Mendelspod Podcast

An inventor of Solexa sequencing by synthesis has a new idea.
On today’s show, Sir Shankar Balasubramanian revisits the accidental origins of Solexa sequencing, born not from a sequencing project at all, but from curiosity-driven experiments watching DNA polymerase at work. What followed helped transform DNA sequencing from a specialized pursuit into a routine engine of modern biology. But as Shankar makes clear, the biggest surprise may not have been genomics itself—it was how next-generation sequencing became a universal readout for biology, powering everything from single-cell and spatial biology to entirely new ways of probing molecules and mechanisms.
Our conversation then turns to his latest venture, Biomodal, and the emerging world of 6-base sequencing. Shankar explains why distinguishing 5mC and 5hmC matters, and how six-base sequencing may improve early cancer detection. 6-base sequencing could also aid researchers in the exciting frontier of neurobiology.
As always with great scientists, the story widens beyond any single technology. Shankar closes by reminding us that discovery follows better measurement. As our tools improve, biology will continue to surprise us.
“That is what research is. It’s stepping into the unknown,” he says.


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You’ve heard of 5-base genomics. How about 6-base? It turns out that separating 5-methylcytosine (mC) and 5-hydroxymethylcytosine (hmC) is pretty important.
Peter Fromen has had a front-row seat to the evolution of sequencing, from the rise of high-throughput genomics at Illumina to long-read technologies at PacBio. Now, as CEO of Biomodal, he’s focused on integrating genetics and epigenetics into a single workflow—and showing that the regulatory layer of the genome may be where the next breakthroughs lie.
Chapters:
0:00: Why epigenetics needed a reset12:07 The colorectal cancer study and early detection signal16:41 Building the 6-base ecosystem21:23 Commercial traction and the road to the clinic
In today’s program, Fromen explains why distinguishing between mC and hmC changes how we read biology. Biomodal’s recent colorectal cancer study begins to demonstrate that value in practice.
“We ultimately ended up generating an AUC of 95%,” he says, describing early-stage detection results that point to the power of combining both signals.
More broadly, he frames hydroxymethylation as an early indicator of disease.
“hmC is essentially the canary in the coal mine for early disease detection.”
We also discuss the practical side—what a 6-base workflow looks like in the lab and where the company sits commercially as it pushes toward clinical validation.
Will this be the new standard for how we read biology?


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There’s a famous line attributed to Ernest Rutherford, the father of nuclear physics: “All science is either physics or stamp collecting.” It’s still provocative. But it’s unfair to biology. Long before today’s omics era, biologists were uncovering causality everywhere from evolution and natural selection to Mendelian inheritance. They have never merely catalogued life. They have explained it. But modern biology has also generated extraordinary inventories of genes, proteins, and pathways, and those inventories now invite a deeper systems-level question: how do the parts behave together in living cells? Could new precise physical measurements aid biology and medicine?
Todays’ guest, Erdinc Sezgin, is an Associate Professor at Karolinska Institute and recipient of the Biophysical Society Early Independent Career Award. His lab is bringing physics to biology. For example, Sezgin studies the cell membrane not as a passive wrapper, but as an active, dynamic system whose physical properties of fluidity, viscosity, charge, and organization help determine how cells signal and survive. His hope is to improve ways to measure these biophysical properties.
Sezgin discusses his recent collaboration with Pixelgen Technologies, where Molecular Pixelation was used to study how changing membrane charge reshapes the cell surface. By knocking out a lipid-regulating complex, Sezgin and his colleagues showed that living cells can adopt surface features that alter immune recognition and may help explain how cancer cells evade destruction. It’s a reminder that major biological insights often arrive hand-in-hand with new tools that make previously hidden phenomena measurable.
The conversation closes on a broader point about scientific boundaries. Biology is not separate from physics or chemistry, but an expression of them in living systems.
“Cells don’t have physics, chemistry, biology. . . It is life,” he says.


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What is the value of someone’s genome over their life? Is a genome today what it was 10 years ago? How does the adoption of genomic testing compare to other areas in medicine, such as imaging or electronic health records?
Today we take a pretty comprehensive look at genomic testing in practice with Damon Hostin, Head of Market Access, Clinical Solutions at Illumina. Damon brings a rare perspective to this conversation. He’s been in the field since the Celera era, when sequencing was helping define modern genomics, and he’s also worked on the front lines in a large community health system, CommonSpirit Health. At Illumina, he speaks regularly with payers and other stakeholders.
Across oncology, rare disease, reproductive health, and pharmacogenomics, Damon describes a field that has clearly moved into standard of care in key areas—but is still very much in the phase of identifying the “eligible but under-tested.” Adoption is real, but it’s incomplete.
Chapters:
0:00 Genomic medicine arrives4:51 Genomics, imaging, and the EMR11:23 Oncology—from diagnostics to decision-making18:16 Rare disease and reproductive genetics28:51 The lifetime value of a genome36:03 Cost, quality, and what a genome is
A central idea running through the podcast is that the genome is no longer a one-time diagnostic. Its value compounds over time as databases grow, variants are reinterpreted, and new therapies emerge.
At the same time, even the basic notion of what a “genome” is, is beginning to shift. With the rise of multi-omic data—transcriptomics, proteomics, methylation—the question is no longer just cost per genome, but what kind of biological insight we’re actually measuring. “A genome isn’t a genome isn’t a genome,” Damon says.
He ends with a line that neatly reframes the entire debate around cost: “When you look at the cost of healthcare . . . the cost of the genomics is almost nothing.”
Genomic medicine is here. We’re now wrestling with how to scale it, how to use it earlier, and how to make it part of the everyday infrastructure of care.
Note: For more discussion and analysis on this topic, check out this upcoming Virtual Roundtable Discussion at GenomeWeb.



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Fei Chen of the Broad Institute describes the original problem simply: genomics gave us powerful inventories of gene expression, while microscopy gave us structure—yet the two lived in separate worlds. “You could either have your structure or you could have gene expression, but you couldn’t have both.”
In this conversation, Fei walks us through how Slide-tags—now commercialized as Takara Bio Trekker technology—set out to close that gap. Instead of mapping gene expression onto a grid, his team flipped the problem: barcoding the cells in place, then reading them out with single-cell sequencing. The result is something closer to a GPS system for cells.
What this unlocks is not just better maps, but better biology. Better questions. In cancer, Fei describes the discovery of local immune “circuits” that determine whether tumors respond to immunotherapy. And more broadly, spatial data turns tissue itself into a kind of experiment itself. Is this the biology of the future? “The spatial context is a natural experiment that has happened.”
Chapters:
0:00 The problem: structure vs gene expression1:36 A GPS for cells8:59 Immune circuits and cancer response20:04 Tissue as experiment26:24 New questions for biology
Across applications, Fei emphasizes that the real shift is conceptual. Spatial biology is not just about adding location to sequencing. It’s about learning how to ask new questions—ones that treat cells not as isolated units, but as participants in research.



This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit www.mendelspod.com/subscribe