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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, which originally aired on January 18, 2021, host Lauren Richardson (@lr_bio) is joined by 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. 

When it comes to healthcare, the topic of how expensive it is and what we can do to lower costs is always top of mind. One area with particularly steep costs is the emergency department. These are hospital departments that can take care of pretty much anything from a cut to a car wreck. But going to an emergency department for something as simple as a cut can result in a high bill for both the patient and the insurer. This is where the urgent care center comes in. Urgent care centers are walk-in clinics focused on caring for minor illnesses and injuries — or in medical speak — low acuity conditions. They are way less expensive than a trip to the emergency department, so funneling these low acuity visits from the emergency department to urgent care centers should result in lower healthcare costs… right? On today’s episode, host Lauren Richardson is joined by a16z general partner Vineeta Agawala and bio deal team member Justin Larkin (who are both medical doctors and experts in healthcare), to discuss new research published in the journal Health Affairs, examining this key assumption. The conversation covers the issues with care utilization and care navigation, how urgent care centers impact healthcare costs, and the implications of these results for builders in the digital health space. The article at the center of today's episode is: "Urgent Care Centers Deter Some Emergency Department Visits But, On Net, Increase Spending" by Bill Wang, Ateev Mehrotra, and Ari B. Friedman, published in Health Affairs.

If there is one rule in biology, it is that there is an exception to every rule. This includes even the basic biochemistry of DNA, which was once thought to be universal. On this episode, host Lauren Richardson and Judy Savitskaya (a16z bio deal team member and synthetic biology expert), discuss the results and implications three related articles co-published in Science, which all advance our understanding of a very unique kind of DNA. If you open any biology text book, it will say that the genetic code is made up of 4 bases: Adenine, Thymine, Cytosine, and Guanine, or ATCG. But, back in 1977, scientists discovered a phage — the technical term a virus that infects bacteria — that encodes its genome in ZTCG. Z is a derivative of A that has an extra amino group tagged on, and while that may sound minor, it changes some of the key properties of DNA. These three new articles seek to understand how Z is made and how it is incorporated into DNA. This is essential information for taking Z from a weird, wild bio story into a practical application. The conversation covers what makes Z different than other bases, what these three articles reveal about the synthesis and polymerization of Z, and how we can use use Z in a wide range of applications, from bio-containment to new therapeutics to DNA storage.The three articles discussed are:"A widespread pathway for substitution of adenine by diaminopurine in phage genomes" by  Yan Zhou, Xuexia Xu, Yifeng Wei, Yu Cheng, Yu Guo, Ivan Khudyakov, Fuli Liu, Ping He, Zhangyue Song, Zhi Li, Yan Gao, Ee Lui Ang, Huimin Zhao, Yan Zhang, and Suwen Zhao"A third purine biosynthetic pathway encoded by aminoadenine-based viral DNA genomes" by Dona Sleiman, Pierre Simon Garcia, Marion Lagune, Jerome Loc’h, Ahmed Haouz, Najwa Taib, Pascal Röthlisberger, Simonetta Gribaldo, Philippe Marlière, and Pierre Alexandre Kaminski"Noncanonical DNA polymerization by aminoadenine-based siphoviruses" by  Valerie Pezo, Faten Jaziri, Pierre-Yves Bourguignon, Dominique Louis, Deborah Jacobs-Sera, Jef Rozenski, Sylvie Pochet, Piet Herdewijn, Graham F. Hatfull, Pierre-Alexandre Kaminski, and Philippe Marliere 

This episode was recorded in March of 2019 to celebrate the 20th anniversary of Folding at Home, the distributed computing project for simulating protein dynamics, and originally aired on The a16z Podcast. Folding at Home is run on millions of devices, is the world’s largest supercomputer, and tackles some of biology’s toughest problems, including COVID-19.Proteins are molecular machines that must first assemble themselves to function. But how does a protein, which is produced as a linear string of amino acids, assume the complex three-dimensional structure needed to carry out its job? That's where Folding at Home comes in. Folding at Home is a sophisticated computer program that simulates the way atoms push and pull on each other, applied to the problem of protein dynamics, aka "folding". These simulations help researchers understand protein function and to design drugs and antibodies to target them. Given the extreme complexity of these simulations, they require an astronomical amount of compute power. Folding at Hold solves this problem with a distributed computing framework: it breaks up the calculations in the smaller pieces that can be run on independent computers. Users of Folding at Home — millions of them today — donate the spare compute power on their PCs to help run these simulations. This aggregate compute power represents the largest super computer in the world: currently 2.4 exaFLOPS!Folding at Home was launched in the lab of Vijay Pande at Stanford. In this episode, Vijay (now a general partner at a16z) is joined by his former student and current director of Folding at Home, Greg Bowman, an associate professor at Washington University in St. Louis, and host Lauren Richardson. The conversation covers the origins of the Folding at Home project and the scientific and technical advances needed to solve the complex protein folding and distributed computing problems.To find out more about how Folding at Home is contributing to the COVID-19 pandemic, check out the recenty published article from the Bowman lab, "SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome", published in Nature Chemistry.

On the path from scientific discovery to new drug, the clinical trial is a huge — and critical — hurdle. Clinical trials are themselves experiments, and to make sure that they are doing the best possible job at determining the safety and efficacy of the new drug, we need to be able to do experiments on those experiments. But how do you do that in such a highly regulated space? Host Lauren Richardson talks to James Zou, Assistant Professor of Biomedical Data Science at Stanford University, and a16z general partner Vineeta Agarwala, physician and expert on real world data in healthcare, about new research from the Zou lab that uses AI-powered simulations of clinical trials and real world patient data to understand how different designs influence trial outcomes. In particular, looking for designs that can make trials more inclusive, which is key for getting patients access to potentially life-saving care and for running trials efficiently. The conversation covers the inherited rules and assumptions governing which patients can participate in trials, how Dr. Zou, lead author Ruishan Liu, and colleagues combined real world data and computer simulations to challenge these assumptions via a data-driven approach, and how this can inform smarter trial design. The article at the center of today's episode is: "Evaluating eligibility criteria of oncology trials using real-world data and AI" by Ruishan Liu, Shemra Rizzo, Samuel Whipple, Navdeep Pal, Arturo Lopez Pineda, Michael Lu, Brandon Arnieri, Ying Lu, William Capra, Ryan Copping & James Zou, published in Nature.

They say you should never judge a book by its cover, but can you judge a cell by its shape? On this episode, host Lauren Richardson is joined by Maddison Masaeli (CEO and cofounder of Deepcell), and a16z general partner Vijay Pande (whose lab at Stanford focused on the development of novel computational methods for simulating biology), to discuss what we can learn by characterizing a  cell's shape — also known as its morphology. We've long appreciated that morphology can be used to discriminate cells, for example, cancer cells look very different than the surrounding tissue and can be spotted in a biopsy, and the various classes of immune cells all have distinct appearances. But characterization of cell shape — and what it can tell us about the underlying biology of those cells and the health of the organism that they came from — has been stuck in the low-tech, manual, qualitative era. To unlock the potential of cell morphology, Maddison and her colleagues are leveraging the power of artificial intelligence to assess and learn from cell images to create a quantitative, scaleable technology. The conversation covers the untapped potential of studying cells and their shape, how Maddison and her team at Deepcell are building an AI with seemingly limitless applications, and where this technology could take us.

Neuroscientists have long been trying to determine what happens in the brain during sleep, but to date, they have overlooked a key player: astrocytes. These star-shaped cells were once thought to be the glue that held the brain together, but we are now beginning to appreciate their importance in a variety of brain functions. In this episode, host Lauren Richardson talks to Kira Poskanzer, Assistant Professor at the University of California, San Francisco, about her group's work showing that neurons are only one piece of the larger sleep puzzle. The conversation covers the complexity of sleep, how astrocytes control two key attributes of sleep (depth and duration), the technology and methods employed to uncover this novel mode of regulation, and how appreciating the role of astrocytes in governing sleep could lead to new insights into neuropsychiatric conditions and how to treat them.  The article at the center of today's episode is: “Cortical astrocytes independently regulate sleep depth and duration via separate GPCR pathways” by Trisha V Vaidyanathan, Max Collard, Sae Yokoyama, Michael E Reitman, and Kira E Poskanzer, published in eLife.

Today we are re-running an episode exploring a question that seems super straightforward, but that on closer examination reveals incredible complexity, and that is "how do we put the patient at the center of the healthcare system?” It almost seems counterintuitive, since aren’t patients always the center of healthcare? But healthcare is a strange industry, in that it is built with the fundamental goal of serving patients, but in many ways, the patient isn’t always the end customer of the system. 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, and in high level policy debates. In this episode, a16z general partner Julie Yoo and deal team partner Jay Rughani talk with Freda Lewis Hall — a physician who was formerly Pfizer’s Chief Patient Officer and Chief Medical Officer; and who among many other roles was appointed by the Obama Administration to the Board of the Patient-Centered Outcomes Research Institute. They discuss what happens when you rethink the entire healthcare system from the patient’s point of view, from drug development to clinical trials to care delivery. What tools and new approaches can we use to truly put the patient at the center of the healthcare system? And how do we update our Flintstones healthcare system to match our Star Wars medicines?

Susan B. Wilde, Ph.D, Associate Professor of Aquatic Science at the University of Georgia, joins host Lauren Richardson to discuss the results and implications of the article "Hunting the eagle killer: A cyanobacterial neurotoxin causes vacuolar myelinopathy" by Steffen Breinlinger, Tabitha J. Phillips, Brigette N. Haram, Jan Mareš, José A. Martínez Yerena, Pavel Hrouzek, Roman Sobotka, W. Matthew Henderson, Peter Schmieder, Susan M. Williams, James D. Lauderdale, H. Dayton Wilde, Wesley Gerrin, Andreja Kust, John W. Washington, Christoph Wagner, Benedikt Geier, Manuel Liebeke, Heike Enke, Timo H. J. Niedermeyer and Susan B. Wilde, published in Science.

Thomas Juenger, Ph.D, Associate Professor of Integrative Biology at the University of Texas at Austin, joins host Lauren Richardson (@lr_bio) to discuss the results and implications of the article “Genomic mechanisms of climate adaptation in polyploid bioenergy switchgrass”, by John T. Lovell, Alice H. MacQueen, Sujan Mamidi, Jason Bonnette, Jerry Jenkins, Joseph D. Napier, Avinash Sreedasyam, Adam Healey, Adam Session, Shengqiang Shu, Kerrie Barry, Stacy Bonos, LoriBeth Boston, Christopher Daum, Shweta Deshpande, Aren Ewing, Paul P. Grabowski, Taslima Haque, Melanie Harrison, Jiming Jiang, Dave Kudrna, Anna Lipzen, Thomas H. Pendergast IV, Chris Plott, Peng Qi, Christopher A. Saski1, Eugene V. Shakirov, David Sims, Manoj Sharma, Rita Sharma, Ada Stewart, Vasanth R. Singan, Yuhong Tang, Sandra Thibivillier, Jenell Webber, Xiaoyu Weng, Melissa Williams, Guohong Albert Wu, Yuko Yoshinaga, Matthew Zane, Li Zhang, Jiyi Zhang, Kathrine D. Behrman, Arvid R. Boe, Philip A. Fay, Felix B. Fritschi, Julie D. Jastrow, John Lloyd-Reilley, Juan Manuel Martínez-Reyna, Roser Matamala, Robert B. Mitchell, Francis M. Rouquette Jr, Pamela Ronald, Malay Saha, Christian M. Tobias, Michael Udvardi, Rod A. Wing, Yanqi Wu, Laura E. Bartley, Michael Casler, Katrien M. Devos, David B. Lowry, Daniel S. Rokhsar, Jane Grimwood, Thomas E. Juenger & Jeremy Schmutz published in Nature.

Arik Kershenbaum, Ph.D, zoologist, and fellow at the University of Cambridge is the author of the new book “The Zoologist’s Guide to the Galaxy: What Animals on Earth Reveal about Aliens — and Ourselves”.  To learn more, check out https://www.zoo.cam.ac.uk/directory/dr-arik-kershenbaum or follow him on twitter at @arikkershenbaum

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 (@lr_bio) to discuss the results and implications of the article "A tissue-engineered uterus supports live births in rabbits" by Renata S. Magalhaes, J. Koudy Williams, Kyung W. Yoo, James J. Yoo & Anthony Atala, published in Nature Biotechnology.In the introduction, we also discuss the new article "Ex utero mouse embryogenesis from pre-gastrulation to late organogenesis" by Alejandro Aguilera-Castrejon, Bernardo Oldak, Tom Shani, Nadir Ghanem, Chen Itzkovich, Sharon Slomovich, Shadi Tarazi, Jonathan Bayerl, Valeriya Chugaeva, Muneef Ayyash, Shahd Ashouokhi, Daoud Sheban, Nir Livnat, Lior Lasman, Sergey Viukov, Mirie Zerbib, Yoseph Addadi, Yoach Rais, Saifeng Cheng, Yonatan Stelzer, Hadas Keren-Shaul, Raanan Shlomo, Rada Massarwa, Noa Novershtern, Itay Maza & Jacob H. Hanna, published in Nature.

In this conversation, Stanford Professor Euan Ashley—geneticist, cardiologist, author of the new book, The Genome Odyssey, and first co-chair of the Undiagnosed Diseases Network—talks with Bio Eats World host Hanne Winarsky about one of the first places that genomic sequencing began to dramatically impact patients’ lives, and those of their families around them: in rare disease. Rare disease is by definition, well, rare. But collectively, it’s surprisingly common: 1 in 15. In this episode, we talk about how rare disease became the clear first use case for genome or exome-scale sequencing, and how sequencing—and other new technologies, and the new information they give us—is changing how rare disease gets diagnosed. Ashley tells the stories of how the Undiagnosed Disease Network solved some of the most perplexing medical mysteries with cutting edge tools and technologies; and the lessons learned from the world of rare disease that we can use to impact our knowledge and our treatment of those with common disease.

Leslie Vosshall, Ph.D, Professor at Rockefeller University and Howard Hughes Medical Institute (@leslievosshall) joins host Lauren Richardson (@lr_bio) to discuss the results and implications of two recent articles from her lab. First, "Sensory Discrimination of Blood and Floral Nectar by Aedes aegypti Mosquitoes" by Veronica Jove, Zhongyan Gong, Felix J.H. Hol, Zhilei Zhao, Trevor R. Sorrells, Thomas S. Carroll, Manu Prakash, Carolyn S. McBride, and Leslie B. Vosshall, published in Neuron. Second, "Fruitless mutant male mosquitoes gain attraction to human odor" by Nipun S Basrur, Maria Elena De Obaldia, Takeshi Morita, Margaret Herre, Ricarda K von Heynitz, Yael N Tsitohay, and Leslie B Vosshall, published in eLife.

In this episode, we talk with Jeff Hawkins—an entrepreneur and scientist, known for inventing some of the earliest handheld computers, the Palm and the Treo, who then turned his career to neuroscience and founded the Redwood Center for Theoretical Neuroscience in 2002 and Numenta in 2005—about a new theory about how the cells in our brain work to create intelligence. What exactly is happening in the neocortex as our brains process and interpret information and sensory input—like sight, smell, touch, or language, or math—to create a perception of and to navigate through the world around us?  a16z General Partner Vijay Pande and I talk to Jeff about the basic principles in this new idea of the brain’s learning methodology for creating not just human intelligence, but animal intelligence, artificial intelligence, even alien intelligence, which he lays out in his newly just released book, A Thousand Brains: A New Theory of Intelligence. The conversation covers how the neocortex builds models of the world around us, and what this could mean for how we design the next generation of truly intelligent machines. This episode goes all the way from tiny neurons and how they speak to each other to what’s happening in optical illusions to the future of humanity and beyond.

Aaron Phillips, CEP, MSc, PhD (Medicine), Assistant Professor at the University of Calgary, joins host Lauren Richardson to discuss the results and implications of the article "Neuroprosthetic baroreflex controls haemodynamics after spinal cord injury" by Jordan W. Squair, Matthieu Gautier, Lois Mahe, Jan Elaine Soriano, Andreas Rowald, Arnaud Bichat, Newton Cho, Mark A. Anderson, Nicholas D. James, Jerome Gandar, Anthony V. Incognito, Giuseppe Schiavone, Zoe K. Sarafis, Achilleas Laskaratos, Kay Bartholdi, Robin Demesmaeker, Salif Komi, Charlotte Moerman, Bita Vaseghi, Berkeley Scott, Ryan Rosentreter, Claudia Kathe, Jimmy Ravier, Laura McCracken, Xiaoyang Kang, Nicolas Vachicouras, Florian Fallegger, Ileana Jelescu, YunLong Cheng, Qin Li, Rik Buschman, Nicolas Buse, Tim Denison, Sean Dukelow, Rebecca Charbonneau, Ian Rigby, Steven K. Boyd, Philip J. Millar, Eduardo Martin Moraud, Marco Capogrosso, Fabien B. Wagner, Quentin Barraud, Erwan Bezard, Stéphanie P. Lacour, Jocelyne Bloch, Grégoire Courtine & Aaron A. Phillips, published in Nature.

Sea turtles occupy a very special biological niche in our world. And we still know relatively little about these creatures, one of the very few marine reptiles on the face of the planet. But as population growth and activity on coasts has exploded, so have our encounters with sea turtles... including, unfortunately, those that cause injury and disease. So what advances in technology and healthcare are helping us treat these incredible, 150 million year old animals—and what are we learning about them as a result? Max Polyak, Director of Rehabilitation at Loggerhead Marine Life Center in Juno Beach, Florida, shares with Bio Eats World host Hanne Winarsky the new advances in science and technology that are helping us treat sea turtles when they get sick or injured—and the new understanding about their biology, their behavior, and how they interact with the world around them those advances are leading to. The conversation covers everything from treating boat injuries with sea turtle-specific prosthetics; to using cutting edge human therapeutics on these animals in new ways; to the unique immune systems of these 2,000 pound leatherbacks (immune systems that have dealt with dinosaurs! meteor strikes! ice ages! and more); to how the microbiome of the sea turtle may answer one of the most intriguing mysteries about how these turtles behave; to ultimately, what sea turtle health can teach us about how we are all linked—and about the health of the entire ocean.

a16z general Vineeta Agarwala, MD Ph.D, and deal partners Judy Savitskaya, Ph.D and Justin Larkin, MD join host Lauren Richardson, Ph.D to discuss the results and implications of the article "Reconstitution of the oocyte transcriptional network with transcription factors" by Nobuhiko Hamazaki, Hirohisa Kyogoku, Hiromitsu Araki, Fumihito Miura, Chisako Horikawa, Norio Hamada, So Shimamoto, Orie Hikabe, Kinichi Nakashima, Tomoya S. Kitajima, Takashi Ito, Harry G. Leitch and Katsuhiko Hayashi, published in Nature.

In this episode of Bio Eats World, we talk to Dr. Jennifer Doudna—winner of the 2020 Nobel Prize for the co-discovery (with Emmanuelle Charpentier) of CRISPR-Cas9—about the art and science of biology. Huge breakthroughs such as Doudna's—which began with the identification of CRISPR in bacteria and was then built into a highly adaptable genome editing platform—are now fueling the evolution of the field. Fundamental knowledge that has largely come from curiosity-driven science has converged with enabling technologies, allowing scientists and biologists in particular to do things that even a couple of years ago, we would have found unimaginable. And biology has begun to shift from an artisanal process, to an industrial one—shifting from qualitative, descriptive science, to quantitative, predictive, high-throughput, science with increasing automation.  In this conversation, a16z General Partner Vijay Pande and Doudna talk about what happens as CRISPR and other tools to engineer and interrogate biology mature. What does the future of biology look like? Can discovery itself be engineered and industrialized—and how do we recognize the moment that becomes possible? Doudna talks about the arc of her career and work through this lens, from basic research to applied; what can be built tomorrow on today’s discoveries; and what at the end of the day may never be engineerable.

Tom  Ellis (@ProfTomEllis), Professor of Synthetic Genome Engineering at Imperial College London, joins host Lauren Richardson (@lr_bio) and a16z bio deal team partner Judy Savitskaya (@heyjudka) to discuss the results and implications of the article "Living materials with programmable functionalities grown from engineered microbial co-cultures" by  Charlie Gilbert, Tzu-Chieh Tang, Wolfgang Ott, Brandon A. Dorr, William M. Shaw, George L. Sun, Timothy K. Lu & Tom Ellis, published in Nature Materials.