For centuries, silkworms have spun threads that bound empires and launched markets. Today, the quiet revolution brewing at KAICO is transforming these creatures from textile icons into potent bioreactors, with the potential to rewrite the rules of recombinant protein production.

In this episode from the Smart Biotech Scientist Podcast, David Brühlmann meets Masafumi Osawa. Trained in cultural anthropology—and shaped by frontline experiences in pharmaceutical business development—Masafumi now leads global strategy at KAICO. 

His journey, from observing healthcare access disparities in Indonesia to championing silkworm-based biomanufacturing, brings a fresh perspective that’s bridging science, business, and public health in unexpected ways.

Key Topics Discussed

• Quality management ensures SPF-grade pupae, controlled diet, rearing, and environment for consistency.
• Silkworms evolved from silk production to biologics, inspiring KAICO’s pioneering innovations.
• Baculovirus expression platform enables GMP-grade recombinant protein production using silkworm pupae.
• KAICO commercializes academic silkworm research to supply reagents and co-develop vaccine antigens.
• Masafumi Osawa transitioned from anthropology and generics to biotech innovation and global partnerships.
• Silkworm platforms offer natural protein folding, high yield, scalability, but require careful variability management.
• Silkworm pupae provide cost-effective, sustainable protein production with higher yield than traditional systems.
• Downstream processing mirrors conventional purification while maintaining cleanroom safety and sterility standards.
• Silkworm platform expresses diverse proteins while facing unique GMP, safety, and regulatory challenges.

Episode Highlights

• Masafumi’s transition from anthropology to biotech, and how cross-cultural expertise benefits global health collaborations. [04:15]
• The founding story of KAICO, spun out from Kyushu University and focused on recombinant proteins and vaccine antigen production. [08:45]
• Step-by-step overview of the silkworm baculovirus expression system, including pupae handling and bioprocessing basics. [10:28]
• Practical differences between silkworms, E. coli, mammalian, and insect cell culture platforms—exploring advantages and drawbacks. [13:10]
• Strategies KAICO uses to control silkworm variability, including SPF grade sourcing, diet, environment, and documentation for pharmaceutical acceptance. [15:08]
• Production scalability: a single pupa can match 100–1000 ml of insect cell culture, with major implications for cost and environmental footprint. [16:42]
• Downstream harvesting and purification—how KAICO extracts and processes proteins from silkworm pupae, keeping methods largely familiar to traditional systems. [19:31]
• Regulatory and GMP challenges of using live organisms, and KAICO’s approach to satisfying authorities and ensuring product consistency. [21:43]

In Their Words

Right now we are working on developing a human norovirus vaccine which is about to enter into a Phase I clinical study next year. So our local authority also asked us how does KAICO manage the quality of the silkworm? So one answer is that we use SPF-grade parent brood (PB) from specialized cell culture facilities, strictly control diet quality, rearing conditions, environmental monitoring, and breeder documentation.

So we collaborate closely with the PMDA, Japan’s Pharmaceuticals and Medical Devices Agency, to establish the acceptance criteria and ensure alignment with pharmaceutical expectations in terms of the differences of each silkworm PB.

Episode Transcript: Silkworm Biomanufacturing: From Ancient Silk Production to Phase I Vaccine Trials - Part 1

David Brühlmann [00:00:50]:
For over 4,000 years, silkworms have spun silk that would eventually connect civilizations and through ancient trade routes. But what if these creatures could do more than weave fabric? What if they could manufacture life-saving biologics? Today’s guest, Masafumi Osawa from KAICO, is pioneering exactly that transformation. His team has developed the silkworm–baculovirus protein expression platform that turns these living organisms into natural bioreactors. Join us as we explore how this technology is evolving from university research to GMP manufacturing reality and what it means for the future of protein production.

Welcome Masafumi, to the Smart Biotech Scientist. It's good to have you on today.

Masafumi Osawa [00:02:51]:
Thank you very much for having me today, David. I'm truly excited to be here.

David Brühlmann [00:02:56]:
Masafumi, share something that you believe about bioprocess development that most people disagree with.

Masafumi Osawa [00:03:04]:
Many people assume a living organism can't be a reliable or consistent biomanufacturing unit, especially when it comes to pharmaceutical-grade materials. But based on our work, I believe the opposite is true. A silkworm can be a highly powerful and surprisingly consistent bioreactor, capable of producing a wide range of recombinant proteins, including vaccine antigens. There has never been a human medicine produced directly from a live silkworm. That's precisely why people question the quality and safety. Yet our experience is showing that silkworm-derived proteins can meet modern pharmaceutical expectations. And with the right controls, this platform can create new possibilities for biomanufacturing.

David Brühlmann [00:03:53]:
I'm looking forward to our conversation, Masafumi, to unpack this and to understand how you produce pharmaceuticals in silkworms. Before we do that, let's talk about yourself. Draw us into your story—what sparked your interest in biotech, and what were some pivotal moments that led you to your current role?

Masafumi Osawa [00:04:15]:
Unlike most of the listeners of Smart Biotech Scientist, my academic background is actually in cultural anthropology, not molecular biology or biochemistry. So during my university studies, I conducted fieldwork on Indonesian society as part of my research. Indonesia is a country rich in cultural diversity, but through my study I also witnessed large disparities in access to healthcare, limited access to clean water, financial barriers to basic medicines, and gaps in essential health services. These experiences made me want to contribute to global health in a more structured way, and this led me to join Towa Pharmaceutical, a Japanese company specializing in orally disintegrating tablets. I began my career as a medical representative and later moved into international business development. I conducted market research in Taiwan and Mongolia, identified product–market fit, and supported regulatory strategies for each region. It was fulfilling to watch new products reach patients and see their real-world impact.

But during the COVID-19 pandemic, coincidentally around the time my child was born, I began reevaluating my career path. I appreciate the importance of generics, but I also realized that generics only exist because someone first innovates and pushes the boundaries of drug development. I felt drawn toward innovation, toward work that might genuinely shift the trajectory of public health. Around that time, JEPRO was strengthening its focus on domestic vaccine development. That was when I discovered KAICO and the silkworm–baculovirus protein expression platform. While my first reaction was a mixture of shock, fascination, and respect, the idea that a silkworm—a small and fragile creature domesticated for thousands of years purely for silk—could produce complex recombinant proteins normally requiring expensive bioreactors was astonishing. I remember thinking, if this organism can produce such complex molecules, it could change the way we address disease.

However, when I entered KAICO, I faced an immediate challenge. I had only worked with small-molecule drugs and needed to learn the fundamentals of proteins, expression systems, and the differences between manufacturing platforms. Thankfully, with 90% of KAICO's employees coming from technical backgrounds, I was surrounded by researchers who generously supported my learning. This environment helped me rapidly bridge the gap, and interestingly, my anthropology background became a strength rather than a mismatch. Understanding how different societies collaborate, how decisions are made in different cultural contexts, and how technologies are adapted across regions became extremely valuable.

KAICO now works actively with international partners in Vietnam, Thailand, and Europe, and my ability to navigate cross-cultural communication has become central to my role. And today, as Business Development Lead, I introduce KAICO's platform globally, support partners working with complex protein targets, promote our first immune-enhancing feed additive product for pigs, and build co-development alliances not only for vaccines, but also for broader protein-based R&D programs. Looking back, joining KAICO was a natural extension of my original interest—connecting people, bridging cultures, and contributing to public health, this time through biotechnology.

David Brühlmann [00:08:11]:
I love listening and discovering your story, and I love seeing that it's not linear. You started at one end and now you ended up in biotech. How fascinating is that? And also what resonated with me is when you were saying you had a non-biotech background, but actually this very experience from your studies is a huge advantage. I love that. So tell us a bit more about how KAICO started as a university spin-off and what the vision is behind your silkworm platform.

Masafumi Osawa [00:08:45]:
Okay, so KAICO was founded at Kyushu University, one of Japan's leading institutions for entomology, with over 100 years of history and more than 450 unique silkworm strains. Our CEO, Mr. Yamato, encountered the silkworm–baculovirus expression system while studying in an MBA program. He was searching for dormant academic technologies with commercial potential, and when he discovered this platform, he recognized its significance immediately. Together with Professor Kusakabe, the principal scientist behind the system, they founded KAICO in 2018.
The company initially focused on two goals: producing recombinant research reagents derived from silkworms and collaborating with pharmaceutical companies to develop recombinant vaccine antigens and APIs. But beyond those objectives was a broader vision. If silkworm pupae could reliably express complex proteins at high yield, they could transform the landscape of biologics manufacturing. Making that vision a reality became KAICO's mission—changing the world with silkworms.

David Brühlmann [00:10:09]:
So let's look at the silkworm more specifically. How do you inject a recombinant baculovirus into a silkworm, and how do you quote-unquote culture your silkworms? Do you just let them grow and eat mulberry leaves, or are they swimming in a bioreactor, or how does that work?

Masafumi Osawa [00:10:28]:
Let me walk you through the basics. So the silkworm system works through a straightforward but powerful mechanism. First, we design the DNA sequence for the protein of interest. This sequence is inserted into a baculovirus vector that infects only silkworms. Once the recombinant virus is ready, we inject a small amount into the silkworm pupa. Over the next four to five days, the virus spreads throughout the pupa, infecting its cells. Each infected cell begins producing the target protein based on the inserted gene.

During the metamorphosis stage, the pupa becomes a highly active biological environment with diverse cell types, abundant molecular chaperones, and physiological conditions that support the correct folding and assembly of complex proteins. So practically speaking, the entire pupa functions as a compact, pupal cell–contained bioreactor with extremely high cellular density.

David Brühlmann [00:11:36]:
And these worms, where do you keep them? Are they in a container or where do they live?

Masafumi Osawa [00:11:44]:
So we purchase all the silkworm cocoons from local farmers or certified manufacturers. Inside each cocoon there is a pupa. We first cut open the cocoon, remove the pupae, and place them in containers, which are then stored in a refrigerator. In the refrigerator, they go into hibernation, and we can keep them for up to one month, or sometimes up to two months, before injecting the baculovirus.

David Brühlmann [00:12:14]:
And how long does the quote-unquote production process last? Is this a few days or weeks until you harvest?

Masafumi Osawa [00:12:22]:
So after inoculating the baculovirus, it takes just four to five days until the target protein is fully expressed inside the body of the pupa. After that, we purify the protein to obtain the reagent. So overall, it can take one to two months if we already have the right construct for the target protein.

David Brühlmann [00:12:41]:
And what I heard is that since the virus infects the entire worm, all different cells express your protein of interest. Is that correct?

Masafumi Osawa [00:12:51]:
Yes, you're correct.

David Brühlmann [00:12:52]:
Okay, let's compare this now to more traditional platforms such as E. coli or mammalian cells, for instance, or conventional insect cell cultures. What are, I'd say, the key advantages of your system, or perhaps also some drawbacks versus the other systems?

Masafumi Osawa [00:13:10]:
So when comparing silkworms to other expression systems, several differences stand out. Compared to E. coli and yeast, silkworms offer more natural folding and more mammalian-like post-translational modifications. These characteristics are especially important for structural proteins and multi-subunit complexes.

Compared to insect cell lines like Sf9 or Hi5, silkworms often provide higher yields, better folding integrity, and dramatically simpler scale-out production. Insect cell lines require large bioreactors, expensive media, and extensive facility infrastructure. Silkworms require none of those. And compared to CHO cells, the gold standard for therapeutic production, silkworms avoid the need for costly media, large-scale tanks, and significant water consumption.

So silkworm-based production follows a fundamentally different philosophy. Instead of scaling up by building larger tanks, we scale out simply by increasing the number of pupae.

David Brühlmann [00:14:19]:
And I guess because you're scaling out and not up, you can much more quickly adapt to different demands, right? Because you're much more flexible. Now, something that comes to my mind—and also that resonates with your first statement about what you think is different from perhaps other people in our field—there are a lot of advantages to using a living organism, as you said. Definitely the cost is much lower. That's one of them. And the drawback, or potential drawback, that comes to my mind is how do you manage the variability? Because if you, for instance, have a CHO cell line, that's a clonal cell line, so it's always the same clone. But I guess in your system you have some genetic variability between one worm and another. How do you manage this?

Masafumi Osawa [00:15:08]:
Thank you very much. That's a very important question. Actually, right now we are working on developing a human norovirus vaccine, which is about to enter Phase I clinical study next year. So our local authority also asked us how does KAICO manage the quality of the silkworms. One answer is that we use SPF-grade parent brood (PB) from specialized sericulture facilities, strictly control diet quality, rearing conditions, environmental monitoring, and breeder documentation. We also collaborate closely with the PMDA, the Japanese Pharmaceuticals and Medical Devices Agency, to establish acceptance criteria and ensure alignment with pharmaceutical expectations in terms of variability among individual silkworm PB.

David Brühlmann [00:16:00]:
And by doing this you can manage the variability. So you can make sure that from one batch to another you get the same product at the end of the day. Because in biologics we say the process is the product. So I imagine that in your system this is true as well.

Masafumi Osawa [00:16:17]:
Yes, you're right.

David Brühlmann [00:16:18]:
Now, I've read on your website that you describe your silkworm pupae as equivalent to about 100 to about 1,000 milliliters of insect cell culture. Can you tell us a bit more about how you came up with these numbers, and what that means for the process economics? Does that mean that you can produce a lot more volume or more product on a smaller footprint?

Masafumi Osawa [00:16:42]:
So this number is not just an estimate; it comes from a published comparative study titled Comparison of recombinant protein expression in a baculovirus system in insect cells and silkworms. In that study, 45 different recombinant proteins were expressed in Sf9 cells, silkworm larvae, and silkworm pupae. When expression levels were normalized, the researchers found that a single pupa yields, on average, the equivalent recombinant protein amount produced by approximately 120 mL of Sf9 culture, with some proteins reaching much higher equivalencies. This is where the 100–1,000 mL per pupa framework originates.

From a production economics perspective, this has important implications. As you know, conventional recombinant protein production requires large bioreactors, sterilized media, and massive amounts of water, followed by extensive cleaning steps. These processes contribute significantly to environmental footprint and operating cost. In contrast, silkworm pupae function as self-contained biological culture vessels. They require no bioreactors, no large volumes of water, and no cleaning validation. The physiological environment is preassembled by nature, eliminating significant upstream costs.

For developers like us, this also means that scaling is far easier. Instead of scaling up by building larger tanks, which adds engineering risk, you simply scale out by increasing the number of pupae, just as I mentioned earlier. This reduces infrastructure burden and supports long-term cost efficiency. This advantage will make it easier to offer stable pricing and a consistent global supply.

David Brühlmann [00:18:48]:
Now I'm curious, Masa, how do you do the downstream processes? Because once you finish your production run, you have these worms that have expressed a certain amount of protein, and you mentioned that then you do the harvesting. So how does that work? And then how does the purification work? Is purification very close to a traditional purification process we see with E. coli, for instance, or with yeast? Or are there some major differences?

Masafumi Osawa [00:19:16]:
The downstream purification process is similar to conventional protein expression systems.

David Brühlmann [00:19:22]:
And how do you get the protein out of your worms? Is that similar to what you would do with E. coli, for instance? How do you quote-unquote harvest your worms?

Masafumi Osawa [00:19:31]:
So after the target protein is fully expressed inside the body of the pupa, we homogenize the whole pupa with buffer, then ultracentrifuge the extract and apply standard chromatography steps to purify the protein. So basically, the system is partly similar to the traditional approach.

David Brühlmann [00:19:54]:
Yeah, I see. And that's also where I imagine you start applying cleanroom and closed-process conditions to make sure that at the end of the day your product is sterile and safe to use. Correct?

Masafumi Osawa [00:20:08]:
Yes, you're correct.

David Brühlmann [00:20:09]:
I'd like to touch upon the quality side of things, because you mentioned glycosylation, which is an important part, especially for more complex molecules. Where do you see the limits of your platform versus CHO? Are there certain molecules that are too complex to produce in worms, or do you think you can produce pretty much any kind of molecule?

Masafumi Osawa [00:20:32]:
We can produce pretty much any kind of molecule. So far, one of our strongest technical advantages is our consistent expression success. Across more than 130 protein expression projects—many of them challenging targets—we have observed successful expression in every case. This includes membrane proteins, intrinsically disordered proteins, allergens, multi-subunit proteins, large virus-like particles, and even certain GPCRs. Many partners approach us after unsuccessful attempts in E. coli or mammalian systems. The silkworm pupal physiological environment provides favorable conditions that artificial bioreactors struggle to replicate.

David Brühlmann [00:21:23]:
As you're interacting now with health authorities, I imagine you have some very interesting conversations with them, as this is a novel host and a novel way to produce pharmaceuticals. What are the unique GMP and regulatory challenges you have encountered so far with your living organism?

Masafumi Osawa [00:21:43]:
So because silkworms are living organisms, GMP considerations focus heavily on raw material controls. This overlaps with what I mentioned earlier. We use SPF-grade parent brood, and there are dedicated facilities that supply only SPF-grade, pharmaceutical-grade silkworms. These facilities strictly control diet, rearing conditions, environmental monitoring, and breeder documentation. So how to monitor safety and quality at this level is something that makes our discussions with local authorities quite unique.

David Brühlmann [00:22:27]:
That's it for Part One. We have explored how KAICO emerged from academic research and how silkworm pupae function as remarkably efficient bioreactors. Next time, we'll dive into production economics, post-translational modifications, and KAICO's vaccine pipeline. If you are finding value in these conversations, please leave a review on Apple Podcasts or your preferred platform. It helps other biotech scientists like you discover these practical insights.

All right, smart scientists—that's all for today on the Smart Biotech Scientist Podcast. Thank you for tuning in and joining us on your journey to bioprocess mastery. If you enjoyed this episode, please leave a review on Apple Podcasts or your favorite podcast platform. By doing so, we can empower more scientists like you. For additional bioprocessing tips, visit us at www.bruehlmann-consulting.com. Stay tuned for more inspiring biotech insights in our next episode. Until then, let's continue to smarten up biotech.

Disclaimer: This transcript was generated with the assistance of artificial intelligence. While efforts have been made to ensure accuracy, it may contain errors, omissions, or misinterpretations. The text has been lightly edited and optimized for readability and flow. Please do not rely on it as a verbatim record.

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About Masafumi Osawa

Masafumi Osawa has over 10 years of experience in the pharmaceutical industry and is dedicated to advancing innovative solutions for global health challenges. He serves as Business Development Lead at KAICO Ltd., a Japanese biotechnology start-up that develops and produces recombinant proteins using silkworms as bioreactors. 

In this role, he identifies and establishes strategic partnerships, represents the company at trade events and workshops, and leverages his expertise in market research, CRM, and public relations to effectively communicate KAICO’s vision and showcase its unique technologies, including oral vaccines for humans and animals.

Connect with Masafumi Osawa on LinkedIn.

He is also a biotech technology innovation coach, technology transfer leader, and host of the Smart Biotech Scientist podcast—the go-to podcast for biotech scientists who want to master biopharma CMC development and biomanufacturing.  

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