Smart Biotech Scientist | Master Bioprocess CMC Development, Biologics Manufacturing & Scale-up, Cell Culture Innovation

What happens when we move beyond oversimplified cell cultures and truly embrace the complexity of human biology? In this episode of the Smart Biotech Scientist Podcast, we explore how advanced 3D cell models are reshaping preclinical research—recreating human tissue microenvironments to better understand tumors, immunotherapies, and gene and cell therapies.
David’s guest is Catarina Brito, Principal Investigator at ITQB NOVA and Head of the Advanced Cell Models Laboratory at iBET and ITQB NOVA (Portugal). Her work bridges academia and industry through iBET, a unique partnering organization that integrates cell engineering, bioprocessing, and translational modeling.
Catarina’s pioneering models help both pharma leaders and startups predict drug resistance and immunogenicity earlier and more reliably, accelerating the path to safer, more effective therapies—well before clinical trials begin.
Topics discussed:
Understanding the contribution of stromal and immune cells to therapy outcomes in tumor microenvironments (03:42)
Studying immune responses to gene therapy vectors with advanced neural models (04:31)
Combining multi-omics and spatial data with AI for predictive biology and patient-specific digital twins (05:16)
Catarina’s advice: Start simple, let the biological question dictate model design, and avoid premature overengineering (06:53)
Importance of reproducibility, process controls, and standardization in advanced models (08:10)
How academic-industry collaborations drive model development, scalability, and real-world relevance (08:42)
Common pitfalls: Overengineering, poor cell source selection, insufficient system validation (11:03)
Next steps for precision medicine and translational research using advanced cell models (13:08)
Want to know how leading scientists make advanced cell models actionable and collaborative for pharma breakthroughs? Tune in for practical strategies, real-world collaborations, and pitfalls to avoid as you scale your own translational research.
Connect with Catarina Brito:
LinkedIn: www.linkedin.com/in/catarina-brito-ibet
Advanced Cell Models Lab – iBET: www.ibet.pt/laboratories/advanced-cell-models-lab
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What if the failure rate in clinical trials isn't about picking the wrong drug candidates—but about testing them in the wrong models?
When you move cells from a 2D culture plate into a bioreactor, you're not simply scaling volume. You're fundamentally changing the biological context. Cell density shifts. Mass transfer dynamics evolve. Mechanical cues emerge. The cells sense these changes and respond—often in ways that derail strategies built on oversimplified assumptions.
Most preclinical research still relies on flat plastic surfaces and animal models that miss critical aspects of human biology. The result? Therapeutics fail late in development because the models couldn't predict how human tissues would actually respond.
In this episode, David Brühlmann speaks with Catarina Brito, Principal Investigator at ITQB NOVA and Head of the Advanced Cell Models Laboratory at iBET and ITQB NOVA in Portugal. Catarina's career-defining insight came early: studying glycan-protein interactions in murine versus human cells revealed that species differences weren't just nuances—they were fundamental gaps that could mislead entire research programs.
Catarina and her team have developed neural, liver, and tumor models that capture the multicellular complexity and microenvironmental cues that 2D cultures cannot replicate. Her work creates preclinical models sophisticated enough to predict human responses while remaining scalable for drug development workflows.
Highlights of the episode:
Limitations of traditional 2D cell cultures and animal models in capturing realistic tissue behavior and therapeutic responses (06:27)
Catarina Brito's personal scientific journey: from discovering model limitations to pioneering 3D culture systems in neural and liver tissues (04:19)
How advanced 3D models recreate cell-to-cell interactions, tissue-specific microenvironments, diffusion gradients, and multicellular complexity (10:35)
Regulatory movements toward reducing animal models, and the challenge of validating advanced alternatives for systemic biology studies (09:10)
Key differences in designing bioreactors for various cell types, with practical examples from liver and neural models (15:16)
The impact of scalable, robust 3D models on accelerating drug development and improving selection of candidate therapies (17:22)
Key Takeaway:
Bioprocess development starts when you choose the model that validates your therapeutic approach. If that model can't capture the biology that matters, every downstream optimization is built on a flawed foundation.
In Part 2, Catarina reveals how 3D tumor microenvironments expose drug resistance mechanisms invisible in 2D cultures, and her vision for AI-powered digital twins enabling personalized medicine.
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Connect with Catarina Brito:
LinkedIn: www.linkedin.com/in/catarina-brito-ibet
Advanced Cell Models Lab – iBET: www.ibet.pt/laboratories/advanced-cell-models-lab
Next step:
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The biotech industry stands on the verge of a radical transformation thanks to artificial intelligence (AI) and machine learning (ML). But even the most sophisticated algorithms are only as smart as the data feeding them.
David Brühlmann sits down with Troy Lionberger, Chief Business Officer at A-Alpha Bio, whose team has quietly shattered the data ceiling by measuring and curating more than 1.8 billion protein interactions. Troy Lionberger brings an insider’s perspective from the frontlines of machine learning-powered drug discovery. From partnering with leading biotechs to redesigning classic antibodies for previously “impossible” targets, Troy’s work pushes the edges of what’s tractable in biologic therapeutics.
What you'll hear in this episode:
Limitations of public data sources like the Protein Data Bank and their impact on current protein engineering approaches (03:11)
Why combining energetic (ΔG) and structural data matters for building predictive protein engineering models (05:43)
A-Alpha Bio’s approach to generating 1.8 billion protein interaction measurements for machine learning—what this enables today and what’s possible next (06:30)
Examples of how A-Alpha Bio’s platform solves challenging therapeutic problems, such as optimizing molecules for 800+ HIV variants and engineering dual-specific antibodies (07:36)
The ongoing debate: What capabilities should biotech companies keep in-house, and what works best outsourced to service providers? (09:59)
The potential of synthetic epitopes as vital tools for training models beyond the Protein Data Bank—introducing the Synthetic Epitope Atlas (12:09)
Key takeaways for scientists: the importance of diligence amidst rapidly evolving AI claims, and advice for accelerating R&D with the right data (14:57)
Wondering how to move protein therapeutics from “interesting” to “impactful” without waiting for years of crystal structures? Listen in to learn how you can harness next-gen machine learning tools and custom datasets for your development projects.
Connect with Troy Lionberger:
LinkedIn: www.linkedin.com/in/troylionberger
A-Alpha Bio website: www.aalphabio.com
Next step:
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Antibody therapeutics have transformed modern medicine, but for many scientists, developing new candidates still feels like searching for a needle in a haystack—a slow, expensive, and unpredictable process. Structural biology and high-throughput data generation are now collapsing that haystack, offering unprecedented visibility into the molecular handshake that drives life: protein-protein interactions.
In this episode, David Brühlmann sits down with Troy Lionberger, Chief Business Officer at A-Alpha Bio, for an in-depth discussion on protein-protein interactions and how advances in data generation and machine learning are transforming antibody discovery and drug development.
Troy Lionberger shares his journey into biotechnology, challenges long-held beliefs about antibody development, and explains how Alphabio's high-throughput affinity measurements are shortening timelines and improving outcomes for therapeutic development.
In this episode, you’ll learn about:
The historical and current challenges in characterizing these interactions at scale (06:22)
How new technologies—especially high-throughput platforms—are changing the needle-in-the-haystack approach (08:40)
A comparison of traditional in vivo and in vitro antibody discovery methods, along with their strengths and limitations (09:06)
The evolving role of AI and machine learning in antibody discovery and lead optimization (12:11)
Real-world examples of how A-Alpha Bio’s approach is compressing years of work into months without sacrificing quality (13:58)
The science behind A-Alpha Bio’s AlphaSeq technology and how it leverages yeast display and genomics for large-scale affinity measurements (20:43)
The practical affinity range the technology can measure, covering most therapeutic applications (23:25)
Whether you’re a scientist navigating CMC or a biotech professional curious about next-generation workflows, this episode offers practical insights into both traditional and emerging methodologies in the field.
Connect with Troy Lionberger:
LinkedIn: www.linkedin.com/in/troylionberger
A-Alpha Bio website: www.aalphabio.com
Next step:
Need fast CMC guidance? → Get rapid CMC decision support here
One bad CDMO decision can cost you two years and your Series A. If you're navigating tech transfer, CDMO selection, or IND prep, let's talk before it gets expensive. Two slots open this month.
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For generations, silkworm pupae were discarded as waste from silk production. Now, KAICO is proving these organisms can function as highly efficient protein factories—producing complex vaccine antigens at yields and costs that challenge conventional bioreactor-based manufacturing. With a PCV2 oral vaccine already registered in Vietnam and a human norovirus vaccine preparing for Phase I clinical trials, the silkworm platform is moving from proof-of-concept to commercial reality.
In Part 2, Masafumi Osawa, Business Development Lead at KAICO, walks us through the company's product pipeline, the regulatory landscape for this unprecedented platform, and why silkworm-based manufacturing could reshape global vaccine accessibility. From farm-scale validation to regulatory dialogue with Japan's PMDA, this episode bridges platform science with product development.
Stops along our Silk Road to biomanufacturing
KAICO’s approach to expressing complex proteins, including oral and injectable vaccines for animals and clinical-stage human health products (00:40)
Immune-enhancing feed additive for pigs against PCV2 (registered in Vietnam), companion animal products, and human norovirus vaccine entering Phase 1 trials (02:50)
Advantages of silkworm-produced antigens for both injectable and oral vaccines, and comparison to plant-based systems (04:57)
How silkworm production enables rapid scale-out and high-yield protein expression for global accessibility (05:34)
Speed of vaccine development with the silkworm platform—example with SARS-CoV-2 recombinant protein produced in three months (08:08)
Key regulatory differences between animal and human vaccine development, including country-specific classification and global harmonization efforts (09:14)
Sustainability and distributed manufacturing potential of silkworm-based systems (11:10)
Milestones toward the first human biologic produced in silkworms, with phase 1 trials starting soon (12:27)
Protein yield per silkworm pupae—scalability advantages compared to conventional bioreactor approaches (14:04)
Masafumi Osawa’s thoughts on the future of silkworm-based biologics: from democratized therapies to personalized medicines (15:15)
Want to know if silkworms can solve your tough protein expression problems? Tune in now to learn how KAICO’s biotech is set to redefine what’s possible for vaccine development, and how their distributed, cost-effective approach could open doors across sectors.
Connect with Masafumi Osawa,:
LinkedIn: www.linkedin.com/in/masa-osawa
KAICO Ltd.: www.kaicoltd.jp/en
Next step:
Need fast CMC guidance? → Get rapid CMC decision support here
Support the show