Deterministic Programming of iPSCs for Disease Modeling

Article Summary

Fiona Connolly, formerly Platform Innovation and Automation Scientist at bit.bio, joins Absolute Gene-ius to discuss how deterministic programming is reshaping stem cell biology, disease modeling, and drug discovery. With a background spanning molecular biology, cell engineering, and automation, Fiona brings a unique perspective on how genetic “cheat codes” can precisely control cell fate.

In this episode, she explains how induced pluripotent stem cells (iPSCs) can be programmed into highly defined cell types using transcription factors, and how technologies like digital PCR, qPCR, and RNA-seq ensure consistency and scalability. Her work highlights a future where reproducible human cell models accelerate research while reducing reliance on animal testing.
Listen to the full episode: thermofisher.com/absolutegeneius

What Are iPSCs and Why Do They Matter in Disease Modeling?

What are induced pluripotent stem cells (iPSCs)?

Fiona Connolly:
“So they are the induced pluripotent stem cells. And what it means is you’ve taken an adult cell, so for instance, like it will be a cell that might have been donated, but you take the known factors, and it’s a fundamental process. It’s a very famous fundamental process where you can revert that cell from an adult cell, back into a pluripotent stem cell. So you take it from its predestined perhaps it’s a skin cell now, and you essentially send it back in time so that it can become anything. And that’s kind of the thinking behind the pluripotent. It has the power to become any cell type that it can essentially. It’s almost like an embryonic stage.”

Why are specific cell types like neurons or oligodendrocytes important to research?

Fiona Connolly:
“It’s really a lot about looking at diseases. So there’s one, there’s a fundamental to understand, so to understand the pathology, so the mechanism of disease, and also researching the treatment of the disease. So there’s two aspects to it, but it’s all about disease research and human health at the end of the day. So we want to understand ourselves, our bodies, better, and also understand the disease versions of those.”

“So for instance, with our oligodendrocytes, our OLCs, which is oligodendrocyte-like cells, they’re the myelinating cells in the brain. And so they’re the myelinating cells of all those nerve cells that you have. And so for instance, with multiple sclerosis research, which is can be a very debilitating disease… when you destroy that myelinating sheath… those nerve cells wear away… and then your ability to pick things up… or even walk as you want, starts to also get degraded.”

How Does Deterministic Programming Control Cell Fate?

What is deterministic programming in stem cell engineering?

Fiona Connolly:
“And so what it does is it allows you to put in the factors that you need, in the way that you want, and then switch them on to turn an iPSC into a cell type that we have predefined. So it’s called deterministic programming. And so you predetermine what that cell is going to be, you give it cell fate, you tell it where to go.”

“So what we try to do is we find the cheat code. So the factors that tell it, “I’m going to be a neuronal cell, I’m going to be a myocyte,” we find those sort of like little coordinates, and we say, “Okay, this is what you need. This is how you get to myocyte.” So we’ll put these in, we’ll give you the cheat codes, and then we switch them on, and it gets straight to neuronal, straight to myocyte.”

How does this compare to traditional iPSC differentiation?

Fiona Connolly:
“So I think typically with iPSC differentiation, it is a stochastic process… it could end up over here in the neuronal side. It could end up towards the cardio heart cells. It’s never 100% sure where you’re going to do, what’s going to happen.”

“So your typical directed differentiation models that people do, iPSC, they, they can take months… and you can get a completely different version of the OLCs each time with your classic differentiation.”

How Do Digital PCR and Real-Time PCR Enable Scalable, Consistent Cell Engineering?

How are engineered cells validated and characterized?

Fiona Connolly:
“So we do a lot of expression-based assays. We’ve used a lot of qPCR, traditionally, and then we brought in digital PCR.”

“So we can use multiplexing, so that we can answer four questions in one reaction, we can say, ‘Okay, is it where I need it to be? Do I have everything I need? Is it in the right way around? And do I have as many as I need?'”

“So it’s been really great for that, because you can quantify with it, and that’s what we really like. We can quantify our transgene copy number. We can really look at it, and we can look at it from batch to batch, from clone to clone.”

Why is consistency so critical in cell engineering?

Fiona Connolly:
“And what we’re really focused on, and what is the key underpinning value of this is that it’s consistent. Each time you do this process, you get the exact same cell type out, and it behaves the exact same way.”

“We’re looking to scale up the cells that we make at bit.bio but we still want to make them exactly the same every time. And that is one thing that robots really excel at doing exactly what you tell them to do. So we’re building very large-scale systems for the production of these cells so we know that it’s consistent in the handling. It’s consistent in the programming, so it’s consistent all the way through.”

What Is the Future of iPSC Technology and Drug Discovery?

How could deterministic iPSCs transform research?

Fiona Connolly:
“They’re trying to create cell types that didn’t exist… these kinds of cell types allow that access to what a researcher wants to study.”

“So to be able to move away from those things, animal models… the regulatory bodies have sort of started to recognize this as well, so they start looking at new approach methodologies.”

What’s next for in vitro and in silico biology?

Fiona Connolly:
“So we can create those accurate models. We can generate all that data… and with that, hopefully we can start to build in silico cells. And you can do in silico tests… and not have to do anything at the bench.”

“So I think that idea that we could just be more efficient with much less resources based it at the bench would be super nice.”

Explore More from Absolute Gene-ius

Deterministic programming, digital PCR, and automation are redefining how scientists approach disease modeling, drug discovery, and scalable cell engineering. Fiona Connolly’s insights highlight a future where precise, reproducible human cell models accelerate breakthroughs in neuroscience and beyond.

To hear the full conversation and explore more episodes featuring cutting-edge science, visit thermofisher .com/absolutegeneius and discover how researchers are pushing the boundaries of biology.

Learn more about qPCR technologies by exploring here.

To learn more about the Applied Biosystems QuantStudio Absolute Q dPCR System, visit thermofisher.com/dPCR