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.

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A 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.

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One might think the pandemic would have been good for diagnostic companies.  So why the financial hangover?Mara Aspinall has 30 years of leadership in genomics and the diagnostics industry.  This has led her to her current role as a new partner at Illumina Ventures, a venture fund independent from Illumina that is focused on funding diagnostics and tools companies.Mara publishes the fantastic newsletter Sensitive and Specific and also a yearly report on industry trends, which is the topic of our show today. We discuss valuations, new regulations, and the latest science. Mara co-founded the Biomedical Diagnostics master’s degree program at Arizona State University, the only program dedicated exclusively to diagnostics, genetics, and genomics.  How is the program faring, and how are we doing as a nation in educating the next generation on a revolution in diagnostic testing?

Working at the Broad Institute early in his career, Michael Schnall Levin was discovering he was a biologist at heart. He’d begun his studies in physics then done his PhD in mathematics. But he'd wanted “to do math that had an application in the real world.” It was at the Broad that Michael came in contact with the new tools that were revolutionizing biology.

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According to scientists, 30,000 species per year are going extinct. That’s 6 an hour, 150 per day. Up to one half of all species could be extinct by 2050.

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Chris Mason is back on the program for our end-of-year special. He’s Professor of Genomics, Physiology, and Biophysics at Weill Cornell School of Medicine and the author of such an outstanding book that we had to have him on the program a second time this year.

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In a joint interview, Sean George, CEO of diagnostics firm, Invitae, and Christian Henry, CEO of sequencing tools company, Pacific Biosciences, say that “it was clear in the first five minutes of a phone call that they shared a vision for doing something big together.”

What comes through the interview is that this partnership is built on a big vision: speeding up the adoption of whole genome sequencing into clinical medicine as the preferred method for genetic testing.

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There are some technologies that become so ubiquitous in biomedical research that their name turns synonymous with their use. This has been the case for the Luminex xMAP platform and multiple biomarker analysis. The product has been applied in just about every area of life sciences including infectious disease, STD, organ transplant rejection, vaccine development, cancer research, immunodeficiency, animal testing, agriculture, and others. (xMAP is a research use only product and not for use in diagnostic procedures.)

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DNA is a multibillion-dollar industry in 2021 and satisfies many life science applications, including drugs, reagents, siRNA, PCR, diagnostics, synthetic biology, and many others. Enzymatic DNA synthesis, or EDS, is a new approach to manufacturing DNA that is much more efficient and user-friendly and could disrupt the current market.

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If one was going to be a cancer researcher, surely one would want to be Christina Curtis. She’s an associate professor of oncology and genetics at Stanford, and she studies tumor evolution. She’s the Darwin of cancer research.

Because scientists can’t see human tumors evolve in real life, in Christina's lab she creates what she calls "virtual tumors that recapitulate the size and spatial properties of an actual tumor. And evaluating patient data,” she says, "we have found that metastatic seeding could happen very early. That these tumors were born to be bad.”

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"Scientists have been putting RNA into cells through a lipid delivery system for 44 years,” says Elie Dolgin. “And that’s ultimately the vaccine that has gone into millions of arms.”
Elie is the author of a recent piece in Nature magazine, The Tangled History of mRNA Vaccines.  He joins us to talk about his quest to uncover the winding journey that led to the cure that is moving the world forward.

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“Why do plants make a host of chemicals they don’t use? One answer that has always intrigued me is that, unlike us, they can’t walk up and walk away from an environment they don’t like. Evolution has honed this space for over 400 million years.”

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David Rimm, Professor of Pathology at Yale, was doing spatial biology since before it was called that. He’s known for counting. And he’s been going beyond—beneath?--the model of the cell in biology for years.

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The genome has been the core focus of biomedical research for twenty years. Although the genome is prewritten and predetermined, much biology happens after it appears. One area is epigenomics, which is the modification of genomic outcomes.

Bret Barnes has spent his career at Illumina developing the DNA methylation Infinium arrays that have become the workhorse of epigenomic studies around the world. Barnes says he was torn as a young person between biochemistry and computer science. He fortuitously ended up at UC Santa Cruz when they launched the first bioinformatics degree. Early on, he was interested in protein structure prediction.

“There are 20 amino acids,” he said. “Way more exciting than DNA with only four bases.”

But then he discovered the fifth base.

“Methylated cystine is the fifth base. So five, not four — a little better,” he continues. At the time of the Solexa acquisition, Illumina recruited Bret to do bioinformatics work on DNA methylation.

“If the king and queen of DNA methylation at Illumina were Kevin Gunderson and Marina Bibikova, then you could think of me as the prince or maybe the joker,” he says, tongue in cheek.

Where are we at today in epigenomics? What applications does Barnes see for the actionable epigenome, and how is the field developing?

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Carlo Bifulco joins us today. He’s an Italian who helped persuade one of America’s largest not-for-profit health systems that providing more genomic information to cancer patients early on was the right thing. With 52 hospitals, over 1,000 physician clinics, more than 120,000 caregivers serving communities across seven states—Alaska, California, Montana, New Mexico, Oregon, Texas, and Washington—Providence and Carlo have quite a task ahead. We ask Carlo what is the state of comprehensive genomic profiling at Providence today?

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If a company knows genome engineering, that would be Emeryville based Amyris, the Bay Area's crown jewel for synthetic biology. Founded back in 2003, the company first worked on creating biofuels from yeast. Today they have retooled their platform to produce a diversified line of consumer products that have not only rewarded their bottom line but point the world to a model of sustainable consumer goods.

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Laura Hercher, host of our sister podcast, The Beagle Has Landed, joins us today to compare notes. Her gig is much more focused on the clinical side of genomics. Genetic counselors are her core audience. Today we do a highlights show looking back over the Beagle's past year.

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Chris Mason, Professor of Physiology and Biophysics and prolific genomics researcher at Weill Cornell Medicine, joins us to talk about what he’s doing with the new generation of spatial biology tools.
The first papers we dive into are his work on COVID. Chris says the spatial tools have shown us the ravages of the coronavirus on the body like nothing we’ve seen before, i.e. the tissue damage from the cytokine storms and “the long term perturbations such as seeing cells far apart that were usually hanging out together.”

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David Steffin is a cancer researcher and physician at Texas Children's whose particular focus is on pediatric cancers. He begins today’s program with some interesting numbers.

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"If you go to a scientific meeting, even with the greatest critics, and you ask, how many people in this audience believe that your entire genome will be part of your everyday medical care in fifty years, every person will raise their hand. So the only questions we’re debating are: how do we get there, how soon can we get there, and what evidence base must we have in place before we get there? What’s really exciting to me is getting there sooner rather than later. If we get there 20 years sooner, we are saving thousands of people's lives.”

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We’re all aware of the way that next gen sequencing has changed many tests in the clinical laboratory. But some testing has held stubbornly resistant to change. This has been the case in cytogenetics, or the analysis of chromosomes. That is now changing thanks to a technology that is making inroads where next gen sequencing could not.

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"We have all of these evidence based tools and evidence based methods, but the problem is it can take upwards of 20 plus years to be truly implemented into care where healthcare providers are using them and patients are receiving them. And this includes medications and diagnostic tools and other types of treatment or screening.”

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One of the hottest new trends in biomedical research today is what is known as spatial biology--the ability to capture tissues in a 3D context. It was named Method of the Year by Nature Magazine in 2020.
And one of the first automated instruments launched in this market was the GeoMx Digital Spatial Profiler by NanoString. CEO Brad Gray is here to tell us the story of the birth of the DSP and the revolution of 3D biology. What will these new tools enable for the basic and translational researcher?

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When Lee Schwartzberg did his training as an oncologist some thirty years ago at Memorial Sloan Kettering in New York, he had a dream. And after training, he set off to make that dream a reality: to bring the resources, expertise, and research that one enjoys at a major research hospital cancer center to the community level.

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Not content to offer “me too” products, a new company in the prenatal arena, Billion to One (BTO), is reimagining prenatal testing. Last year, their new Unity Fetal Risk Screen was featured in the American Journal of Human Genomics as a top advancement in applying genomics to clinical care. Joining us today is Jennifer Hoskovec, Senior Director of Medical Affairs at BTO. She says the new Unity Screen offers two steps in testing: the first screen and, if necessary, a risk assessment for the baby. These can both be done with a single blood draw from the mother. Up until now, the father’s DNA was needed as well as the mother’s to determine risk assessment. Because a sample of the father’s DNA may not be easily attainable or can just cost more, Jennifer says that the new Unity Screen is further democratizing prenatal testing.

“The new drug is the engaged individual,” says today’s guest, Daniel Kraft.
Daniel is the founder of Exponential Medicine where he has championed digital health and the explosion of wearable technologies.  He's also hosting the new Healthy Conversations podcast--go check it out!  There you will find interviews with the innovator’s of today’s medical culture, including shows with former FDA Director, Scott Gottlieb, and genomic medicine guru, Eric Topol.

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First comes love, then comes marriage; then comes the genomic couple's report.  Isn't that how the line goes?
Perhaps that's a how it will begin to go.
Today's guest is the founder of Orchid Health, which as of this week is offering the world’s first risk prediction couple’s report. Based on whole genome sequencing from a saliva sample that expectant parents take from home, the report will tell them their genetic risk for the major diseases, including brain, heart, cancer, diabetes, and inflammatory bowel.

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Will there be a fourth surge of COVID here in the U.S.? Already that we’re asking the question and it’s not an inevitability is a good sign. It’s become a race between vaccination clinics and viral variants.

The U.S. was a bit slow to this race, but we are catching up. Viral surveillance has become a key part of any nation’s pandemic strategy. This past month, PacBio and Labcorp announced a partnership that brings the tool of long read sequencing to this effort.

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Kevin Hrusovosky’s career has been dedicated to transforming medicine from reactive “sick care” to preventative personalized care. A serial entrepreneur, he currently serves as the CEO of Quanterix, a company which has just nabbed $700 million and is raising the bar on proteomics testing.

“Genomics can tell you what your predisposition is,” he says in today’s interview, “proteomics can tell you the earliest moment you are in a disease cascade.”

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Raj Krishnan has a good story, and probably a good product. More data will tell. He's the CEO of Biological Dynamics, a new liquid biopsy company that is able to detect biomarkers in not only blood but other biological fluids. And the company's products are good for not only cancer but Alzheimer's and other disease areas as well.

Raj comes to precision medicine from electrical engineering. You don't hear that very often. One day in his lab while working on his PhD he had a classic eureka! moment. That unexpected discovery for which every scientist longs.

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Mendelspod was live this week at AGBT 2021 where Theral interviewed CEO Erik Holmlin and CMO Alka Chaubey of Bionano Genomics on Tuesday. The topic was the future of big biology.

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How fast is the coronavirus mutating? Why is the U.K. variant, or B.1.1.7, more transmissible than original strains of the virus? Is viral surveillance the weak spot in the U.S.'s fight against the pandemic?

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It’s been a year since the coronavirus breached American shores. Here to look back with some perspective is New York Times science writer, Carl Zimmer. Carl has authored thirteen books on science, including Planet of Viruses which includes an essay titled, "Predicting the Next Plague."

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We’ve all heard of and perhaps worked with data from The Cancer Atlas Project. Now, with the help of new spatial biology tools, researchers at the Mayo Clinic are developing what they call The Cancer Immunome Project. This is a comprehensive effort to fully characterize the immune system and how it interacts with and fights off cancer.

Today we talk with J C Villasboas, a physician-scientist at Mayo who co-started the project. He’s also Director of Mayo’s Immune Monitoring Core Facility.

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A discovery here. A paper there. An important paper gets passed over. A fortuitous encounter in a coffee shop among two ambitious scientists. A yogurt company just being a yogurt company. Science moves forward in fits and starts.
By the time we read the headline in the paper, “breakthrough of the year,” it can have an inevitable quality about it. Then, in a few years, the historian comes and shows us just how random, messy, and, yes, how beautiful is the business of science.

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This week, we saw Dr. Anthony Fauci being grilled by an angry congress over, among other things, the origin of COVID-19, which is estimated killed at least 25 million people.  He was asked about how the National Institute of Allergy and Infectious Diseases, which he directed until 2022, funded risky virus research at the Wuhan lab in China.

Ever since the pandemic broke out, scientists, as well as policymakers, have been debating new restrictions on pathogen research, and last month, the White House released a new policy for what it calls “dual use research of concern and pathogens with enhanced pandemic potential.

Marc Lipsitch is Professor of Epidemiology and Director of the Center for Communicable Disease Dynamics at the Harvard Chan School of Public Health.  He joins us to talk about the pros and cons of the new policy and explain how it might work moving forward.

Marc acknowledges there is legitimate disagreement among scientists, but these are value-laden questions, so it's for more than scientists to decide. It should include ethicists and the public. What are some of these value-laden questions? Will this impact privately funded research, and what are some of the alternative possibilities to high-risk research?

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At the beginning of the year, we were all holding our breath for the future of PacBio. And by all, I mean all. It seems everyone has been rooting for this sequencing technology company.

And why? It’s simple. Pretty much everyone is in agreement that they have the highest quality reads on the market.

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We speak directly with the Oracle today. It's Keith Robison, blogger at Omics Omics. Your All Knowingness, we ask, what has happened in the world of sequencing technology this year?

“The companies may need a mulligan,” he quips and laughs.

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Our October Review show is a Halloween special this year. Join us around the campfire amidst the sounds of howling wolves as Nathan, Laura, and Count Theracula recall some of their creepiest and spookiest times in the world of genomics.

It's Mendelspod's Haunted House of the Genome.

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There’s an urgency about Stephen Kingsmore. Which is not to say he’s in a rush.

He’s the CEO of the Rady’s Children’s Genomics Institute. He and his team have two world records to their name for the incredible speed of diagnosing a rare disease using whole genome sequencing. The latest is 19.5 hours.

Dr. Kingsmore feels they can even shave time off that. They’re shooting for a new record of somewhere around 12 hours.

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Diversity’s in the news these days. It's not just political correctness. Let’s look deeper into our field at how limited diversity in genetics is affecting all of us.
If you are a member of a minority population and you go into a cancer clinic seeking help, some of the genetic tests on offer may not work for you because of your ethnic background. Not only is this wrong on a social justice level. It turns out it's just bad science.

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“In an era where we look at these surveys about trust and everything’s going off the cliff, everyone still trusts the NHS. It’s so deep in the British psyche."

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We take a deep dive into a core genomics question that is somewhat philosophical today: “what is a disease, or disability?” This month we heard about a new experimental drug for dwarfism called vosoritide that raised questions for parents of dwarfism. If the drug could make their children taller, would they give it to them? Laura asks “can we put forth a medication for a condition saying those who take it are better off getting rid of it and not be saying those who are not getting it are unacceptable to have these different lives?"

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From a career at NIH where he was Chief of the Genetic Disease Branch to academic Chief of Medical Genetics at UCSF to his current business title of Chief Medical Officer at InVitae, Bob Nussbaum has been a central figure in the field of genetic testing. A chief among chiefs. Today he gives our State of Genetic Testing: 2020 Edition.

Our approach is to ask Bob to weigh into the recent debates that have come up this past year. And they can be summarized into one question. Even one word. "Expanded."

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Synthetic biology was surging like perhaps no other bio-based industry when the pandemic struck, and it has had some unique weapons in its arsenal for aiding in the fight against COVID. There are the leading vaccine makers such as Moderna using synthetic biology, as well as antibody technology and CRISPR based testing. But many of the surging trends from the last year have only been made more urgent this year: small molecules, food tech, synthetic materials.
Living with a pandemic is making humans more aware of our scientific dependence.

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First it was all about biomarkers. Then panels of biomarkers. But biology is complicated. Why does one patient respond to an immuno therapy when another which shares the same biomarker does not?
Welcome to the age of spatial biology.
Garry Nolan joins us today. He's a professor in the Department of Pathology at Stanford who's career has been a journey of seeing intracellular happenings more and more in context. Check out this cool analogy from a new paper his lab put out in Cell.

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A new precision medicine startup has launched that uses transcriptomic and epigenetic information to help with therapy for a wide range of chronic disorders. Hayward, California-based Aqtual emerged from stealth at the end of last year with data on its first assay, a blood-based test for rheumatoid arthritis.Today, we’re joined by Diana Abdueva, Aqtual’s Founder and CEO, and Maggie Louie, VP of Translational Research and Strategic Partnerships."We are complex organisms that work beautifully for many years,” says Diana in today’s interview.  "But when something goes wrong, it is very hard to detect where the pathology originates.  There are many applications other than oncology, such as dermatology or immunology.”We explore Aqtual’s technology and history and consider the exciting possibilities for liquid biopsy beyond oncology.

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After a long break, the world's first genomics pundits are back for the season. And they are calm and collected in the face of the strorm on Pennsylvania Ave. We're sixty days from an election. How serious should we be taking politicization of the COVID vaccine, this radical shift on LDTs at the FDA?

We also discuss some regular approvals and on rejection that sent the industry reeling with disappointment. Then it's on to Laura's, Nathan's, and Theral's picks for science of the month.

Welcome back!

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We see this new ingredient appearing advertised and in products everywhere. On the billboards, in the new shops next to our favorite restaurant, on the counters at the barbershop and when we pick up our prescriptions at the pharmacy.

C-B-D.

It has to do with the ongoing revolution that’s happening around the country—around the world—regarding the deregulation of marijuana. But there’s another revolution that will change our consumption of cannabinoids. That of synthetic biology.

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Mary Norton is a perinatologist and clinical geneticist at UCSF who says that in the age when we are diagnosing ever more rare diseases, adding to the carrier screening panel can be a good thing, but it’s complicated.

But it can be a good thing.

But it’s complicated.

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