Mendelspod Podcast

Precision oncology is entering a new phase. Rather than simply profiling a tumor and matching it to a drug, physicians are increasingly able to follow a patient’s cancer over time, measuring treatment response, detecting residual disease, and adjusting therapy as the disease evolves.Jerry Radich of Fred Hutch Cancer Center has been at the forefront of this evolution. His pioneering work in chronic myeloid leukemia (CML) helped establish molecular monitoring as a critical part of cancer care and prefigured the rise we see in MRD testing today. Some CML patients can even discontinue treatment after achieving a sustained deep molecular response. Radich discusses how this remarkable success has become a model for other blood cancers.He’s now helping lead myeloMATCH, a national precision oncology initiative that brings together clinical trial groups across North America. With some 350 participating sites and molecular results typically available in less than 48 hours, the program is matching patients with acute myeloid leukemia to clinical trials based on their cancer’s genetic profile. Radich sees an opportunity not only to personalize treatment but to accelerate drug development by using molecular response as an earlier measure of efficacy.We also explore the limits of molecular profiling, the emerging role of the immune system, and why increasingly sensitive tests may transform how we understand cancer. Looking ahead, Radich imagines a future in which patients could monitor their disease burden almost continuously, perhaps even through wearable or implantable devices.Radich is co-chairing the upcoming APOAPE conference in Seattle on January 15, bringing oncologists and pathologists together to connect advances in molecular diagnostics with real-world treatment decisions. The conference is free for healthcare professionals.Learn more about the APOAPE conference 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

In the US, we have the All of Us Research Program. In the UK, they have Our Future Health, an ambitious new population health research program that aims to make healthcare more preventive than reactive. Launched just four years ago, it has already recruited nearly three million volunteers toward a goal of five million, making it one of the world’s largest health research initiatives.Today we’re joined by Raghib Ali, CEO and Principal Investigator of Our Future Health, to discuss how the program builds on the success of UK Biobank while pursuing a different goal. Rather than simply studying the causes of disease, Our Future Health aims to establish the evidence needed to move healthcare from diagnosis and treatment toward prediction and prevention.Ali discusses the program’s plans to combine polygenic risk scores with clinical and lifestyle data to develop integrated disease risk scores. A new clinical trials platform will test whether personalized prevention actually improves outcomes. The ultimate ambition is to bring successful approaches into routine NHS care.Perhaps most encouraging is the public response. More than a million participants have come from historically underrepresented groups, raising the possibility that precision medicine could help reduce health inequalities rather than widen them.As Ali puts it, the goal is to move from a national sickness service to a true national health service. 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

In recent months on Mendelspod, we’ve explored how new sequencing and proteomics technologies are revealing biology in regions of the genome (and proteome) that have long escaped our attention. From repeat expansion disorders to new approaches in cancer diagnostics, the dark genome is increasingly becoming clinically relevant.Today we’re revisiting a conversation from earlier in the year that asks an even bigger question. What if much of this unexplored genomic territory is not simply functional, but a reservoir of evolutionary possibility?Last March, we talked with Sudhakaran Prabakaran, computational biologist at Northeastern University, founder of NonExomics, and author of Eclipsed Horizons: Unveiling the Dark Genome.Drawing on his lab’s work cataloging more than 250,000 non-canonical proteins, Prabakaran argued that regions outside traditional gene definitions may be continually generating new proteins with implications for adaptation, evolution, and disease.From rapidly diversifying cichlid fishes to human accelerated regions (HARs) of the human genome linked to schizophrenia, Sudhakaran makes the case that protein birth and death is continuous, cheap, and exploratory. In his framing, the “dark genome” functions less like debris and more like a flexible evolutionary sandbox. His company, NonExomics, is also exploring how these previously overlooked proteins might become biomarkers for cancer and other diseases.As our recent interviews have demonstrated, we’re entering a new era of genomic discovery. Prabakaran challenges us to think about just how much biology remains to be found. 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

Repeat expansions are places where the genome has remained stubbornly dark. Long-read sequencing is beginning to illuminate them, and now that new visibility is moving into clinical testing.Today we’re joined by Simon Sadedin, Head of Clinical Bioinformatics at Victorian Clinical Genetics Services in Australia, and Alex Lindell, Senior Director of Product Marketing at Oxford Nanopore. Until now, testing for repeat expansions has largely meant building a separate assay for each disorder. A patient might be tested for Fragile X, get a negative result, and then move on to another test, sometimes waiting months at each step. Some repeat expansions have been difficult to test for at all. Simon’s group is trying to replace that serial approach with a single assay covering roughly 60 repeat expansion loci, which is now being submitted for clinical accreditation.The promise goes beyond simply finding an expansion. Long reads can reveal its length, sequence, methylation and mosaicism, while adaptive sampling makes it possible to target these difficult regions in software rather than building a new wet lab assay for each one.Some say we are at a new threshold in genomics, where parts of the genome that have remained dark are finally becoming accessible to both discovery and clinical medicine. 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

Sometimes the best evidence that a new medical technology is working is simply that doctors start depending on it. For years, the promise of molecular medicine has been that better genomic information would lead to better patient care. At Roswell Park Comprehensive Cancer Center, Vice Chair of Molecular Pathology, Sean Glenn, offers a compelling example of that promise becoming routine clinical practice.Hematologic cancers can require information from many different kinds of genomic alterations and traditionally from multiple tests and laboratories. Glenn and his team developed a comprehensive pan-hematological assay that brings much of that information together, using both DNA and RNA to detect alterations across myeloid and lymphoid cancers. The panel targets nearly 400 genes on the DNA side and about 125 on the RNA side, while automation has helped Roswell Park achieve an average turnaround time of roughly two and a half days for the 50 to 60 tests it runs each week.And the oncologists are depending on it. Since introducing the panel, Glenn says Roswell Park has seen “a transformation and a resurgence of clinical care” in its leukemia and lymphoma clinics. His favorite measure of success is wonderfully practical. The oncologists are no longer calling the lab every few days asking where their results are. The information simply arrives in the patient’s record, in time to help make treatment decisions. 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

Plant biology too is benefiting from single cell resolution.Unlike animals, plants cannot move away from environmental stress. They have evolved tremendous biological complexity to stay rooted in one place. Their genomes are complex too, with repeated genome duplications producing families of related genes that can take on different functions. And within a single leaf are many specialized cell types, from photosynthetic and epidermal cells to vasculature and rare trichomes, each with its own patterns of gene expression. It’s early days for plant science. The field is only beginning to assemble the large, high quality single cell atlases needed to understand that complexity and eventually make better predictions and enable a new world of plant engineering.Robin Buell and Anita Giabardo join us from the University of Georgia to discuss one of those new atlases. Their BioPoplar project aims to engineer fast growing poplar trees to produce new biomaterials, bioproducts and biofuels. Using Illumina’s PIPseq, Anita and colleagues created an atlas of more than 159,000 cells across the developing poplar shoot.That resolution matters. The researchers were able to find rare trichome cells, the tiny hairs on leaves whose specialized metabolism makes them attractive little factories for engineered products. They then identified a promoter that can specifically direct gene expression to those cells.Robin has watched plant genomics progress from Northern blots to bulk RNA sequencing and now to single cell. She predicts that within ten years single cell could become the standard. The ability to see biology cell by cell is not only changing what scientists can discover about plants. It will mostly likely change what they can build. 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

What new insights can we learn about cancer when researchers are able to look at the genome and the methylome together?Recently, Illumina launched its 5-base for Cancer Research Grant Contest to explore that question. Today, the three winners join us on Mendelspod with three very different problems in cancer research.Richard Tothill of the University of Melbourne is studying cancers of unknown primary and in collaboration with Hartwig Medical Foundation is combining DNA methylation and mutation profiling to reveal the primary origins of these aggressive cancers. Jacob Blum of Johns Hopkins is working with tiny amounts of circulating tumor DNA, combining genetic variants with methylation signals in hopes of improving detection of minimal residual disease and developing a model that other researchers could use. And Alfonso Bellacosa of Fox Chase Cancer Center is investigating what methylation can reveal about the mechanisms behind response and resistance to cancer immunotherapy.The projects are early stage, but together they give us a snapshot of how cancer researchers are using a new tool that brings epigenetics and genetics into the same experiment and analysis. Joining the discussion is Danielle Goldberg from Illumina, who talks about what the company saw across nearly 200 grant applications and the growing interest in combining genomic and methylation data in cancer research. 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.comA recent New York Times article highlighted a remarkable study showing that exercise can help keep colon cancer in remission. After eight years, 90 percent of patients in a structured exercise program were still alive, compared with 83 percent in the control group. Yet despite these results, such programs are rarely covered by insurance. It’s a striking example of something our guest today, Mayo Clinic physiologist Mike Joyner, has argued for years. Are we overlooking some of the most powerful ways to improve human health in our pursuit of molecular medicine?Over a decade ago, we invited Joyner on as a skeptic of the emerging precision medicine revolution. He questioned whether breaking biology into ever smaller molecular pieces would deliver the improvements in human health being promised. Ten years later, we begin by asking Mike a simple question. Was he right? “I think I was more right than wrong,” he says. Despite important successes in oncology and drug development, he argues that precision medicine has yet to make the broad impact on public health its advocates envisioned.Joyner remains as provocative as ever. He argues that biomedical researchers have become too dependent on engineered animal models and should pay more attention to nature’s own experiments. The discovery of GLP-1 drugs is a case in point. He welcomes their enormous potential for improving public health but worries that people taking them without exercising may lose valuable muscle mass and miss the additional benefits of physical activity.We also venture into the contentious debate over transgender athletes in women’s sports. Drawing on physiological research, Joyner argues that suppressing testosterone does not fully eliminate the athletic advantages associated with male puberty. For him, the evidence supports maintaining biological sex categories to preserve fair competition for women.Throughout the conversation, Joyner challenges us to think beyond the molecular and ask a bigger question. Are we doing the kind of science that will actually make people healthier?

This is a free preview of a paid episode. To hear more, visit www.mendelspod.comIs biology headed back into the genome?While much of biology has been expanding outward into single cells, spatial biology and ever more biological context, Žiga Avsec and his team at Google DeepMind are making the case that there is still an enormous amount to learn by going deeper into DNA itself.Their new AlphaGenome Atlas uses AlphaGenome to predict the molecular effects of every possible single letter change in the human genome. That’s some nine billion variants. Now researchers can easily explore how a variant might affect gene expression, or splicing, or other layers of gene regulation across different cell types. The Atlas also introduces a variant impact score (AVI) designed to help researchers quickly identify which variants deserve a closer look.Avsec argues that the scale itself opens new possibilities. Researchers can use the Atlas to prioritize rare variants across enormous cohorts, but they can also work backward from the predictions to investigate something more fundamental, the regulatory grammar of the genome. The grammar of the genome—long a provocative idea, but still not cracked. Short DNA motifs could act something like words, and AlphaGenome may help reveal how those words work together to activate or repress genes across different biological contexts.There are important limitations. AlphaGenome predicts molecular consequences rather than phenotype, and Avsec says the distance between genotype and phenotype remains long and complex. The model also has more difficulty with regulatory elements that far from genes—a proximity issue—and has so far been trained largely on bulk tissue data rather than the much richer universe of individual cell types and cell states.For now, Avsec just wants researchers to use the Atlas. The portal is free for noncommercial research, and he explicitly invites scientists to tell the DeepMind team what works and what does not. That feedback matters because the Atlas is not being presented as a finished map. It is part of a cycle in which better models suggest better experiments, those experiments generate better data, and better data produce the next generation of models. Bioinformaticians always want two things. Better data and more data.This may be an argument for where genomics is headed. Rather than AI replacing experiments, Avsec hopes it will give researchers greater confidence about which experiments are worth doing and ultimately lead to more experiments with more positive findings.The AlphaGenome Atlas is available free for noncommercial research here:https://deepmind.google/science/alphagenome/

Mass spectrometry has been one of the most powerful technologies in clinical testing for decades. So why is it still largely confined to specialty labs?Don Mason has spent more than 25 years in clinical mass spectrometry. Now Senior Marketing Manager for Mass Spectrometry at Roche Diagnostics, he says the technology’s strength has also been its weakness: “Part of its power and part of its challenges are linked.” Mass spec is extraordinarily sensitive, selective and flexible, but traditionally requires specialized operators, complicated workflows and batch processing.That may finally be changing. Last year Roche launched their new cobas Mass Spec solution designed to automate the process from sample preparation through result reporting. It also brings random-access mass spectrometry into the routine clinical lab. Mason says a sample can now produce a numerical result in as little as 34 minutes, compared with turnaround times that can stretch into days with traditional workflows. He points to transplant drug monitoring and antibiotic and antifungal monitoring in critically ill patients as examples where that difference could matter clinically.But automation isn’t simply about replacing expertise. Mason argues that moving established assays onto standardized systems could free mass spectrometrists to develop the next generation of tests: “This in turn becomes the innovation engine for tomorrow’s routine mass spectrometry-based tests.”Roche currently has seven assays available in the U.S., with more expected beginning in 2027. Looking further ahead, Mason sees a much bigger transition. Just as MALDI-TOF transformed microbial identification, he predicts LC-MS will become standard equipment in more and more clinical laboratories over the coming decade. 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