Mendelspod Podcast

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.

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.

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.

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.”

Alzheimer’s disease is now one of the hottest areas of research despite little progress in the decades up to about five years ago. The disease was proving especially difficult to diagnose early and to treat.

Today researchers are largely on board with the amyloid cascade hypothesis. There are several FDA-approved drugs for treating the disease, with another just around the corner. New biomarkers for Alzheimer’s enabled by a new generation of proteomics tools promise to change care by giving patients the chance to be treated early before “the neural networks are too damaged.”

Henrik Zetterberg joins us to give an inside look at the exciting developments in Alzheimer’s. Zetterberg is a professor at the University of Gothenburg and one of the world’s leading experts in the field. He has been using innovative new technologies, including Alamar’s NULISAseq CNS Disease Panel, to help detect key and difficult-to-find protein biomarkers of neurodegeneration in blood.

“In the US, there are studies ongoing with people who do not have symptoms but are biomarker positive for Alzheimer’s pathology,” he says in the interview. “These studies are going to be so exciting because they answer the question, ‘If you remove amyloid before you have clinically significant neural network breakdown, will that stop the disease or slow it down?’”

After his summary of the field, Zetterberg ends with an appeal to the European Medical Agency: approve these new drugs. They’re working.

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."

Avi 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?

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?

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?

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.

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?

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.

Today, we pursue an exciting area of medicine for the first time:  cell therapy for solid tumors.Most, if not all, of our audience will be familiar with the success of CAR-T therapies for blood cancers.  But only 10% of cancer is in the blood.  The other 90% develop solid tumors. Jason Bock is the CEO and founder of CTMC, a new company aiming to speed the advancement of the entire field of cell therapies. First, we cover this new treatment for solid tumors and discuss the near-science-fiction action of tumor-infiltrating lymphocytes (til). 

The Clinical Knowledge Base (CKB) powered by The Jackson Laboratory (JAX) is a dynamic digital resource for interpreting complex cancer genomic profiles in the context of gene variant knowledge and protein impact, therapies, and clinical trials. Illumina has teamed up with JAX in the newly released Connected Insights software, which integrates CKB as a knowledge source.We’re joined by Cara Statz from JAX and Erica Schnettler from Illumina to discuss how their combined technologies are helping researchers and oncologists deal with the increasing complexity of cancer genomic data. They discuss oncologists' experience with an overwhelming amount of new scientific data, and both guests give their advice for new labs setting up cancer testing.

A paper out this week in Nature Methods demonstrates a new technology which shows novel patterns of protein spatial polarization and co-localization in immune cells. The technology launched by Swedish startup Pixelgen has been dubbed “molecular pixelation” because it uses DNA pixels to tag and reveal relative locations. Unlike most other spatial technologies, molecular pixelation does not involve microscopy.Lead author of the paper, Filip Karlsson, joins us today to explain the technology and how it might enable new proteomics research.  He says that immunology is a great application area.How does this technology fit in the spatial landscape, and how might it enable new medicine that could impact patients?

Damon Hostin has had an active and exciting journey in genomic medicine.  He’s now at Illumina, where his title is illuminative:  Lead, Health System Market Access.A regular on the precision medicine stage, Damon has some insights into what he calls the “blindingly fast progression” of genomic medicine that should convince the most jaded of its critics.  Compared to other areas of medicine, we are witnessing a rapid uptake of new science.  

Damon’s biography includes work at Celera in the age of the Drosophila and Human Genome papers and at a large community health system, Catholic Health Initiatives, where he was in charge of precision medicine.   At Illumina, he’s part of the large vision of seeing that genomic medicine has every chance at adoption.Today, we ask Damon what has changed about access to genomic testing in the past five years and where we are seeing success. Damon brings a refreshingly optimistic viewpoint to the show. We talk about everything from PGx testing to whole genome sequencing, which he calls an “amazing win” for reimbursement.

Sarah LeBaron von Baeyer studied anthropology at Yale. Today she serves as the Director of Ethics Engagement at the new drug development company, Variant Bio, not a job she ever imagined at university.

In today’s show, we talk with Kyle Fahr, the VP and Distinguished Scientist leading Illumina’s Artificial Intelligence Lab.

"We lack a way of training genomics AI as readily as you would for natural language processing, says Fahr.  "There are vast amounts of data, but there are no labels, no supervision.  One of the most powerful tools that we’ve found is using clues from natural selection.

Fahr says the company began the AI lab seven years ago when deep learning took off. Two of the team’s AI algorithms, PrimateAI-3D and SpliceAI, published in Cell and Nature Genetics, were among the first examples of deep learning algorithms in genomics to become widely used by clinical labs and researchers in interpreting variants of unknown significance.  

We take a close look at Illumina’s work in AI and delve into the long-term impact of AI on genomics.

Today, we continue our look into the gap in the adoption of precision medicine. Why are those who need it not getting genetic testing? Patrick Short is the Host of The Genetics Podcast and CEO and Co-founder of Sano Genetics.

Through its Center for Personalized Medicine, the University of Colorado Health offers its 2.2 million patients some of the country's most advanced precision medicine initiatives.

A  new spatial biology company is promising to shake up the field. Last month, Curio Bioscience launched a new technology to early access customers that provides transcriptomic spatial data without the need to b…

John Cumbers is back on the show to preview the annual SynBioBeta, the leading global conference for the synthetic biology crowd. This year’s show includes 18 tracks on AI, space, longevity, and DNA synthesis. Speakers will include Stephen Wolfram and Stephen Quake, who will discuss large language models and biology.

While 2024 saw a total investment of over $6 billion (not as high as the pandemic year of 2021), John says the new technologies and startups keep coming.

"We’re seeing just a ton of new entrepreneurs coming out of graduate and undergraduate programs and starting companies.”

John is the founder and CEO of SynBioBeta which takes place May 6-9th in the San Jose Convention Center.

Most of the news coming from Illumina has had to do with their leadership in the sequencing instrument space. What is lesser known is that they offer an end-to-end solution for the clinical lab, including variant calling and genome interpretation.In this podcast, we’re joined by Sam Strom, Principal Scientist at Illumina and a certified Clinical Lab Director.  Sam comes to Illumina from the clinical testing side; for example, he’s co-chair for the expert curation panel for Parkinson’s Disease and sits on a working group at ClinGen.In the interview, Sam addresses two of the big challenges in clinical sequencing, which are variant calling and variant interpretation. Sam says Illumina has created its own multi-sample genomic reference and is also making use of artificial intelligence to improve variant calling. He also shares how Illumina supports scaling variant interpretation for genomes and other assays with an AI and automation comprehensive solution, enabling high-quality genetic testing workflows to reach next level accessibility.“I think we’re going to see more “lights out” testing where there really isn’t an interpretation component to the test.   It’s a pure technical test.  It has certain limitations.  But it gets you 99.9% of the way there.  The technology is ready."

Today, we feature a new DNA synthesis company out of Sweden that is making a name with long, single-stranded DNA at scale. How long? Over 10,000 bases. Why single-stranded vs. genes? And what is meant by scale?According to Cosimo Ducani, CEO and co-founder of Moligo Technologies, the business of making DNA is just getting started.  So much for thinking it was a mature business in the early 2000s when Integrated DNA Technologies (IDT) dominated the market.

The rise of RNA therapeutics and cell therapies promises to take us where we’ve never been in medicine.  The growing understanding of RNA, mRNA, and circular RNA and their crucial roles in disease has led to their application in targeting previously “undruggable” targets.  Meanwhile, new cell therapies are promising cures to diseases that have plagued us without mercy.  Scientists now ask what can’t we do.  Still, biology remains dauntingly complex.At the base of these fields is a revolution in biological engineering. One company stands out with the impressive vision of making engineering biology easier: Boston-based Ginkgo Bioworks. This past month, Ginkgo announced that it was buying three companies to boost its AI footprint in diagnostics and therapeutics. We think of burgers and perfumes, but Ginkgo’s customer base is impressively diverse. Today, we talk with Jennifer Wipf, Head of Commercial Cell Engineering at Ginkgo. Jennifer says FNA is giving drug developers “access to the cell” which is opening up a whole new approach to therapeutics.    How does Ginkgo help out?  What are the promises and challenges?We end with a question about Ginkgo’s new acquisitions to beef up its AI capabilities after last year's partnership with Google.“If  you want to make biology easier to engineer, we need a way to answer some of these questions without doing a lot of lab work."

Chapters:

0:00 Number one unmet medical need for dogs

6:25 Using “extra label” for cross species

12:57 Ideal for understanding human cancers

21:25 Playing catch-up with human medicine

28:04 1,000 pet clinic customers

Precision medicine for dogs?— as in tumor profiling for the right therapies to treat man’s best friends at the right time? Yes, that’s right. …

There’s a new genome editing company that everyone is talking about this year.  Tome Biosciences came out of stealth in December, claiming the ability to insert DNA sequences of any size at any location across in vivo and ex vivo modalities. Their website says they’re “taking us into the final chapter of medicine.”Tome’s CEO, Rahul Kakkar, joins us today on the program.  He’s a physician-scientist (cardiology) who has previously led a couple of biotech companies, Pandion Therapeutics and Corvidia Therapeutics, through initial funding and acquisition.  Rahul says that even though we’ve seen incredible breakthroughs in the gene therapy arena, all of the current editing technologies are “profoundly limited.”  That includes the technology for the first CRISPR-based drug approval, Casgevy.“Gene therapy today is putting a gene into a cell that has no relationship to the genome itself.  It’s quite unrefined.  From a clinical perspective, their impact is limited because their technology is limited.”Why so limited, and what is this great advancement in editing technology that everyone is talking about?  Rahul says the tech is able to “reprogram” a cell.What are the history and current state of the company and this new technology?  How are they dealing with the infamous “off-target effects?”  And what is the overall opportunity?Rahul talks in grand terms.  He says there is a need for genomic-based therapies if we’re going to move medicine away from treating to curing disease.  

0:00 Long reads at scale has made what difference?6:15 The long or short of it:  How does one decide?12:31 Long reads in the clinic20:37 Apton tech to compete with Illumina’s NovaSeq X26:30 Plans for next instruments35:00 Surveying the competitionIn our first post-AGBT show of the year, we’re talking with the CEO of Pacific Biosciences, Ch…

Why aren’t more folks receiving genetic testing?In a study published in JAMA last year, Stanford cancer researcher Alison Kurian found a surprising gap between those who need genetic testing and those who receive it.  Among more than a million patients with cancer, only 6.8% underwent germline testing.Today, we begin a new series exploring this gap in testing with Robert Michel.  He's the Editor-in-Chief at The Dark Report, reporting on the laboratory industry since 1996.   Robert says the problem is multi-faceted and argues that the leading cause is that it takes years for physicians to learn about a new area of medicine.“Factor number one is simply the speed of genetic science,” says Robert.  "You’ve got to train the physician and for them to be able to incorporate genetics in their practice.  It can take years for the average practitioner.  Part two,” he says, "is reimbursement.”We spend the bulk of the interview discussing the role of pathologists in genetic testing, who he refers to as "the guardians of the medical purse."Robert also puts on the leading conference in the lab testing industry, the Executive War College Conference on Diagnostics, Clinical Laboratory, and Pathology Management.  The conference for 2024 is coming up from April 30th to May 2nd in New Orleans.

Batten disease is a group of neurodegenerative lysosomal storage disorders that result from pathogenic variants in one of 13 CLN genes. Collectively, Batten disease affects approximately 1 in 100,000 individuals worldwide, making it the most common pediatric neurodegenerative disorder. The most common form of Batten Disease, CLN3 disease, is a rare and fatal autosomal recessive disorder caused by mutations in CLN3. Individuals with CLN3 disease typically experience vision loss in early childhood, followed by seizures, motor and cognitive decline, and premature death by the third decade of life. Importantly, despite decades of intense research, specific biomarkers of disease status have not been reported, hindering the clinical development of therapies.Today, two researchers join us to talk about how their use of new proteomics tools has pushed their biomarker research forward in novel ways. Jon Brudvig is the Director of Discovery Research and Gene Therapy at Amicus Therapeutics, where he leads biomarker discovery in neurogenerative disease.  He is also an Assistant Professor in Pediatrics at the University of South Dakota. Bruce Wilcox is the Chief Technology Officer at PrognomiQ which is focused on early cancer detection and treatment. “Proteomics technology and the enthusiasm for it are advancing rapidly.  Proteomics is at the stage where it is translating to tools that will help physicians and patients,” says Bruce.   "It’s a lot of fun to talk about what we work on, not just from a research standpoint, but for the impact that is coming from this work."

After ten years, the human brain mapping project has achieved some major milestones, says Tom Nowakowski, a researcher at UCSF, on today’s program.  He says that mapping the brain is a “moon shot” easily on par with the Human Genome Project.So much of biology is basic quantification.  Brain scientists are beginning to quantify how many kinds of brain cells there are.  They are learning more about the function of various cells such as glial cells..  And they are developing a common language with each other.  A few years ago, if you put two brain scientists in a room together, they would not know how to speak to each other.One of the major technologies that have enabled this new quantification and characterization of the human brain is spatial genomics. Tom and other scientists have learned that there are 5,000 transcriptomic clusters that they associate with cell type. '“If you told me ten years ago when I was finishing my Ph.D. that one day we’d be making real progress on neurological and neuropsychiatric disorders without having to rely on a mouse model.  I would think it was unthinkable.  Here we are; we finally have technologies where you don’t need transgenic mouse models to make progress.  That is just terribly exciting.”

Karen Tumulty, a political writer for the Washington Post, was diagnosed with multiple myeloma. She was told she had five years to live.  Then she went to book club with friends. On the way home she came out about her diagnosis—and that changed her life.  Someone in the car happened to be the President of the Personalized Medicine Coalition, Ed Abrahams.  He made a referral and that led to better treatment and better survival. Karen’s story, along with that of her brother, is a must-listen for everyone involved in healthcare.  How does Karen’s story line up with the industry’s stories we tell ourselves? Does she think that the tale of precision medicine is getting out there?“What blew me away at the recent conference,” she says, “was that so many amazing medical advances that I was thinking were way over the horizon are here.”Are they really here, if people have to be in the right book club to hear about them?

Fun fact:  we are composed of 90% bacterial cells and 10% human cells.  Surely, the company that begins to turn that knowledge into health products will be the next billion-dollar startup. Pendulum Therapeutics is doing just that.  Started in 2012, the company now boasts a full product line of probiotics that are not your typical probiotics.  In 2020, the company released a scientific study showing that their glucose control product lowered blood glucose spikes by 30%.“It’s the first microbiome product that has shown that kind of efficacy,” says Pendulum CEO Colleen Cutcliffe.  “We did a placebo-controlled double-blind, randomized trial that showed that compared to placebo, people who were on this formulation could see their A1C go down by 0.6 points, which can be the difference between having diabetes or not.”Colleen is a return champion here on the show, and it’s great to see the company raising real money and pioneering the microbiome space with credibility.  Will naturally occurring probiotics become the next breakthrough in therapeutics?  We’re talking about the "safety of a probiotic with the efficacy of a drug."

"We can now begin to look at disease before it happens,” says today’s guest, Todd Druley.  He’s the Chief Medical Officer at Mission Bio who has been offering the world’s first single cell and multi-omics instrument. 

This month, the FDA approved the first CRISPR-based gene therapy called Casgevy (pronounced with a soft g). It’s a one-and-done treatment for sickle cell disease and is being hailed as major step forward in medicine. Joining us to discuss this breakthrough is our return champion, Kevin Davies, author of Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing and Executive Editor of the CRISPR Journal and GEN Biotechnology.Kevin takes us into the science of the new gene therapy and what it means for patients. He also gives a captivating history of sickle cell disease itself. How will sickle cell patients afford the $2.2 million price list? How has CRISPR as a tool been evolving this year?  What other areas are heating up for gene therapy?  And we do a little catch-up on a certain scandal around genome editing. 

Many of our shows this year have explored a new wave of proteomics tools and research.  So today, we wanted to get a snapshot of the field of proteomics, and to do that, we turned to John Yates III, Ernest W. Hahn Professor at The Scripps Research Institute.  John was on the proteomics side of the famous Lee Hood lab in the 1980s.  The most exciting work to come out of Hood’s lab was the first automated DNA sequencer commercialized by Applied Biosystems and led by Mike Hunkapillar, also from the lab.

This month, a new philosophy of biology series premiers on PBS hosted by Robert Lawrence Kuhn.  The series will go for thirteen episodes and includes over 250 interview clips with some of the world’s leading biologists and philosophers, including Richard Dawkins, Terrence Deacon, Peter Godfrey Smith, and Samir Okasha. Show titles include: Why Philosophy of Biology?, Philosophy of Units/Levels of Natural Selection, and Philosophy of Sex and Gender.Robert joins us today to preview the series, his first in 25 years on biology.  At the heart of the interview is a discussion of reductionism and emergence,  a familiar subject for this show. 

John Shon is the Chief Technology Officer at Serimmune, a company specializing in precision immunology.  Serimmune maintains a library of over 10 million random peptides that can mimic almost any disease.  With this library, they are able to comprehensively map the relationship between antibodies and antigens.What does this mean?  Take COVID, for instance; rather than just offering a diagnostic, Serimmune can show disease history in the body.  They partnered with Moderna to look at the epitopes from their vaccines and boosters.  For those patients who took vaccines, the company saw a different and more focused response to the COVID-19 virus.This is a comprehensive measuring of human immunity.  The technology can be used with almost any disease.  And it picks up cross-disease interactions. So, where is the company today?  And how does John see their powerful technology being adopted in medicine?

Our guest today introduced us to a new kind of immunotherapy called Super-NK.  Imagine CAR-T, but in this case, the immune cells from the patient are not engineered, but rather “supercharged.”  What’s remarkable is that the company is having success with the therapy against neurological conditions such as Alzheimer’s and Parkinson's.Paul Song is the CEO of NKGen Biotech.  The company just presented results from a Phase I trial at the 16th Annual Clinical Trials on Alzheimer’s Disease Conference (CTAD), showing that enhanced killer cells could be an effective treatment against Alzheimer’s.  90% of patients demonstrated improvement or maintained stable cognitive function as per Alzheimer’s disease composite score (ADCOMS) following 11 weeks.Paul says that the idea of treating neurological disease with the super killer cells is quite novel and came somewhat randomly.  They had their sights set on treating cancer.“It’s by chance that we saw some activity with Alzheimer’s disease.  The co-founder’s father, sitting in a nursing home with advanced Alzheimer’s, wanted to know if we were to give him some enhanced NK cells whether that might make his immune system stronger to fend off an infection.  It was not to treat any neurological disorder.”Paul says they were confident that there were no safety issues and decided it was a reasonable thing to treat him.  After three or four treatments, the patient was talking to his son where he hadn’t been able to previously. “Nobody had ever heard of why an NK cell could cause improvement in neurological conditions.  There was nothing in the literature.”Now, with a Phase I trial showing great results, the company is excited to move forward in neuro and hopes to be treating patients by 2025.  What is the supercharging process?  Does Paul now understand more of the science behind these positive results?  And what is the biggest challenge moving forward?

Personalis, a company launched during the early days of whole genome testing and analysis, is claiming to have the most sensitive MRD testing available to date.  They are demonstrating this with the results of their recently released TRACERx study of patients with non-small cell lung cancer. CEO Chris Hall and CMO Rich Chen both join us to profile these exciting results and debut the entrance of Personalis into MRD testing. “This test is 10 to 100 times more sensitive than other tests,” says Rich Chen.  “And so how do we do this?  We’re creating a personalized test for each and every cancer patient.”First making their name in whole genome analysis, Personalis is not only looking at the ctDNA but also sequencing the tumor for each test.   The test is available now.  While the technology is validated for all cancers, Rich and John say they are going after the hardest-to-detect cancers first. What is their goal for the next two years, and how will the company push up the low rate of adoption in the field?   Join us for a comprehensive interview into the next generation of MRD testing.

Chapters:

0:00 Delivering on last year’s announcements

8:50 Illumina

14:25 Long reads

25:50 PacBio vs Oxford Nanopore

31:36 Element

38:27 MGI

45:47 The rise of proteomics

51:20 What next?

The end of the year approaches, and we look back today on the state of DNA sequencing with two of our return champions, Shawn Baker, genomics consultant, and…

Chapters:

0:00   State of the field: reviewing ICoNS conference

22:20 What evidence is enough?

Today, we’re joined by a panel of four guests who have all attended the recent International Conference on Newborn Sequencing held at the Royal Institution in London.  This discussion serves as the second part in a series we are co-producing with GenomeWeb that began with last month’s panel.  At the conference, researchers representing 12 newborn sequencing research programs in the US, the UK, Europe, Australia, and the Middle East discussed their progress to date and future plans.   It’s our good fortune to hear about the conference and get some thoughts on the field going forward.  Julia Karow is the Managing Editor at GenomeWeb, who tracks trends in next-gen sequencing for research and clinical applications.Robert Green is a physician-scientist who directs the Genomes2People Research Program in translational genomics and health outcomes.  He also co-chairs the International Consortium on Newborn Sequencing, the group which hosted the conference.Wendy Chung is Chair of Pediatrics in Medicine at Boston Children’s Hospital.  She directs one of the largest newborn sequencing studies,  called the Guardian Study.James Buchanan is a Senior Lecturer in Health Economics at Queen Mary University in London.  He does research into the health economics of precision medicine and genetic testing, including newborn screening.

Chapters:0:00 Precision oncology is standard of care13:50 Culmination Bio23:25 Hopeful about early cancer screening25:45 Biggest challenge for the field?When Lincoln Nadauld began Precision Genomics at Utah-based Intermountain Healthcare, he told the administrators that precision oncology is coming and will be standard of care. He urged them to d…

Chapters:0:00 What are transcription factors?7:00 The MARMOT platform11:22 In the ’90s, people thought kinases were undruggable19:00 Where’s the company at today?

We begin today’s show with definitions.  What are transcription factors?  What is functional proteomics?  And what is meant by “undruggable?"According to a study in Nature from las…

Chapters:0:00 Attending this year’s Human Proteome Organization (HUPO) conference4:40 Mass spec vs. sequencing8:12 How does the Orbitrap Astral fit into the market?12:55 Customer applications

Thermo Fisher Scientific is a name synonymous with life science tools.  They have been at the vanguard of every important trend in our field for decades.…

Chapters:0:00 What does treatment look like?7:25 Light treatment has been approved for years20:10 Could this be a primary therapy for all cancers?25:05 Challenges?

We often cover new therapies for cancer.  They are usually derived from “chemistry."  But what about using “physics” in a non-invasive way for treatment?  A new company named SonA…

Chapters:0:00  “It’s a magical time.”9:55 Tracking low-concentration proteins in real-time19:20 What next?24:40 Proteins act in community29:30 Challenges ahead?Many new drugs and clinical diagnostics are being derived from proteins. Today we take our proteomics series into the clinic with Jenny Van Eyk from Cedars Sinai Hospital in Los Angeles and Daniel Hornburg of the proteomics company, Seer. Jenny works at that sweet spot with one foot in the clinic and the other in research, specifically tool development.  The two talk about the new ability made possible by Seer’s Proteograph to look at proteins in real-time, to capture not only the biomarker but the activity of the biomarker.  They talk of the importance of being able to see the concerted effort of multiple proteins in developing clinical assays.Jenny highlights her work with the GLP1 peptide, which is key to the new weight loss and diabetes drugs.   She says there are two main ways that proteins regulate the body.  One is through degradation and the other is to be sequestered by other proteins.  “Sometimes only a small portion of the proteins are active.  And that’s what we need to know,”  says Jenny.  "Only by understanding what’s really close to the biology, close to the disease can we get it right."

Today’s show is made free through the generous support of Seer. For decades, a limiting factor in proteomics research has been the inability to access the proteome in ways necessary to survey and understand its diversity. So, Seer created their new Proteograph(TM) to provide a more transformative lens of the proteome.

Today’s show is made free by the generous support of Twist Bioscience. Twist works in service of people changing the world for the better in fields such as medicine, agriculture, industrial chemicals, and data storage. Their unique silicon-based DNA synthesis platform provides precision that is otherwise unavailable. Check out their products at www.twistbioscience.com. And join them as they write the future of science.

Chapters:0:00 Pet dogs have complex genetics and phenotypic data8:00 What is the primary interest of pet owners?16:00 Breeds are relatively new—Victorian era new25:53 Findings that relate to human genetics34:00 Future goalsSummary:Elinor Karlsson began studying pet genetics when doing her PhD.  Today she directs the largest pet dog genetics databases and citizen science projects, Darwin’s Ark (www.darwinsark.org). Elinor is a Professor at UMass Chan and the Broad Institute.Why dogs?  Well, she works specifically with pet dogs who are tied to humans.  Dog owners love learning about their dogs--breed, behavior, anything—almost as much as they love sharing about them.  This opens up an opportunity for researchers to study an animal with complex genetics which also has tons of phenotypic data recorded.

 So what is Elinor able to tell these pet-loving owners?  How is the project improving dog medicine?  And what is canine genetics teaching us about us?

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Chapters:

0:00 World’s longest oligo

8:45 Why is it difficult to synthesize long DNA?

12:00 Proprietary TdT conjugate

16:00 A billion-dollar market

24:20 The computation model and its challenges

28:35 More customers using generative AI

Mendelspod is now reader supported. Please consider upgrading to a paid subscription for the price of a couple cof…

Chapters:0:00 Novel Cas enzymes help overcome CRISPR challenges11:37 New pipeline of therapies will go after novel targets14:52 How does the new platform open up possibilities for new diagnostics?21:05 What risks do you think about?26:47 What are the company’s two-year goals?31:07 On the possibilitiesCRISPR technology is enabling a new generation …

0:00 Latest paper on multi-omics microsampling6:30 Is it useful?  Two scenarios13:00 How might entrepreneurs bring this to healthcare?18:15 How do you convince physicians?25:48 Are you a reductionist?31:00 Impact of generative AI38:15 Thoughts on the renaissance in proteomics

We open our 13th season here at Mendelspod with guest, Mike Snyder, S…

"There's an entire field of fragmentomics with a whole lot of people working on it. The DNA which is shed into the bloodstream has a certain length. The length of ctDNA is shorter than cfDNA, and depending on where the cancer cell is located, the fragment size and pattern is different. So you can actually deduce information about the tissue of origin from the fragment length and pattern. And that's just the beginning."