Mendelspod Podcast

Genetic studies of human populations have become a major tool for drug development. In the last few years, these studies have moved toward comprehensive proteomics profiling as well. In late 2023, a paper was published in Nature by the Pharma Proteomics Project, which characterized the plasma proteomic profiles of 54,219 UK Biobank participants. This was a precompetitive biopharmaceutical consortium that sought to provide a mapping of 2,923 proteins that identified 14,287 primary genetic associations, of which 81 percent were previously undescribed.Chris Whelan was the lead author of this project paper, and he joins the show to discuss what’s next for these kinds of studies and their results. Whelan is a director of neuroscience on the data science and digital health team at Janssen Research & Development. He’s also chair and co-founder of the Pharma Proteomics Project. 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 new blood collection device offered by startup company Tasso is a blood lancet that collects whole liquid blood samples. Its ease of use for at-home collection could dramatically improve patient testing compliance and impact the scale of clinical trials.Ben Casavant is the co-founder and CEO of Tasso. He joins us to discuss the possibilities for at-home testing.  Ben and the company have raised over $100 million dollars.

Today, we continue “The New Biology” series with a non-reductive geneticist from Trinity College in Dublin.  Kevin Mitchell is the author of Free Agents: How Evolution Gave Us Free Will.The problem of free will has dogged philosophers and scientists as much as any question going back to the Greeks.  Determinism, typically argued by physicists, usually goes something like: the laws of physics predict the future, and therefore, there is no free will. In our lives, however, the experience of making choices is fundamental to our well being, to our culture and our system of morality.  There would not be a legal system without free will. Or is the Supreme Court just an illusion, as determinists say about free will?  Does the murderer always have an alibi? Kevin says at the core of the debate is the question of “the self" and whether it can be its own cause. Through several chapters, he develops the history of “motility” in life, the ability of single cells to move around.“The environment may be so inhospitable that you need to move, especially if you’ve been dividing and dividing and using up all the food. Being able to move is a really good trick, and then you must ask, well, where?  Which way should I move?  Moving toward a food source and away from a threat becomes selectable over time,” says Kevin.Does Kevin think of this single cell that has just learned to move as an "agent?”   (The Latin root for agent is “agere,” meaning to do, to move.) As life evolved, Kevin argues, it developed purpose and meaning which will guide it in a “top-down” way. What are the broad implications of Kevin’s work on free will for further study of biology and philosophy? How might his thinking extend to robots and AI?We finish with a discussion on reductive and non-reductive biology.Note: Coincidentally, another book written by a biologist arguing the other way on free will hit shelves at the same time Kevin’s book came out. In Determined: A Science of Life Without Free Will,  Stanford neuroscientist Robert Sapolsky uses biology to argue that we do not have free will. We have invited Robert to the program. 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

Today, we go to the frontlines of cancer treatment for a case study on the use of ctDNA testing in the clinic. ctDNA, or circulating tumor DNA, is now used as a biomarker in new testing to detect cancer in a patient’s blood. Oncologists, such as today’s guest, Dr. Ben Weinberg, are increasingly using this testing. Dr. Weinberg is an associate professor of medicine and an attending physician specializing in colorectal cancer at MedStar Georgetown University Hospital.“Even though I give chemotherapy for a living, I would love to give less chemotherapy,” he says in today’s show, speaking about the primary use for ctDNA testing.   “We have to break apart some of the older paradigms of how we stage patients."Ben says that if a patient is ctDNA undetectable, it may not matter if they are stage 2 or stage 3.  Staging has been part of the guidelines suggesting that the doctor must give chemotherapy because there’s a survival benefit. “That was true in large randomized studies, but that may not be true for the patient sitting in front of us,” he says.Where are we at in the treatment of colorectal cancer today, and how is this new testing impacting oncology are the questions of today’s program.  Ben ends with the hope that this could also be a new biomarker for drug development. 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 over a hundred years, biologists have been working to fully understand biology at the level of chemistry, in other words unite biology with chemistry. This is considered the reductive approach inspired by the unification of chemistry with physics in the early 20th century with the Periodic Table and the Bohr model of the atom. In the attempt to reduce biology to chemistry, the gene has been the star player. The gene linked phenotype to the molecules of chemistry and to the more abstract and promising world of information. There have been many great successes, from new understanding and treatment of cancer to gene therapy for sickle cell disease. There have also been many failures. Drugs flop and are not approved; diagnostics fall short; and much about our bodies remains shrouded in mystery. Over the years, we have heard that if DNA sequencing (the way we characterize genes and the genome) was much cheaper and we just did more of it, then we would solve the hard questions. In the meantime, some researchers are taking a new approach to biology. Many consider themselves non-reductionists, and they are looking for answers beyond the genome.Today, we begin our 14th season with a new series exploring these alternated approaches to biology with Michael Levin, a developmental and synthetic biologist and professor at Tufts University. Mike also directs the Allen Discovery Center and the Tufts Center for Regenerative and Developmental Biology and is co-director of the Institute for Computationally Designed Organisms.   He has a Wyss Institute appointment at Harvard.Mike’s less traveled path is focused on the innate intelligence of tissues and organs. He argues that networks of cells are goal-oriented and achieve their goals through the medium of bioelectricity, a kind of proto-brain.   He knows that terms like "intelligence” and “goal” are taboo in the field and insists on fundamental basic definitions for the terms.  The idea is to go in and “reprogram” the goals of a group of cells and let them do the work of reversing disease.  Talk about gene therapy—Mike says he can imagine biological machines that are already in our bodies finding and repairing damaged DNA, tissue, and organs. Already, he has published work of reprogramming nematode worms to have two heads or to express their head on a different part of their bodies.  You can find over 300 publications on his website where he has painstakingly laid out his ideas and detailed his successes.We’re very excited to get Mike on the show to discuss his work and the implications.  What response is he hearing from the research community? What is his roadmap for the future? Should there be a change in priorities among funding agencies such as NIH?  "I want to get across one very simple idea from which bioelectricity and a million other things flow—and I’m not the only one saying this—and that is the idea that the need to go down to the level of chemistry for understanding and control is just an assumption.  It is not necessarily the optimal level,” 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

Adham Jurdi was an oncologist at the Austin Cancer Center when the pandemic hit. His cancer patients were a doubly vulnerable population. Office visits, follow-up care — every interaction between the patient and the healthcare system put them at risk for COVID-19 infection, which would hit extra hard because of their compromised immunity. It was then that he discovered a blood test that could monitor the patient’s cancer using ctDNA and keep the patient more at home.Jurdi is now the medical director of oncology at Natera. He tells the story of how he began using Natera’s tests and eventually decided to join the company based on the promise of this new technology.“In 2020, everything shut down because of COVID-19. It was a really interesting time to take care of cancer patients. One of our top priorities was to minimize cancer patient interaction in the clinic to avoid exposure to COVID-19. And that includes getting scans,” says Jurdi at the outset of today’s program.This was precisely when Natera’s ctDNA testing came on the market. Jurdi said it looked very promising, so he “dipped his toes in the water.” He soon saw that the ctDNA test was predicting what would happen several months before the scans would show anything and decided to use it across the board with his patients. Fast forward a year, and he would join Natera to get the chance to help shape the field.And how is ctDNA testing impacting cancer, particularly colorectal cancer, today? For what applications throughout treatment are oncologists using ctDNA testing? What are the results of some extensive ongoing studies? When might major guidelines include ctDNA testing as routine care?Jurdi says that 40 percent of oncologists are now using this testing from Natera, and “we’re just scratching the surface.” 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

Henrik Zetterberg, a leading expert in Alzheimer’s research from the University of Gothenburg, discusses the recent breakthroughs in understanding and treating the disease. He highlights the growing acceptance of the amyloid cascade hypothesis and the development of FDA-approved drugs. Zetterberg elaborates on exciting studies involving biomarker-positive individuals without symptoms, questioning if early amyloid removal can slow down disease progression. He advocates for quicker approvals of new treatments to enhance patient care.

There’s a new company in the consumer genomics space that last month released results for the first adopters of its new consumer-facing whole genome product. Nucleus Genomics, founded by Kian Sadeghi, aims to reinvent direct-to-consumer genomic testing with "the consumer reach of 23andMe and the clinical consequence of Myriad Genetics.”Kian joins us today to talk about his vision for the company and why consumer genomics is still a great idea.“To know that we can potentially give someone an insight that could save their life—that’s so powerful,” he says in today’s show. I’m excited to bring genomics to a wider audience than it’s ever been delivered to.  If you look at 23andMe and the other consumer companies, we’re talking about 14 to 15 million people.  The United States has over 300 million people.  There are hundreds of millions of people who have never done a genetic test.”What does the Nucleus testing process look like?  How is the company determining which variants and PRS scores to return?  What about recent LDT regulation implementation?According to Illumina, which partners with the new company, Nucleus raised 18 million in funding in 2022, largely from Reddit founder Alexis Ohanian’s venture capital firm, Seven Seven Six, and Peter Thiel’s Founders Fund. Kian is just twenty-four years old.  He says he became highly motivated to do something when a teenage cousin died suddenly in her sleep and her doctors attributed it to long QT syndrome.   “Hundreds of millions of people in the United States are carriers for a DNA variant that they do not know about.  There’s a narrative that consumer genetics is dying, but less than .001% of the population has done a whole genome test,” he says.  “There’s so much to build here." 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.comAvi Veidman spent over 20 years in the IDF (Israel Defense Forces), leading multi-disciplinary teams in the use of AI, machine learning, and data science.  One of his key projects involved developing systems that mapped the world with satellite images to spot adversaries from space.  Upon retirement, he co-founded Nucleai with a couple of his former defense colleagues, believing that the AI technology they had seen and developed would be useful to a pathologist in tracking cancer.

Yuling Luo is a serial entrepreneur who has founded three significant companies in life science tools. Most recently, he is the founder and CEO of Alamar Biosciences which this year commercially launched its ARGO HT instrument as well as a powerful new panel to detect inflammatory proteins called NULISA.Before founding Alamar, Luo was the founder and CEO of Advanced Cell Diagnostics, which was acquired by BioTechne in 2016. He was also a co-founder of Panomics, which was scooped up by Affymetrix.Yuling recently lost his mother to cancer and feels the compelling case that we can do better with early detection. In founding Alamar, he realized this was really a technical problem.He says that “liquid biopsy is quite popular, but the performance is limited. Detection for stage I cancer is 25 percent. That is not good enough. We need to get to 80 to 90 percent for it to really be meaningful. Why not use proteins for markers?" he asked. "There are hundreds of thousands to millions of copies of proteins. And proteins are more specific to tissue type.”How does the new Alamar technology work and fit in the overall proteomics tools landscape? Yuling says it is more sensitive and able to detect 90 percent of the proteins in blood plasma, up from 50 percent with other tools. The new sensitivity comes from suppressing background noise 10,000 fold.How is Alamar’s technology impacting research in the hot areas of Alzheimer’s and inflammatory disease? What is the overall opportunity with this new sensitivity? And what is the biggest challenge for the company over the next couple of years? 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