past, and so complex, it's been extremely difficult to translate samples that are, say, gel smudges on a plate into the kind of qualitative data we need for these simulations and models. But we're finally reaching the “Google Maps” moment in biology, Covert says, beginning to be able to build models at the single molecule level, of genetic circuits, whole cells, the dynamic interactions between different cells, map them onto larger networks like tissue… even, of course, model on a global level the effects of a pandemic. The conversation covers Marcus’ story of the Eureka moment behind the first whole cell model; what this new ability to simulate and model will allow us to understand and predict that we haven’t been able to before; and why it all matters—how these tools are bringing us into a new era of designing new functionalities, even new kinds of biological life.

Anthony Atala, MD (the G. Link Professor and Director of the Wake Forest Institute for Regenerative Medicine, and the W. Boyce Professor and Chair of Urology), joins host Lauren Richardson to discuss the results and implications of the article "A tissue-engineered uterus supports live births in rabbits" published in Nature Biotechnology.

Descriptions of the mental illness we today call schizophrenia are as old as humankind itself. And more than likely, we are are all familiar with this disease in some way, as it touches 1% of us—millions of lives—and of course, their families. In this episode, we dive into the remarkable story of one such American family, the Galvins: Mimi, Don, and their 12 children, 6 of whom were afflicted with schizophrenia. In his book, Hidden Valley Road: Inside the Mind of an American Family, Robert Kolker follows the Galvins from the 1950s to today—through, he writes, “the eras of institutionalization and shock therapy, the debates between psycho-therapy versus medication, the needle-in-a-haystack search for genetic markers for the disease, and the profound disagreements about the cause and origin of the illness itself.” Because of that, this is really more than just a portrait of one family; it’s a portrait of how we have struggled over the last decades to understand this mysterious and devastating mental illness: the biology of it, the drivers, the behaviors and pathology, the genomics, and of course the search for treatments that might help, from lobotomies to ECT to thorazine. Also joining Robert Kolker and a16z’s Hanne Winarsky in this conversation is Stefan McDonough, Executive Director of Genetics at Pfizer World R&D, one of the genetic researchers who worked closely with the Galvins. The conversation follows the key moments where our understanding of this disease began to shift, especially with new technologies and the advent of the Human Genome Project—and finally where we are today, and where our next big break might come from.

We all know that eating healthy is better for you—and that following that advice is far harder than it sounds, for a multitude of reasons, from culture to preferences to access and affordability. And yet the reality is that access to good, nutritious food is perhaps the most powerful medical treatment we have, when it comes not just preventing sickness, but helping sick people get better—and potentially saving the healthcare system potentially billions in treating chronic disease. So what happens if we begin to treat food truly as a medicine in the healthcare system? How can we really implement this "medicine" into the healthcare system? What are the different approaches, from food delivery to packaging to the content of the meal itself? How can food as a medicine be distributed, paid for and reimbursed, and what role can technology take in increasing access, distribution, and more? In this conversation, a16z General Partner Julie Yoo talks with Dr. Andrea Feinberg, previously the Founder and Medical Director of Geisinger Fresh Food Farmacy and Josh Hix, entrepreneur and co-founder of the food delivery start up Plated; a16z all about what food as a medicine might look like, whether personal taste and variety matters, how technology might not just help access but shift our snacking tendencies towards health, and the enormous opportunity to impact chronic disease through addressing food insecurity.

Vineeta Agarwala, physician and a16z general partner, and host Lauren Richardson discuss the Nature article "Evidence for 28 genetic disorders discovered by combining healthcare and research data", its key implications, and how this work can impact patients and parents.  

Imagine if the airline industry did not post prices for flights in advance. What if instead of posting fares on travel sites, airlines argued they could only bill you after the flight, because they didn't know what the fuel price will be that day; whether or not you would consume a beverage; if the flight might be diverted or delayed; whether that pilot would have to work harder and bill more in their coding of the flight after they land? And yet, this is exactly what happens in healthcare. Despite the cost crisis in healthcare, we still don't talk about prices—prices for procedures, for visits, for services. But in January 2021, thanks to new regulation, that will change. In this episode, a16z General Partner Julie Yoo talks with Dr. Marty Makary, surgical oncologist at Johns Hopkins University School of Medicine, health policy expert—and a longtime advocate for transparent pricing in the healthcare system. Makary argues that making prices obvious will change all kinds of behaviors in the healthcare system, not just allowing consumers to "shop" for the best value of different healthcare services, but will drive higher quality standards; minimize things like surprise billing and incentives towards volume; increase the rigor of analyzing the medical appropriateness of certain clinical decisions (do we need this elective procedure or not? is it good longterm value?); affect even how we choose our doctors; and much more.

Type 1 Diabetes is an autoimmune disease with no cure and challenging treatment regimes. The disease is characterized by self-reactive immune cells that attack and destroy cells in the pancreas that produce insulin and are essential for regulating metabolism, called beta cells.Since the advent of stem cell technology, scientists have dreamed of curing Type 1 Diabetes by replacing the beta cells lost to disease with lab grown, stem cell-derived beta cells. However, it wasn't until recent work from Ronald Evans' lab at the Salk Institute that this dream started to become a reality. First, in 2016, Evans and colleagues identified a critical genetic switch needed to activate stem cell-derived beta cells. Second, in the article we discuss today, they figured out how to produce not just the beta cells from stem cells, but their entire cellular compartment, called the pancreatic islet. They call these synthetic islets HILOs (human islet-like organoids). Even more importantly, they devised a way to shield the HILOs from the immune system. This molecular shield, which they learned about from studying how pancreatic cancer cells evade the immune system, is the key to the long term survival of the HILOs despite this chronic autoimmune response.In this conversation, host Lauren Richardson and Dr. Evans cover these key breakthroughs, the next steps for moving this proof-of-concept research into the clinic, and how these HILOs might represent a curative treatment for this devastating and life-long condition. 

Healthcare is perhaps unique in that the entire system exists entirely to serve the patient... and yet, in many ways, that same patient is not the customer. In fact, the patient—and the patient's voice—can often be lost or overlooked in the enormous, complex, convoluted business flows, between a huge system of providers, in elaborate clinical work flows, in insurance coverage and reimbursements, or in high level policy debates. In this episode, a16z General Partner Julie Yoo and a16z partner Jay Rughani talk with Freda Lewis Hall—a physician; formerly Pfizer’s Chief Patient Officer and Chief Medical Officer; Chief Medical Officer at Vertex; and who among many other roles was appointed by the Obama Administration to the Board of the Patient-Centered Outcomes Research Institute (PCORI)—all about what happens when you rethink the entire healthcare system from the patient's point of view. We tell patients what they need, instead of asking them what they need—let alone listen to the answer. From drug development to healthcare delivery to clinical trials, what changes in our system when we think about everything from the patient’s perspective? How do we better understand what patients need, and better serve them? What tools and new approaches can we use to truly put the patient at the center of the healthcare system?

Mechanical forces and architecture may not sound very "bio", but they are key tools of epidermal stem cells.  These stem cells essentially engineer their environment by producing both the cells above them (the skin cells) and the extracellular matrix mesh (the basement membrane) that they sit on. In this episode we explore whether, when these stem cells acquire oncogenic mutations (the ones that cause cancer), do they now architect in a different way, and does this influence the development of cancer?Host Lauren Richardson and Professor Elaine Fuchs of Rockefeller University discuss her lab's recent Nature article "Mechanics of a multilayer epithelium instruct tumour architecture and function". The article investigates the differences in mechanical forces and tissue architecture in two distinct types of skin cancer: one that tends to be begin and non-invasive and one that tends to be aggressive and metastatic. The conversation covers how computational modeling played a critical role in uncovering new sources of forces and how changes in architecture influence invasive properties.

with @lifelikephysics, @vijaypande, and @omnivorousread Where does life truly begin? How do we understand the fundamental nature of what is “alive” and what is “not alive”? In this episode of Bio Eats World, Professor Jeremy England discusses his new book, Every Life is on Fire, all about how what we might use physics to understand to be the origins of life—and how we define what being alive is. As biologists, we are taught that life evolved as the result of Darwinian natural selection. But what happens if instead, you use a physicist’s lens to examine what life looks to be—and define it as a specialized order and relationship between matter and the patterns of it’s an environment? England—a senior director in artificial intelligence at GlaxoSmithKline, principal research scientist at Georgia Tech, former associate professor of physics at MIT, and one of Forbes’ “30 Under 30 Rising Stars of Science”—describes this new idea as “dissapative adaptation”. The conversation covers how looking at “life” in these terms changes what we understand to be alive and what the nature of "life" is; sheds new light on the “queasy middle ground” between those definitions, especially in areas like machine learning and AI; and allows us to ask new questions about things like what makes DNA so special, and what life can do.