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.