On this episode, we are taking a pulse-check on the state of the intersection between biology, healthcare, and technology with two scientists that sit at another intersection, that of academia and industry: Alexander Marson and Patrick Hsu, who are professors at UC San Francisco and UC Berkeley, respectively, who both use cutting edge gene editing technology to create next generation therapies, and are prolific biotech founders. Patrick also recently co-wrote an article on Fast Grants, one of the speediest sources of emergency science funding during the pandemic, which you can read about on our media site Future.com. But in this conversation, Patrick and Alex discuss ? with a16z bio general partner Jorge Conde ? what is different about this moment in bio.
On today?s episode we are discussing the results and implications of a recent study that describes the creation of a new set of tools to turn off or on any region in the genome with high specificity. Host Lauren Richardson and a16z general partner Vijay Pande are joined by the senior author of the article, ?Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing?, Jonathan Weissman, Professor of Biology at the Whitehead Institute at MIT. Jonathan talks about how they developed these tools using the CRISPR gene editor as a backbone, the advantages of modulating the epigenome as opposed to the genome, and the various applications ? both in the lab and in the clinic ? for these epigenome editors.
On today?s episode, we are making the full arc from the theoretical and borderline philosophical to the applied. Let?s start with the theory: embodied intelligence posits that the body, or the physical form, plays an active and significant role in shaping an agent's mind and cognitive capacities. For example, human intelligence is not just the function of our brain, but a combination of our brain, our body, and the environment in which we exist. But when it comes to designing artificial intelligence (AI), a physical form and an environment are typically not part of the equation. It?s a disembodied cognition. Our guests, Li Fei-Fei and Surya Ganguli of the Stanford Institute for Human-Centered AI, set out to develop what they call an ?evolutionary playground? to explore the development of embodied intelligence in AI and its connection with the environment and with learning using in silico experiments. They discuss with a16z general partner Vijay Pande and host Lauren Richardson how they created a suite of virtual environments in which agents evolve through a process that mimics aspects of Darwinian evolution. These agents, called the unimal, or universal animal, start off as a central node, and with each generation can add or subtract limbs and change various properties of their physical forms, like how flexible their joints are. Just like in real evolution, different forms arose based on the particularities of the environment, but what is really exciting is what Fei-Fei, Surya, and colleagues discovered about the intelligence encoded in some of these forms, such as an increased ability to learn a novel task. Which brings us to the applied section of our discussion. These results provide new insights for how we think about designing robots capable of performing unique tasks, and for understanding the possible limitations of disembodied AI models, like GTP-3.
The results are described in the pre-print "Embodied Intelligence via Learning and Evolution" posted on arXiv.org.
And watch the unimal evolve here!
Today?s episode is all about the history and future of infusing tech into healthcare with the goals of improving outcomes and lowering costs, and features one of the leading voices in this field, Jonathan Bush. Jonathan, aka JB, started his career in healthcare as an ambulance driver and army medic, and then met Todd Park, another Bio Eats World guest, while at Booz Allen. Together they founded Athena Women?s Health Clinic, which evolved from a clinic specializing in maternity care to one of the original digital health companies providing cloud-based services and point-of-care clinical and back office tools for providers, later called Athenahealth. In this conversation with a16z general partner Julie Yoo ? who is also a digital health builder ? JB discusses this evolution, how it mirrors the bigger trend shifts in healthcare, and how it has informed the mission of his new company, Zus, which he compares to a Github for healthtech. JB and Julie cover what?s changed since the launch of Athena, 25 years ago, how to disrupt an entrenched system like healthcare, the role regulation plays in the space, and the under appreciated importance of bottom-up sales.
Please note there is some colorful language used in this episode, in case you have young children listening.
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?
In 1994, 29 bald eagles were found dead at DeGray Lake in Arkansas. This mass mortality event kicked off a search for the culprit which has last over 25 years. On this episode of the Bio Eats World Journal Club, host Lauren Richardson talks to Susan B. Wilde of the University of Georgia about her group's work finally identifying the eagle killer, and revealing a complex web of ecosystem dysfunction. Solving this mystery required a fresh point of view, a wide range of techniques and technologies, and an international collaborative effort.
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 Mares?, Jose? A. Marti?nez 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.
Understanding how plants have adapted to natural climate change over millions of years provides a playbook of evolutionary strategies to help us prepare for and respond to man-made climate change. On this episode, host Lauren Richardson talks to Thomas Juenger, Associate Professor at the University of Texas in Austin and co-senior author of the recent article ?Genomic mechanisms of climate adaptation in polyploid bioenergy switchgrass?, published in Nature. They discuss how studying native plants ? like switchgrass ? can inform crop improvement strategies, the import role of switchgrass as a possible future source of biofuels, how advances in sequencing technology have unlocked the secrets hidden in plant genomes, and more.
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 Marti?nez-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.
The search for and conjecture about alien life has evolved, from science fiction to just plain science. On this episode, host Lauren Richardson talks to Arik Kershenbaum, Ph.D, author of the new book ?The Zoologist?s Guide to the Galaxy: What Animals on Earth Reveal about Aliens ? and Ourselves?, about what we can conjecture about alien life, based on the laws that govern life on Earth, and the universe at large. The conversation covers big questions like: Does biology have universal properties like physics does? Will the process of evolution be distinct on different planets? Are limbs, sex, and intelligence Earth-specific features of evolution? And importantly, what does the study of alien life teach us about our place on here on earth.
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
Today we are re-running a previous episode of Journal Club ? our show where we curate breakthrough research and bridge paper to practice ? in light of a recent article published in the journal Nature (see show notes below). In this episode, host Lauren Richardson talks to Professor Anthony Atala from the Wake Forest School of Medicine about his lab?s work creating an engineered uterus that can support live births. This work represents a major milestone in regenerative medicine and could be used to address a pressing unmet clinical need ? and it might even be laying the groundwork for the ability to gestate babies outside of the body. That is where the recent Nature article, entitled ?Ex utero mouse embryogenesis from pre-gastrulation to late organogenesis? by Aguilera-Castrejon et al., comes in. That article describes the creation of a cell culture system that can support embryonic development ? up to a certain point, that is.
So in this episode we are talking about creating a tissue engineered uterus, that could be used to replace a defective uterus and that might one day possibly support pregnancy out of the body ? whereas in the recent Nature article, they do away with the uterus entirely and culture the embryos in a fully mechanical set up. While this kind of ex vivo pregnancy still seems like sci-fi, both of these articles make steps in that general direction, and more importantly, increase our understanding of the female reproductive system and early development.
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.
Mosquitoes are the deadliest animals on Earth and for millennia humans have tried to rid themselves of these disease-spreading pests, with shockingly little success. On this episode of the Bio Eats World Journal Club, host Lauren Richardson talks to Leslie Vosshall of Rockefeller University about two articles from her lab investigating the neural and genetic basis of the mosquito's love for us and our blood. The conversation covers how mosquitoes taste blood, the critical differences between male mosquitoes and female mosquitoes, and of course, what this all means for controlling the spread of the deadly pathogens transmitted by the mosquito.
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.
In a healthy person, your body automatically adjusts blood pressure constantly, and this adjustment is governed by what?s called the baroreflex. However, a spinal cord injury can disrupt this reflex, which has both short term consequences, like passing out, but also long term consequences like an increased risk of heart disease and stroke. On this episode of the Bio Eats World Journal Club, host Lauren Richardson is joined by Dr. Aaron Phillips of the University of Calgary to talk about his lab?s work to reinstate this reflex in patients after a spinal cord injury using a neuroprosthetic device. This device both senses blood pressure changes and then activates the necessary neuronal structures to restore the connection to the blood vessels. We discuss how his group determined which neuronal structures to stimulate, how they developed this medical device, and the exciting results from their studies in rats, non-human primates and humans.
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, Ste?phanie P. Lacour, Jocelyne Bloch, Gre?goire 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.
On this episode of the Bio Eats World Journal Club, we explore the very compelling question of whether we can use our understanding of developmental biology to create oocytes (aka eggs or female gametes) from stem cells in the lab. If possible, this could be on par with the development of in vitro fertilization in terms of extending fertility. But creating an oocyte from a stem cell has some unique and high-stakes challenges. Host Lauren Richardson is joined by a16z general partner Vineeta Agarwala and deal partners Judy Savitskaya and Justin Larkin to discuss a recent research article in Nature by Hamazaki et al that makes a big step towards this goal. The conversation covers which aspects of oocyte biology the authors were able to replicate, which they were not, and where we think this field might be heading.
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.
To date, synthetic biology has been mainly focused on reproducing existing compounds and materials with biomanufacturing. Think of engineering yeast to produce anti-malarial drugs, or bacteria producing spider silk. But as our guest ? Professor Tom Ellis of Imperial College London ? argues, the future of synthetic biology is in creating materials with fundamentally new and distinct functions. Imagine, a spider silk rope that it is interwoven with cells that can catalyze the dissolution of that rope in certain circumstances. Host Lauren Richardson and a16z bio deal team partner Judy Savitskaya talk to Dr. Ellis about his group's work creating a prototype of an engineered living material (ELM) that can be iterated on and programmed with a huge array of different functions, how ELMs can disrupt established markets, and their varied uses in industry, healthcare, fashion, consumer products, and even potentially in space travel.
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.
Ticks are "master scientists of our skin," says our guest ? Seemay Chou, Assistant Professor at University of California, San Francisco. On this episode of the Bio Eats World Journal Club, Dr. Chou and host Lauren Richardson discuss how, over millions of years of evolution, ticks have developed a suite of tools to manipulate our skin physiology, all of which are delivered through their saliva as they feed. Pathogens, like the bacteria that cause Lyme Disease, take advantage of the tick's tools to infect new hosts. But what if we could also learn to use these tools? In this conversation, we discuss the dynamic nature of host-pathogen interactions, how ticks stole a tool from bacteria and then modified it to suit their needs, how our microbiome helps to protect us from ticks, how bias can influence how you set up experiments and interpret data, and how an un-fundable research project inspired a startup.
Seemay Chou (@seemaychou), Assistant Professor at the University of California, San Francisco, joins host Lauren Richardson (@lr_bio) to discuss the results and implications of the article ?Ticks Resist Skin Commensals with Immune Factor of Bacterial Origin?, by Beth M. Hayes, Atanas D. Radkov, Fauna Yarza, Sebastian Flores, Jungyun Kim, Ziyi Zhao, Katrina W. Lexa, Liron Marnin, Jacob Biboy, Victoria Bowcut, Waldemar Vollmer, Joao H.F. Pedra, and Seemay Chou, published in Cell.
"Superbug" is shorthand for multi-drug resistant bacteria. Infections with superbugs are the most difficult to treat, because these bacteria have evolved ways of evading multiple ? and sometimes all! ? of our available antibiotics. This multi-drug resistance can arise in the bacteria that are causing disease, meaning doctors have to find new ways to treat the infection, but also in the bacteria that harmlessly live in our gastrointestinal tract. Critically, if these gut bacteria become superbugs, they can spread resistance throughout a hospital setting via fecal-oral contamination. On this episode of the Bio Eats World Journal Club, we discuss a new strategy for protecting those harmless bacteria from antibiotics while still treating the infection. Host Lauren Richardson (@lr_bio) is joined by Professor Andrew Read of Penn State University to discuss his team's work preventing resistance evolution by repurposing an old, FDA-approved drug. The conversation covers the scope of the antibiotic resistance problem, the insights that lead to the discovery of this adjuvant therapy, and the fundamentally novel nature of anti-evolution drugs.
Andrew Read, Ph.D is the director of Huck Institutes of the Life Sciences, the Evan Pugh Professor of Biology and Entomology, and the Eberly Professor of Biotechnology at Pennsylvania State University. He joins host Lauren Richardson to discuss the results and implications of the article "An adjunctive therapy administered with an antibiotic prevents enrichment of antibiotic-resistant clones of a colonizing opportunistic pathogen" by Valerie J Morley, Clare L Kinnear , Derek G Sim, Samantha N Olson , Lindsey M Jackson, Elsa Hansen, Grace A Usher, Scott A Showalter, Manjunath P Pai, Robert J Woods, and Andrew F Read, published in eLife.
Today we are revisiting a topic and episode that was originally aired back when Journal Club was part of the a16z podcast. We are covering it again in light of a new research article published in Science, as both this episode and this newer research article are trying to find a way to kill senescent cells.
The article we discuss in this episode, "Senolytic CAR T cells reverse senescence-associated pathologies" by Amor et al, published in Nature, selectively targets senescent cells with engineered T cells.
The new article, "Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders" by Johmura et al, published in Science, kills senescent cells by inhibiting an enzyme essential for their metabolism.
So what are senescent cells, and why is killing them so important? Senescent cells are those in a non-dividing but metabolically active state, and what?s interesting is that they play both protective and pathological roles in the body. When senescent cells accumulate, as often happens during aging, they kick off an inflammatory process that underlies many age-related diseases. Thus the targeted destruction of senescent cells has the potential to treat a wide range of conditions, and possibly to improve longevity.
Both of the approaches described in these two articles have their pros and cons, and it remains to be seen which will be effective in humans, but together they highlight the interest and importance of senescence-killing, or senolytic, methods for future therapeutics.
On this episode, a16z general partner Jorge Conde (@JorgeCondeBio) and bio deal team partner Andy Tran (@andy23tran) join host Lauren Richardson (@lr_bio) to discuss the results and implications of the article "Senolytic CAR T cells reverse senescence-associated pathologies" by Corina Amor, Judith Feucht, Josef Leibold, Yu-Jui Ho, Changyu Zhu, Direna Alonso-Curbelo, Jorge Mansilla-Soto, Jacob A. Boyer, Xiang Li, Theodoros Giavridis, Amanda Kulick, Shauna Houlihan, Ellinor Peerschke, Scott L. Friedman, Vladimir Ponomarev, Alessandra Piersigilli, Michel Sadelain & Scott W. Lowe, published in Nature.
The introduction also references the article "Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders" by Yoshikazu Johmura, Takehiro Yamanaka, Satotaka Omori, Teh-Wei Wang, Yuki Sugiura, Masaki Matsumoto, Narumi Suzuki, Soichiro Kumamoto, Kiyoshi Yamaguchi, Seira Hatakeyama, Tomoyo Takami, Rui Yamaguchi, Eigo Shimizu, Kazutaka Ikeda, Nobuyuki Okahashi, Ryuta Mikawa, Makoto Suematsu, Makoto Arita, Masataka Sugimoto, Keiichi I. Nakayama, Yoichi Furukawa, Seiya Imoto, Makoto Nakanishi
Move over microdosing, there is a new approach to psychedelic medicine. Psychedelics ? like LSD and psilocybin ? are some of the most powerful drugs that affect our brains, but their therapeutic potential has been limited due to their adverse side effects. This is where the work of today's guest, Dr. David Olson (@DEOlsonLab) of UC Davis, comes in. He talks to host Lauren Richardson (@lr_bio) about his lab's effort to develop new drugs based off the structure of psychedelics that retain their therapeutic properties, but that have better safety profiles, and that importantly, are non-hallucinogenic. The conversation covers his team?s recent Nature paper creating a non-hallucinogenic derivative of ibogaine, the evidence from animal models of its ability to treat depression and alcohol- and heroin-seeking behaviors, and the unexpected challenges facing the psychedelic medicine field.
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.
Immuno-oncology, which leverages the body's own immune system to fight cancer, is a true medical revolution. But to date, these therapies have only targeted one of the two arms of the immune system: the adaptive immune system. This is the arm that contains T cells, B cells, and antibodies and is what we generally think of when talking about immunity. But the second arm, the innate immune system, is equally important, as it mounts a fast-acting, non-specific immune response to a board range of invaders. Importantly, some cancers co-opt the innate immune system and use it as a shield against attacks by the adaptive immune system. In today's episode, host Lauren Richardson (@lr_bio) is joined by Dr. Willem Mulder (@WillemNANO), Professor at the Icahn School of Medicine at Mt. Sinai, to discuss a new approach to immuno-oncology that engages both arms of the immune system. This method uses engineered, synthetic, nano-scale "germs" to activate the innate immune system, and which works in combination with T cell-activating therapies to destroy cancer cells, even leading to complete tumor remission in mice. The conversation covers how these synthetic germs were developed from an early vaccine to tuberculosis, how they influence immune cell activity, their potential for treating cancer and an array of other conditions, and what is needed to take them out of the lab and into the clinic.
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.
One of the enduring mysteries of COVID-19 is why some people get a severe disease that can be fatal, whereas the majority experience a very mild or even asymptomatic disease. On this episode of the Bio Eats World Journal Club, host Lauren Richardson (@lr_bio) discussed this discrepancy with Dr. Helen Su of the NIH and co-leader of the COVID Human Genetic Effort. This international collaboration set out to investigate whether there is a genetic component to severe COVID and published the first of their findings in two articles in Science. Both papers demonstrate that dysfunction in a very specific part of the immune system leads to severe COVID, but through distinct mechanisms. We break down these results, how they can inform treatment, and how this collaboration was able to uncover these important findings in record time.
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.
Viruses (like HIV) and their hosts (like humans) are locked in an evolutionary arms race, with each trying to outwit the other. But viruses seem to have a big advantage (MUCH faster evolution), so how can the slowly evolving human arsenal keep pace? On this episode of the Bio Eats World Journal Club, host Lauren Richardson (@lr_bio) talks to Professor Harmit Malik (@HarmitMalik) about new research from his lab determining some surprising characteristics of human antiviral proteins that allow them to persevere in this evolutionary fight and how this information could be used to develop new, possibly curative, treatments for HIV.
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 TRIM5? in host-virus evolutionary arms races", by Jeannette L Tenthorey, Candice Young, Afeez Sodeinde, Michael Emerman, and Harmit S Malik, published in eLife.
Infertility is a common struggle with limited treatment options, particularly if caused by an issue with the uterus. On this episode of Journal Club host Lauren Richardson (@lr_bio) talks to Professor Anthony Atala about his lab's work engineering a replacement uterus that can -- incredibly! -- support pregnancy and live birth in rabbits. They discuss how the Atala lab created these bioengineered uteruses and tested their functionality, what kinds of conditions they can be used to treat, and potential sci-fi-esque applications.
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.
Approximately half of all severe developmental disorders are caused by de novo (new, not inherited) mutations in protein-coding genes. But which genes? In this episode of the Bio Eats World Journal Club, Vineeta Agarwala (@vintweeta) and Lauren Richardson (@lr_bio) discuss a recent article finding new genes linked to developmental disorders and highlighting how many still need to be decoded.
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.
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.
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.