Welcome to the second episode of Mendelspod’s 16th season. We’re grateful to everyone who has followed the show over the years, and we have a terrific lineup ahead as we continue asking some bigger questions about where biology and medicine are going.Few projects embody those ambitions quite like the NIH All of Us Research Program. The latest release includes data from more than 747,000 participants, 535,000 whole genomes, 480,000 electronic health records, and—for the first time—long-read sequencing, proteomics, transcriptomics, and a large collection of information extracted from clinical notes. More than 24,000 researchers are now using the resource. But the program is also arriving at an important transition: roughly 80 percent of its original ten-year funding runs out this year.So what happens when a massive national research experiment begins to come of age?Josh Denny, CEO of All of Us, joins us to talk about what the program has accomplished, what researchers are beginning to learn from the data, and what comes next. We discuss the extraordinary scale and diversity of the resource and the growing use of genetics alongside electronic health records and other forms of health data. All of Us is beginning to move from building infrastructure toward producing discoveries that could affect patient care.Denny explains why the program’s diversity is not simply a matter of representation but a scientific necessity. The project has already identified roughly 1.3 billion genetic variants, including more than 275 million that had not previously been observed. That diversity becomes even more important, Denny argues, as medicine moves toward increasingly personalized predictions and treatments.“We are capturing such a richer population and so much more kinds of data that we can’t actually reason through it as humans,” he says. “If the data underneath it are highly biased and not representative, then we’re going to make the wrong conclusions.”We also discuss All of Us as a platform for a much broader picture of human health—from electronic health records and wearables to nutrition, the microbiome, multiomics, environmental exposures, and eventually pediatric data. Denny shares examples of participants whose lives have already been changed by medically actionable genetic results and describes how researchers can build new studies on top of the All of Us population.What is the next phase of the program and that of precision medicine? “We’re going to have to redefine our definition of disease,” Denny says. Rather than treating something like type 2 diabetes as a single condition, he imagines increasingly precise descriptions of an individual’s biology, exposures, risk, and response.After years spent building one of the largest health datasets in the world, All of Us is beginning to show what we might actually do with it. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe

Welcome to Mendelspod’s 16th season!It’s hard to believe we’ve been doing this for just over 15 years, following first and foremost the people reshaping biology and medicine. But also the technologies and ideas. Our original vision was to feature the “people behind the headlines” and you’ll see that what we continue to do in this first show of the new season. A sincere thank you to everyone who has listened, watched, subscribed, sponsored, recommended guests, shared a show, told your friends, and simply kept coming back. We have a terrific season ahead, with some of the biggest names in the life sciences as well as some you may not know yet who are asking entirely new questions.To begin, we wanted to go big picture.Rob Phillips, professor of biophysics, biology, and physics at Caltech and co-author of Physical Biology of the Cell, thinks this could be the “Newtonian moment” for biology. We have extraordinary amounts of data. What biology needs now, he argues, are concepts that can organize those observations into a more predictive understanding of life.“The data in biology is getting to the point where we have no excuse,” Rob says.The conversation ranges from the limits of molecular reductionism to the meaning of prediction, the role of AI, and why better measurement still matters enormously. Phillips makes the case for explanations at many different scales. Understanding a wildebeest migration through molecules, he says, would be like explaining the Golden Gate Bridge through its iron atoms.Rob is nothing if not provocative—in the best sense. His style is to pile up ideas and questions one on the other to propel his listeners into that creative space of wonder. “We need more opinions. We need more authenticity,” Phillips says. “I want to hear how people think about things differently.” This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe

On Mendelspod, we’re always searching for scientists who are looking at biology in new ways. Sometimes that means a new technology. Sometimes it means asking entirely different questions. Erdinc Sezgin is bringing the tools of physics to biology.Sezgin is a group leader at the Max Planck Institute of Molecular Cell Biology and Genetics, where he heads the Membrane Biophysics Group. His research focuses on one of the most familiar yet least understood structures in biology: the cell membrane.In this conversation from April, Sezgin explains why the membrane isn’t a smooth sea of lipids, but a dynamic landscape of tiny molecular neighborhoods that constantly assemble, disappear, and reorganize. We discuss how he is using the tools of physics to better understand the membrane’s inner and outer lipid layers, each with distinct electrical properties.Sezgin also talks about his collaboration with Pixelgen Technologies, where Molecular Pixelation was used to study how changes in membrane charge reshape the cell surface. By knocking out a lipid-regulating complex, Sezgin and his colleagues showed that living cells can adopt surface features that alter immune recognition and may help explain how cancer cells evade destruction.It’s a reminder that major biological insights often arrive alongside new tools that make previously hidden phenomena measurable. Sezgin’s work is also a broader comment on scientific boundaries. Biology is not separate from physics or chemistry, but an expression of them in living systems.“Cells don’t have physics, chemistry, biology... It is life,” he says. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe

One of the biggest technology shifts we saw in biology over the past year came from the young company, Cellanome. Instead of relying only on static single-cell snapshots, the Cellanome platform enables longitudinal observation of live cells.In this conversation, Pier Federico Gherardini, VP of Computational Biology at Cellanome, joins Matthew Spitzer of UCSF, whose lab is putting the Cellanome platform to work in cancer immunology.The new CellCage technology allows researchers to follow individual cells and their interactions over time, then pair that behavior with transcriptomic and other molecular readouts. As Gherardini explains, this creates “a new data type” that connects functional behavior directly to molecular biology.For Spitzer, the breakthrough is linking phenotype and function in the same individual cell. His lab can watch dendritic cells activate T cells, or T cells interact with tumor cells, and then ask what was molecularly different about the cells that actually performed the function.“Now we have measured the function of the cell and the phenotype for the same exact individual cell,” Spitzer says.The result is a new way to study cell biology that could have implications for cancer immunology, cell therapy, target discovery, and functional screening. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe

Acute leukemia patients often wait days or even weeks for the full battery of molecular tests needed to guide treatment decisions. Dr. Parth Shah from Dartmouth believes long read sequencing can dramatically shorten that timeline. In this episode, Shah joins Agilent's Rita Shaknovich and Oxford Nanopore's Claire Attwooll to discuss some details of how long reads are beginning to move from research applications into routine clinical testing.Along the way, we explore the role of targeted enrichment, quality control, automation, and informatics in making these workflows practical for real-world laboratories.For Shah, the field has reached an inflection point. After more than a decade of development, he argues that long reads are finally positioned to make the leap into clinical genomics. “As we ask more complex questions of human biology, long read is probably going to be the best ammunition that we have,” he says. His team at Dartmouth has already demonstrated the potential in acute myeloid leukemia, where a long-read workflow can now generate a comprehensive molecular profile within 24 hours rather than the weeks often required by conventional testing.Shaknovich emphasizes that the opportunity is not simply generating more data, but generating better data. Long reads, she notes, can simultaneously capture mutations, structural variants, and epigenetic information, creating a richer biological picture than many existing approaches. Attwooll highlights the flexibility that has emerged in the long-read ecosystem. Researchers can now choose among whole-genome sequencing, targeted enrichment, and Oxford Nanopore’s adaptive sampling approaches depending on the clinical question. She argues that the field is moving from a niche technology toward a mainstream platform for translational and clinical applications.A recurring theme throughout the conversation is that no single technology will dominate every application. Whole-genome long reads, targeted enrichment, and adaptive approaches each have a role to play. As these methods move from research into routine testing, success will depend on more than sequencing alone. Agilent's established customer base, automation capabilities, quality-control tools, and experience supporting laboratories help provide the infrastructure needed to bring Oxford Nanopore's rapidly advancing long-read technology into practical clinical workflows. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe

This is a free preview of a paid episode. To hear more, visit www.mendelspod.comWe’ve become remarkably good at reading cancer cells. Spatial biology enabled us to read them in context. Today we discuss a new Nature study suggesting that the tumor microenvironment—the immune cells, stromal cells, and surrounding biology that often determines whether a therapy succeeds or fails—can be measured from a simple blood draw, or liquid biopsy. To do that we’re joined by Dr. Vincent Miller, an oncologist and former founding Chief Medical Officer of Foundation Medicine, and Dr. Mirna Jarosz, CEO of LiquidCell Dx.The work introduces a striking idea. Rather than focusing only on mutations inside tumor cells, it identifies recurring spatial ecosystems within tumors and then shows that their signatures can be recovered from plasma cell-free DNA using methylation patterns. The implication is that liquid biopsy may soon reveal not only what mutations a tumor carries, but how its surrounding biology is organized before treatment ever begins.But wait. How can blood possibly contain information about spatial organization inside a tumor? That answer unfolds gradually on today’s show, making the final portion of the discussion particularly rewarding.As Jarosz explains, “We’ve condensed spatial biology to really critical and recurring biological programs. And then we can measure those in blood. So now we have that spatial insight of the tumor microenvironment in a liquid biopsy.”For Miller, the significance is ultimately clinical. “The tumor is almost like an organ,” he says. “The ability to understand how that organ is constructed and what structures are near one another and how they’re functioning... is really the underpinning” of why patients with seemingly similar cancers can have dramatically different responses to therapy.If this approach continues to hold up in larger clinical studies, liquid biopsy may expand from reading the genetics of cancer to reading its ecosystem. This shift could improve immunotherapy selection, longitudinal monitoring, and our understanding of cancer biology itself.

This is a free preview of a paid episode. To hear more, visit www.mendelspod.comFor the past decade, liquid biopsy has largely been defined by oncology. Tumors shed DNA carrying mutations and epigenetic changes which allows researchers to detect cancer and monitor response. With this physicians are increasingly able to guide treatment. But chronic diseases are different. There is no tumor. Biological signals are subtle and quite d…

The future of genomics has arrived in Abu Dhabi.On today’s show, Dr. Mohamed Alameri of the UAE Department of Health and Albarah El-Khani of M42 describe one of the most ambitious precision medicine efforts underway anywhere in the world: the Emirati Genome Program, which has already sequenced more than 900,000 genomes and is rapidly integrating that data into everyday healthcare.The UAE program is not only a large sequencing effort and database—soon to be made available for research anywhere—but a coordinated national strategy built on prevention, diagnosis, and long-term population health. Particularly striking is the UAE’s focus on inherited and autosomal recessive diseases, which occur at significantly higher prevalence in the region than in many Western populations. Rather than treating genomics as an isolated research exercise, the program has pushed aggressively into premarital screening, newborn genomic screening, pharmacogenomics, hereditary cancer risk assessment, and rare disease diagnosis. “We truly believe in the philosophy of ‘sequence once, analyze for life,’” says El-Khani. “Imagine a society where every individual from birth holds a whole genome sequence throughout their life. How powerful is that tool at every intersection of public health, clinical care, and screening?”The scale of the project is already yielding discoveries difficult to achieve elsewhere. According to Alameri, roughly 12% of the variants identified in the Emirati population are not represented in existing global databases, underscoring just how underrepresented Middle Eastern populations remain in genomics research. In some cases, variants previously considered pathogenic in European populations appear to behave differently in Emirati patients, opening entirely new biological questions.Perhaps the most impressive aspect of the program is the degree to which genomics has been operationalized across the healthcare system. The UAE has invested heavily in physician education and public engagement to move genomics from bench to bedside. Our guests describe a healthcare ecosystem where genomic reports, pharmacogenomic guidance, and hereditary risk assessments are increasingly available directly within clinical workflows.“The vision was not sequencing everyone for its own sake,” says Dr. Alameri. “It was to build a national asset that could support more predictive, preventative, personalized healthcare for our population and for future generations.”There is always hype in genomics, as with other emerging technologies. But the UAE effort is already very comprehensive and clinically grounded. This is genomics functioning as healthcare infrastructure in real time. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe

On today’s show, Dr. Ryan Flynn of Harvard Medical School and Boston Children’s Hospital takes us into a newly emerging layer of biology: the architecture of the cell surface itself. Flynn first gained attention for the discovery of glycoRNA — RNA molecules displayed on the outside of cells — a finding that challenged the traditional picture of the cell surface as a world composed primarily of proteins and glycans. RNA has long been understood mainly as a carrier of genetic information (messenger RNA), but Flynn’s work has show that it has other functions critical to basic processes in the cell. As we’ve been hearing on the program, biology has largely been a science of inventory. Throughout today’s conversation, Flynn argues that molecular organization itself may be a fundamental biological variable. Not simply whether a molecule exists, but where it exists, what it is adjacent to. Using technologies such as Pixelgen’s Proximity Network Assay, his lab is beginning to map the “cell surface architecture,” or the arrangement of proteins, glycans, and nucleic acids that together govern signaling and cellular behavior.The implications stretch across biology. Flynn describes early evidence that extracellular RNA can tune classical signaling pathways such as VEGF-mediated angiogenesis by physically modulating how growth factors engage receptors on endothelial cells. Remove the RNA, and growth factor binding changes dramatically. Rather than acting as a simple on/off switch, the RNA appears to function as a finely tuned regulatory layer controlling signaling strength.In cancer, where cell-surface signaling drives growth, invasion, and immune escape, looking at the organization of the cell surface may determine whether therapies can physically access their targets. Flynn points to bispecific antibodies and T-cell engagers as examples of drugs whose function already depends on proximity and molecular arrangement, even if work in biology has not fully measured those variables before. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe

For decades, biology has been driven by the powerful notion that if we could sequence enough genomes, transcriptomes, epigenomes, then we could finally explain the cell. On today’s show, Gary Schroth, the Chief Scientific Officer at Cellanome, argues that something essential was still missing.Schroth spent nearly two decades at Illumina helping build the sequencing revolution. He has now joined Cellanome to pursue an expanded vision of biology that connects transcriptomics with live-cell imaging. Our conversation centers around two newly released preprints describing the company’s platform and its application to CRISPR screening, where imaging and transcriptomic data are explicitly linked in the very same cells.“What we show in a few examples in both papers,” Schroth explains, “is that it’s the combination of transcriptome information and imaging information that really gives us the complete story of what that cell is doing.”That idea—linking what researchers literally see under the microscope with the molecular state of the exact same cell—emerges as the core concept of the interview. Rather than treating imaging and transcriptomics as separate measurements, Cellanome brings them together in a longitudinal workflow where cells can be observed alive over time and then profiled at the transcriptomic level. “Sequencing has certainly taught us a lot about cells and sort of the parts list inside cells,” he says. “But it doesn’t really explain biology.”Will this be the next phase of post-genomic biology where the field moves beyond static snapshots toward directly observing cellular function as it unfolds? This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe