If biotech had a “cheat code” for sustainable manufacturing, what would it look like? Imagine harnessing sunlight and seawater to create valuable molecules—no fermentation tanks, minimal waste, virtually carbon neutral.
In this episode of Smart Biotech Scientist Podcast, David Brühlmann speaks with Tim Corcoran, CEO and Co-Founder of Deep Blue Biotech. Tim is on a mission to transform cyanobacteria from scientific curiosity into a foundation for commercially viable, carbon-neutral specialty chemicals.
One of the very first pieces of research we did was to look at what our cyanobacteria were predisposed to make. Because if all you're doing is giving it a little nudge and encouraging it and joining up a pathway here and there, it's akin to pushing a car down a hill as opposed to pushing a car up a hill. Again, I'm always wary of making it sound easy because it's definitely not, but it's a much more efficient R&D process when you do it that way. And so again, it comes back to looking at what are we able to make, but also how does that suit the market? And when you join all of those things up together, hopefully you get a much more viable company.
David Brühlmann [00:00:34]:
Welcome back! In part 1, Tim Corcoran explained how Deep Blue Biotech’s ocean-derived cyanobacteria produce molecules through photosynthesis while secreting them directly into the media — a game-changing advantage. Now, we tackle the hard questions: How do you choose your first product when hyaluronic acid sells for $2,000 per kilogram but your ultimate target biofuel sells for $2 per liter? How do you scale photobioreactors when the infrastructure barely exists? And what separates technologies that commercialize from those that die in the valley of death? Let's find out.
We're going to get to the scale-up and the huge scale in a minute. I just want to focus a bit more on your deliberate choice to go into the consumer care market. This is quite a competitive market. You have all these big players out there. How do you compete against these players, especially with a limited budget?
Tim Corcoran [00:02:46]:
I guess one of the key factors is what we're doing is B2B rather than B2C. So that means things like marketing costs are less of a worry. If you try and produce a consumer product, the cost — I think Amyris is a good example. They're a synthetic biology company who got themselves into a bit of trouble. I think they've bounced back now, but they tried to launch consumer products and they spent an enormous amount of money on marketing. So being a B2B model helps. It means, for example, if you target the 10 biggest personal care manufacturers in the world, that's relatively achievable through a few conversations, a few emails, a few meetings. Then you've got distributors who are seeking an advantage over their competitors. You know, they want to be able to sell their hyaluronic acid at the expense of their competitors.
So being able to offer a distributor a unique product with significant advantages that we've already discussed over existing products, potentially that gives you the opportunity to tap into quite a large distribution network.Now the other factor is the actual amount that you can supply. If you speak to one of the large personal care companies, potentially they want tonnes of the product, and it will take a little while to scale up to that. So initially you need to engage with some of the smaller, more agile personal care companies as well, who might only want a few kilograms of the product so that they can do a product launch and get it out there. That serves a number of advantages. It means you've got products in other products that are on the market now. It means you're generating revenue quickly, and you're able to do that before you've scaled up to significant industrial scale. And it gives you some really useful case studies. People can see how these products perform.
David Brühlmann [00:04:17]:
Moving on to the scale-up aspects, what I see, Tim, is you have a promising technology — it's novel, you have a tremendous market, you have a great business model, and potentially you will have a huge demand and you will need to scale up not just to 20,000 liters, probably to 100,000 liters or beyond. What is your strategy there? Because the reason I'm asking this question is you have a novel technology and not many CDMOs have photobioreactors for photosynthetic organisms. What are you going to do, or what is the best strategy from your point of view?
Tim Corcoran [00:04:50]:
It is the flip side of a novel technology, as you say, that the infrastructure isn't abundant, shall we say. Now, fortunately, there are companies like A4F – Algae for Future in Portugal, for example, who can act as both a CRO and a CMO. They have very large-scale photobioreactors, so we're working with them at the moment. Plans to initially scale up one of our strains to about a 1,000-liter photobioreactor scale. But they don't have the downstream processing capabilities that you need. So you then need to take what comes out of that and find a suitable downstream processing CMO. So in the very first instance, our first commercial sales will be working with probably two different CMOs, one to grow it, one to process it. And that gets us that commercial revenue, which is an important stepping stone in the development of a company.
Now, our goal then is to build our own pilot facility so that we can refine the process. And the pilot facility, because of the sort of highly efficient process and the profitability profile that we have, that pilot will be profitable. It will make the company self-sustaining from a research point of view. And it will prove the technology at a reasonable scale, and it will provide you with enough samples and small volumes to generate regular commercial quantities, and for the big companies to be able to do all the testing they need to do in their formulations.At that point, potentially you can secure pre-sale agreements, which then you take to the bank against building an industrial facility. Now, whenever you speak to investors in particular, the idea of building a large industrial facility is a concern. But if you can show that you've got pre-sales from these big companies, then it becomes much more viable.
Now, our plan is to build one industrial facility. We don't want to build loads and loads of them. If we can build one, show that it's profitable, show that it's working, show that it's doing all the things that it should be doing, at that point, the intention is to move to a sort of technology licensing model because you can scale and reach the market much faster that way. So working with other chemical companies, licensing the technology to them, supporting them to scale it up. A lot of them will have much of the downstream processing side of things in-house already. So the bit that they will need to invest in will be the photobioreactor side.
And the interesting thing is one of the fringe benefits of this is as they do that, the photobioreactor technology and the industry as a whole will grow and it will develop and more efficiencies will be built in. But yeah, once you start licensing, obviously you're able to scale. You do leave a bit of profit on the table. I think it's not as profitable long-term as building multiple facilities, but I think it is a faster way to reach the entire market.
And because of the CO₂ aspect, because of the cost of production aspect, I think our method for hyaluronic acid will become the default mechanism for making hyaluronic acid. Much in the same way as precision fermentation took over from extraction from rooster combs about 25 years ago. This will be a substantial change in the industry. And just the cold logic of, well, it's carbon-neutral and it's cheaper, why wouldn't I do it this way, will lead it to become the dominant method.
David Brühlmann [00:07:42]:
Since you're going to build a facility, do you also have in mind becoming a CDMO at one stage or renting part of your capacity to other developers?
Tim Corcoran [00:07:51]:
We have a strong interest in helping the industry develop, but we are not particularly thinking at the moment of becoming a CMO or CRO, partly because we have so much additional research we want to do for ourselves. When you look at, as I say, the number of other chemicals we can make is in the hundreds. And so there's a lot of additional research. Now, potentially what we can do is take that pilot facility and take that industrial facility down the line and repurpose them to focus on these second-, third-, fourth-generation chemicals, proving it each time and then licensing them out and then moving on to the next one. The goal ultimately is that we have a full spectrum of chemical solutions — carbon-neutral, cost-efficient — you start to, when I'm sort of daydreaming, you start to think about the potential scale of the company as a whole and you think it could rival some of the really, really big chemical manufacturers.
David Brühlmann [00:08:38]:
Yeah, definitely. What comes into my mind, Tim, is your technology needs a lot of light. So where is the best location to build your facility? Because not only do you need a lot of light, you need skilled labor, which is probably quite difficult to find right now. So where are you going to build your facility?
Tim Corcoran [00:08:57]:
We're based in Sheffield, and from a skilled labor point of view, we've been very fortunate. The University of Sheffield is brilliant at cyanobacteria. They have two separate labs working on it. So we've been able to tap into, from an R&D perspective, we've been able to tap into that. Now, as you scale, that engineering side of things becomes more and more important. Again, actually the University of Sheffield is very, very strong at that. So that gives us a good starting point.But when you think about where you're going to get your light from, there are two main sources. One is natural light and the other is LEDs. Now if you want natural light, obviously moving somewhere where that is abundant helps. My feeling is probably it'll be natural light supported by LEDs, but time will tell.
So Portugal has a thriving and growing ecosystem around photosynthetic production, around photobioreactors and cyanobacteria and microalgae. So there's expertise and there's a degree of infrastructure and there's natural light there. They have relatively cheap electricity. Portugal is really attractive. Plus I'm a big fan of Lisbon. I think it's a lovely city.But the other end of the spectrum, interestingly, is Iceland. Iceland is developing a photobioreactor industry built around cheap, extremely clean geothermal electricity. So the cost of electricity and the CO₂ footprint of the electricity there are very favorable. So at that point you're not going to be relying on natural light — obviously Iceland being where it is — it's going to be LEDs. But if the LEDs are powered by geothermal electricity, it's cheap and it's carbon-neutral.
Now, obviously Iceland is a little bit further away, it's a bit colder, but there are companies operating there now who are working with microalgae in particular. And when you speak to them, they say, no, we have absolutely no problems attracting people to come and work here. People who want to work on this will travel. So that's another interesting location for us.
David Brühlmann [00:10:38]:
And how does the business case change as you're factoring in the additional electricity costs for LED lighting?
Tim Corcoran [00:10:45]:
It does make a difference. I think if you go somewhere like Iceland where the cost of electricity is, I think it's less than a quarter of what it is in the UK, then it becomes much less of a factor. But certainly I think if you're using artificial light, then your electricity profile is going to change quite substantially. So you do have to think about that. One of the advantages of Portugal is if you can get sensors which detect the intensity of the light, you can potentially say, okay, it's a cloudy day, we'll dial up the LEDs, or it's a particularly bright day, we can turn the LEDs off. And then you're using LEDs sparingly, you're using them as and when. The other factor is to look at which wavelength and intensity of light the cyanobacteria most respond to because you can make it a much more efficient process if you understand the mix of wavelengths and the intensity of light that benefits them, and you can calibrate it really quite precisely.
David Brühlmann [00:11:32]:
I'd like to focus on the lab-to-market journey. You have seen a lot of companies succeed, a lot of companies fail. From your perspective, what makes a company succeed in that? Because finally, we have great technology in the lab, but if we fail to transfer it into a commercial setting, it will be of no use to society.
Tim Corcoran [00:11:53]:
I agree. I think one of the big factors — one side in particular — as I alluded to earlier, around 2023, money tightened up substantially. A lot of synthetic biology companies had grown up and developed based upon access to easy, cheap money. And when that stopped, a lot of them suddenly struggled, and they'd got these long timeframes for their research and development and all of a sudden they couldn't afford that.
At the same time, because they thought they had access to all this money and all this time, they were targeting commodity products — for good reasons: big markets, potentially the biggest environmental impact. But it meant that to get to a point where they were economically and financially viable, where they could compete with the products they were replacing, required an enormous amount of research. And again, that made it very hard for them. And a lot of them ran out of money and went bust. And some of them have since bounced back, I'm pleased to say.
I think the synthetic biology industry has grown a lot leaner and a lot cleverer about how it works. So it has improved. It's learned from that. That pressure has forced the evolution of the industry as a whole, and it's in much better shape now than it was.I mentioned, I think it was Amyris who launched consumer brands. That is a real challenge. As I say, things like marketing costs can drain your resources very quickly. My preference — I come from a B2B background — would always be to operate in a B2B fashion because generally it's easier from a commercial point of view. The sales and marketing process is simpler.
And then the other one that I think ties in — and it probably particularly relates to the earlier stages of synthetic biology — was people would choose their favourite microbe and they would try and make their favourite product — oversimplification. But what it meant was there was a lot of genetic engineering to make whatever it might be — Escherichia coli, yeast, whatever — produce this product.
Now, as I mentioned earlier, one of the very first pieces of research we did was to look at what our cyanobacteria were predisposed to make. Because if all you're doing is giving them a little nudge and encouraging them and joining up a pathway here and there, it's akin to pushing a car down a hill as opposed to pushing a car up a hill. Again, I'm always wary of making it sound easy because it's definitely not, but it's a much more efficient R&D process when you do it that way.
And so again, it comes back to looking at what we're able to make, but also how does that suit the market? And when you join all of those things up together, hopefully you get a much more viable company.
David Brühlmann [00:14:02]:
What piece of advice would you give to a brilliant scientist sitting on the fence about starting their own company?
Tim Corcoran [00:14:08]:
I would 100% encourage them to do it. There are so many good ideas that don't get exploited, and it bothers me that there are all these brilliant things that may never see the light of day. Now, the scientists can do the technical bit. The other side of it, the commercial, the corporate bit, that's where they're going to need help. And there are, I would say, depending upon their context, there are three ways they can go about it.
One, if they're at a university, go and speak to your commercialization department or technology transfer office. They will have people who have expertise and knowledge about how to do this. Often you can get funding from the university to help you achieve that.
The second, people like me, like I used to be — business development consultants who will work with early-stage companies. They might work with you as a consultant, they might join you as a business partner. They can take care of that side of things, and that works.
And then the last one, I would always recommend it to anyone that wants to try it, is Carbon13 Venture Builder. Their concept is all about bringing technically minded people together with commercially minded people, putting the two in a room and seeing what comes out. So as I said, that's how I met my co-founder. It was a brilliant process. We weren't the only ones. A lot of good companies have come out of that. I'm sure there are other venture builder programmes. That's just the one that we worked on. But I thought Carbon13 did a brilliant job of creating the opportunity for these ideas to be realised.
David Brühlmann [00:15:19]:
Before we wrap up, Tim, what burning question haven't I asked that you're eager to share with our biotech community?
Tim Corcoran [00:15:27]:
Oh goodness. If I was thinking about it, the thing that I always ponder when I'm sort of looking at it is where can synthetic biology go? What is its ceiling? Because it's a relatively young industry. It's learning from its mistakes and it's improving.
Generally speaking, you see synthetic biology focusing on fuels and plastics and materials and that sort of thing. But what else could it do? Certainly I think there is potential in biodegrading products and dealing with issues like microplastics potentially. There is a lot of scope for it.
There's a cyanobacteria company I came across a little while ago who were developing a cyanobacteria-based paint which would be photosynthetic. So you'd paint it on a building and it would capture CO₂ and fix it. There's all sorts of areas it can potentially go. And frankly, I'd like imagination to give the answer to it. But I think the potential is enormous and it's worth anyone with either a commercial or a technical perspective thinking, I wonder if it could do this. Hopefully over time it becomes a significant part of the answer to the challenges we face with climate change.
David Brühlmann [00:16:28]:
This has been great, Tim. What is the most important takeaway from our conversation?
Tim Corcoran [00:16:34]:
A: I love cyanobacteria. And B: science has enormous potential, but it needs to be aligned with commercial expertise. If you take the two and they work together, I think you can achieve great things.
David Brühlmann [00:16:51]:
And that's the way forward, I think. Thank you so much, Tim, for sharing your passion, letting us into the world of cyanobacteria. Where can people get a hold of you?
Tim Corcoran [00:17:01]:
You can reach us — I'm on LinkedIn. I discovered actually there is more than one Tim Corcoran on LinkedIn. Or you can email me. My email address is tim@deepbluebiotech.com. Or you can visit our website, deepbluebiotech.com. I'm always happy to talk. It's one of my philosophies. I'll try and talk to anyone with an interesting idea or question, because sometimes you get some really interesting opportunities as a consequence.
David Brühlmann [00:17:21]:
Smart biotech scientists, use this opportunity. You'll find the links in the show notes. And thank you once again, Tim, for being on the show today.
Tim Corcoran [00:17:30]:
Thank you very much for having me, David.
David Brühlmann [00:17:31]:
It's been a pleasure. Tim's journey from three decades in commercial and leadership roles to founding Deep Blue Biotech reveals a critical truth: breakthrough science needs disciplined commercialization strategy. Start with high-value products, prove the case, move down the value chain, build one factory, then license broadly. And balance organism health with yield optimization. These principles separate innovations that reach market from those that don't.
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 smartbiotechscientist.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.
Book a free consultation to help you get started on any questions you may have about bioprocess development: https://bruehlmann-consulting.com/call
About Tim Corcoran
Tim Corcoran, Co-Founder and CEO of Deep Blue Biotech, brings more than 25 years of commercial and leadership experience across multiple sectors. He has a proven track record in designing growth strategies, advising start-ups and scale-ups from early stages to successful exits, and building robust networks of investors, partners, and clients.
Tim’s experience spans both established international corporations and entrepreneurial ventures, giving him a unique perspective on driving innovation and creating long-term business value.
Connect with Tim Corcoran on LinkedIn.
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
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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What if the ocean’s tiniest inhabitants held the secret to decarbonizing the entire chemicals industry? With mounting pressures for sustainability, biotechnology is urgently seeking efficient, eco-friendly alternatives to traditional manufacturing—and marine microbes just might be the missing link.
In this episode of Smart Biotech Scientist Podcast, David Brühlmann speaks with Tim Corcoran, CEO and Co-Founder of Deep Blue Biotech, whose unconventional path led him from a commercial background to pioneering synthetic biology with ocean-derived cyanobacteria.
Generally, when people think about cyanobacteria, it's often in the news for negative reasons. It's clogging up a lake somewhere. There's a loch in Northern Ireland where it seems to do that quite a lot. But actually, the things people don't realize about cyanobacteria are that they are among the most efficient photosynthetic organisms on the planet. They are the reason our planet developed a breathable atmosphere in the first place. So that was our starting point. We thought, well, that's got great potential.
And then you look at the similarities with other microbes — Escherichia coli, Streptococcus, yeast, and so on — that have been engineered to make useful products. And we think, well, can cyanobacteria do that? And the more we looked at it, the more we realized cyanobacteria could do that for a whole swathe of chemicals.
David Brühlmann [00:00:43]:
What if the ocean held the key to decarbonizing the entire chemicals industry? Today's guest spent three decades in commercial and leadership roles before discovering a remarkable microbe floating off Singapore's coast — cyanobacteria that could revolutionize how we manufacture everything from cosmetics to fuels. Tim Corcoran, CEO of Deep Blue Biotech, joins us to reveal how this marine organism secretes high-value molecules directly into seawater, why photosynthesis changes manufacturing economics, and what finally makes cyanobacteria commercially viable after years of failed attempts.
Welcome, Tim. It's good to have you on today.
Tim Corcoran [00:02:42]:
Thank you for having me.
David Brühlmann [00:02:44]:
It's a pleasure, Tim. Share something that you believe about bioprocess development that most people disagree with.
Tim Corcoran [00:02:53]:
Oh goodness. I think a lot of people view scaling bioprocesses as inherently difficult and quite off-putting. I don't think it necessarily needs to be the case. I think the technology is improving. People are learning at a tremendous pace. We personally have designed our technology specifically with scale-up in mind to make it as easy and as straightforward as possible. But certainly, when you speak to people, that is often one of the primary concerns on their minds.
David Brühlmann [00:03:22]:
Take us back into your story before we talk about the exciting science and technology you're developing. Tell us what sparked your interest in commercial and leadership. You're coming from a different background. And tell us also what led you to science and finally to the role you're currently in.
Tim Corcoran [00:03:41]:
I started off, I think when I was about 16, with my first sales job, just a summer job selling double glazing, which does not have a great reputation here in the UK, and it may well be the case elsewhere. But I realised that I quite enjoyed it and that I was competent. So when I left university, I didn't know what to do with my economic history degree. So I thought, I've been doing this through university to pay some bills, I'll carry on doing it. And then over the years that developed from sales into broader commercial and operations roles. I enjoyed looking at how businesses could commercialise, how they could grow revenues, how they could improve profits.
For a good number of years, I worked for a market research company that was dealing with innovation, specifically within the FMCG market. They were looking at what successful innovations did as case studies and why some innovations failed. And I always found that very thought-provoking. There were certain traits you saw time and time again in successful innovations. And so that informed a lot of my thinking about product development and about how you could create new things that people actually wanted and that would succeed.
I then became a business development consultant, and I was working with a lot of early-stage companies, helping them take what was often just an idea on a piece of paper and turn it into reality — helping them with investment, planning, strategy, and commercialisation. In particular, I was running a company called Master Investor at the time, working with a chap called Jim Mellon, who’s a fairly visionary investor. He's very keen on science in particular — how it can fix a lot of our problems and how you can use that to make money at the same time.
In particular, he was very interested in alternative proteins. He has a company called Agronomics — and still does — which has invested heavily in the alternative proteins market. Through him, I was exposed to a lot of really interesting companies. And it was that gradual process of thinking about innovation, thinking about how you commercialise things, talking to people who were frankly brilliant at what they did, and learning from them about how they could transform that into a living, breathing, hopefully profitable company.
David Brühlmann [00:05:42]:
What was that pivotal moment then that made you take the leap and found Deep Blue Biotech? And what was the vision behind it?
Tim Corcoran [00:05:49]:
It had been percolating away at the back of my mind for a while. I'd been working with these companies and I knew I'd been able to help them. And I thought, well, why don't I try and do it for myself?
At the same time, I have a longstanding and deep concern about climate change. I'd wanted to do something about it. I wasn't sure exactly how I could contribute, but I wanted to do something meaningful. I thought, well, if I help to commercialise climate-friendly technologies, then potentially that means I can sleep at night — I feel as though I've made a positive difference.
So I joined an accelerator — or more precisely, a venture builder programme — run by an organisation called Carbon13. They are focused on creating climate-focused companies, and they bring together technical people — scientists and engineers — and commercial people like me, essentially putting them in a room together for a three-month period to see what emerges.
That’s where I met my co-founder. He's a chemical engineer by training. He had been working as VP of Sustainable Innovation at Unilever, and he'd grown increasingly frustrated because all the sustainable ingredients and chemicals brought to him were either too expensive or not as performant as the ingredients they were already using. And Unilever weren’t going to accept that — and consumers weren’t going to accept it either. They didn’t want to pay more, and they certainly didn’t want something less effective.
So he had left, looking for a way to create a technology that could overcome that trade-off. Over the course of those three months at Carbon13, we looked at different technological options. We explored several approaches and eventually settled on cyanobacteria. And the more we looked at them, the more we thought this has huge potential.
David Brühlmann [00:07:15]:
That sounds exciting. And tell us more about these cyanobacteria and why this is an interesting host organism to work with.
Tim Corcoran [00:07:22]:
I have a tendency to get overexcited at this point, so I'll try to keep myself calm. Generally, when people think about cyanobacteria, it's often in the news for negative reasons. It’s clogging up a lake somewhere. There’s a loch in Northern Ireland where it seems to do that quite a lot.
But actually, what people don’t realise about cyanobacteria is that they are among the most efficient photosynthetic organisms on the planet. They are the reason our planet developed a breathable atmosphere in the first place. So that was our starting point. We thought, well, that’s got great potential.
And then you look at the similarities with other microbes — Escherichia coli, Streptococcus, yeast, and so on — that have been engineered to make useful products. And we think, well, can cyanobacteria do that? And the more we looked at it, the more we realised cyanobacteria could do that for a whole swathe of chemicals.
Now, traditionally, people have been held back with cyanobacteria because they grow more slowly than some of these other microbes, and the yields were often quite disappointing. So it was hard to commercialise. There was also a relative lack of scientific knowledge about cyanobacteria — the tools for genetically modifying them and the understanding of how to cultivate them efficiently were less developed.
That has changed significantly over the last few years. The strain that we're working with was discovered about five years ago, so it's a relatively recently discovered and not widely characterised strain. That does create challenges when you're trying to engineer it, because you're learning things for the first time that no one else has encountered. But equally, it has huge potential because it grows much faster than many other cyanobacterial strains. It achieves relatively high biomass productivity and has been shown to yield commercially relevant amounts of chemicals and ingredients.
So when you take that as your base chassis organism and then think, okay, how can I improve it? It holds enormous potential to finally realise what cyanobacteria can truly do.
David Brühlmann [00:09:06]:
How is that vision linked to the discovery of this cyanobacterial strain? Tell us more about that.
Tim Corcoran [00:09:11]:
Our strain of cyanobacteria is an ocean-based strain. Now, that's important because it means it tends to be more robust. It’s used to dealing with a range of different light intensities, temperatures, CO₂ concentrations, and varying nutrient levels in the ocean. Because it’s robust, it can tolerate environmental fluctuations much better. And potentially — and we're working on this at the moment — you can fine-tune its cultivation conditions to reach a point where growth and product formation are optimised.
The fact that it's an ocean-based strain also means the chemicals it produces can legitimately be described as ocean-derived. In certain industries that may not matter as much, but in personal care — which is the industry we're focused on at the moment — that matters a great deal. Consumers respond positively to ocean-derived ingredients. They may pay more for them and choose them over other alternatives. There is a clear brand and marketing advantage.
Now, our first product is hyaluronic acid. Our hyaluronic acid would be the only ocean-derived hyaluronic acid on the market. And when you speak to personal care companies about that — and we've spoken to many — that’s the point where they start to see strong commercial potential. They can envision unique products with distinctive marketing claims that justify premium pricing, grow sales, and improve profits.
At the same time, we can say: the primary carbon feedstock here is CO₂. So the process is carbon-neutral and it is potentially carbon negative if we choose our electricity sources quite carefully. And because it's such a simple mechanism, it's a very clean, efficient process. We can make these ingredients for less than you are currently paying. So that green premium I mentioned earlier, that's no longer a factor. Worries about whether or not it's effective or not are no longer a factor because it's a drop-in solution. And you've got these unique marketing claims around the ocean-derived side, and it creates quite a compelling proposition.
David Brühlmann [00:10:54]:
You definitely have a lot of unique selling points — net zero, ocean-derived — it’s compelling. Help people better understand the differences between cyanobacteria and some more established production hosts. It can get confusing quickly. We have Escherichia coli, we have moss, we have microalgae. What are the main differences?
Tim Corcoran [00:11:15]:
I guess the starting point is prokaryotes, which include Escherichia coli and cyanobacteria — organisms without a membrane-bound nucleus — versus eukaryotes, which include microalgae, moss, yeast, and essentially most multicellular organisms. Eukaryotes are fundamentally more complex. Prokaryotes are simpler, and from a genetic engineering perspective, that simplicity can be advantageous. It can also make them metabolically efficient.
So from a cyanobacteria point of view versus microalgae, for example, which are essentially very small single-cellular plants. Cyanobacteria are simpler, and that means the photosynthetic process tends to be more efficient. Because the photosynthetic process is more efficient, that conversion of CO₂ into chemicals is more efficient. So that's sort of where it lies.
Other prokaryotes like E. coli and things like that, they're not photosynthetic. Cyanobacteria are somewhat unique in being essentially photosynthetic bacteria. So they sit almost in between the two, and arguably you could create a whole separate sort of classification for them.
David Brühlmann [00:12:09]:
Besides photosynthesis and the CO₂ aspect, are there other advantages to working with cyanobacteria?
Tim Corcoran [00:12:15]:
Because the inputs are so limited, you're not feeding sugar. Take Escherichia coli as an example — it generally requires sugar-based feedstocks. Cyanobacteria use CO₂ as their carbon source and light as their energy source, which means you can potentially leverage natural sunlight. That reduces both your carbon footprint and your input costs.
Another key aspect is the cultivation medium and the resulting broth composition. Compared with organisms like Streptococcus species or E. coli, the medium is much simpler. For marine cyanobacteria, it’s essentially water with defined mineral salts. That simplicity can make downstream processing more straightforward.
It’s worth noting that Gram-negative bacteria, including cyanobacteria and E. coli, do contain lipopolysaccharides (endotoxins). However, depending on the product and application — particularly for non-parenteral uses like cosmetics — the regulatory and purification requirements are different.
Because the cultivation inputs are defined and relatively simple, and because we design the system for secretion of the target molecule into the medium, downstream processing can be highly efficient. That efficiency is a key driver in reducing our overall cost of production and improving competitiveness versus incumbent manufacturing methods.
David Brühlmann [00:13:02]:
So this leads me to this question then. What I'm hearing, Tim, is that the current strain has many advantages and significant potential. But why haven’t more people worked with cyanobacteria historically? And why does it seem that now several companies are starting to see the opportunity? Why now?
Tim Corcoran [00:13:24]:
People have been trying to make this into an industrially viable organism — or platform technology, depending on how you want to describe it — for well over a decade. Most cyanobacterial strains grow several-fold more slowly than conventional production hosts. That’s a challenge from the outset.
Then there’s titre. Even after genetic engineering, product titres were often only a small fraction of what you might achieve with Escherichia coli, Streptococcus, or yeast. That combination — slow growth and low titres — is what historically put people off.
As I mentioned, the discovery of this relatively recent strain was one of the triggers for renewed interest. It’s still not as fast as those heterotrophic microbes, but the gap is significantly reduced. That enables greater volumetric productivity. At the same time, the molecular biology toolkit for cyanobacteria has improved considerably. Genome annotation, transformation methods, promoter systems, CRISPR-based editing — these tools have matured.
We’re working with researchers such as Alastair McCormick at the University of Edinburgh, who has developed tools for more efficient genetic modification of cyanobacteria, including our strain. That makes the R&D process far more tractable. I wouldn’t say it’s easy — it isn’t — but it makes development feasible within reasonable budgets and timelines.
David Brühlmann [00:14:38]:
One advantage I see is that your product is directly secreted. When you work with E. coli, for example, you often have to lyse the cells first. That could offset slower growth rates or even lower titres.
Tim Corcoran [00:14:53]:
Definitely. Secretion into the culture medium simplifies downstream processing substantially. We estimate that it reduces cost of goods by roughly 25–35%, which is significant. It reduces the number of unit operations and simplifies purification.
It also lowers energy demand because you’re avoiding mechanical cell disruption and some of the associated clarification steps. Fewer and simpler downstream steps mean lower overall energy consumption and a reduced carbon footprint.
David Brühlmann [00:15:17]:
And how about scale-up? You need light, CO₂, temperature control. You mentioned that scale-up was built into your thinking from the beginning.
Tim Corcoran [00:15:27]:
One of the things that we liked about cyanobacteria is that they typically grow in photobioreactors, which are essentially a series of glass tubes. They're modular by nature, and that means you don't see a significant difference in performance between, say, 100 or 1,000 litres or 10,000 litres because you're just adding more glass tubes. It's more a case of scaling out than it is scaling up. Now, I don't want to minimise the challenges involved. There will always be some challenges. So as you scale up, you have to think about access to light. You've got to make sure all of the microbes are getting access to the light coming in. You've got to make sure that the temperature remains roughly consistent because again, the more light generally, the more heat you get with it. So you've got to try and keep that controlled.
And you've also got to think about the CO₂ mixing, making sure all of the cyanobacteria are getting equal access. But actually there is enormous headroom on photobioreactor development. There's some really interesting companies coming up with some unique models to tackle these things and make it more repeatable and scalable. Companies like Algenie, for example, in Australia, who are developing a helical photobioreactor for continuous production. It makes the entire process substantially more efficient. Now, we've actually not factored in these yet. We're hoping to do some testing with these new photobioreactors in the future where potentially our cost of production comes down even further because of them. In contrast to bioreactors, I think people have been investing in and developing bioreactor technology and infrastructure for a long time now, and that reached a fairly sophisticated level. I think photobioreactors will take a similar path, but they're probably 10, 20 years behind. So the headroom for improvement is really quite exciting.
David Brühlmann [00:17:02]:
Now let's talk about the business side of things. And since you have a commercial background, I'm very curious about your thinking behind what kinds of products you have chosen. And tell us, what were the reasons behind the choices and also the business choices you made?
Tim Corcoran [00:17:17]:
It's a good question. So at the time that we formed in 2023, it was around the time that money was getting quite expensive. Interest rates were going up. People weren't investing in lending money quite like they had done for the previous 10 or 20 years. So we consciously thought about how can we be profitable quickly so that we don't have to keep going back to the well? I think the days when synthetic biology companies take 10 years to develop a product that was commercially viable are gone. You won't get the time for that. The very first piece of research we did was what is our cyanobacteria predisposed to make? What chemical precursors does it contain? And there's a really long list. So that was a good starting point. It did then make a lot of work for us though, because what we had to do is take that list and combine it with market sizes and market prices, because we wanted something with a large market and ideally a high price. If it's got a high price, then we could be competitive quickly. So when you take that Venn diagram and you sort of transpose all of those different factors, there were a number of candidates in there, but the single best candidate to start with was hyaluronic acid because it's expensive. You're generally looking $2,000 per kilogram, often sometimes quite a bit more than that. The market is big and it's growing quickly.
But also the other factor was hyaluronic acid is very popular in the personal care sector where storytelling matters. Now you can use it in pharmaceuticals, for example, and sort of therapeutics, but the storytelling matters a lot less there. If you're in that sector, people just want it to work. Whereas in personal care, when you talk about the origins of the ingredient, you talk about ocean-derived, you talk about carbon neutral, that matters and that adds value to the product. People will pay to a greater or lesser extent for that.
The other factor that we like about personal care sector is from a regulatory point of view, it's much more accessible. If you want to go into pharma or food, the regulatory barriers are somewhat intimidating. They are time-consuming and they're expensive to deal with. Personal care, obviously there are regulatory barriers, particularly safety and efficacy testing and things like that. But relatively speaking, it's a shorter, less expensive process, and there is a well-trodden path for biotech-type solutions in personal care products. So all of that together, it meant that we ended up with a nigh on, as far as we were concerned, a more or less perfect business case for hyaluronic acid. We do have a list of second, third, and fourth generation products that we're going to tap into once we've got the hyaluronic acid up and running and profitable. But also as the technology improves and becomes more efficient, you can move down the value chain and tackle slightly less expensive products until hopefully you get towards the sort of the commodity end of the market. Because from an environmental perspective, that's where you'll have the biggest impact.
David Brühlmann [00:19:51]:
Your approach sounds a lot like the Tesla model where you start with the premium products to earn some money quickly and then you walk down, should I say, the value chain, or at least the cost. This is an important message. I just want to stress that again because a lot of people listening are scientists and we think about the science. Tim, you have a commercial background, so tell the scientists listening why your approach is such a game changer. What changes when you start with the premium product first?
Tim Corcoran [00:20:20]:
When you start with a premium product, it means the technology doesn't have to be perfect to go to market. You've got a far better chance of taking something which is good enough and turning it into a profitable business. Now, in the years I worked as a business development consultant, I worked with a lot of brilliant people who were fantastic at what they did, but they didn't have that commercial expertise. They didn't know how to translate that. There are people all over the place, business development consultants like me. If you're at a university, they will have entire departments dedicated to taking technical ideas and translating those. And what I would say I'd say to any scientist with an idea out there is go and speak to these people. Ask them, do you think this could work? How could it work? Because they can help you with the planning. They can help you with identifying the customers.
One of the things when I was working in innovation market research a few years ago, one of the key characteristics of successful innovation, successful new products, was understanding the market, understanding what people want. Now, that's not necessarily a job for scientists. They'll need people to help them with that. But speak to your potential customers. Understand what it is they want. I think if you go back 20 years, maybe more, companies used to come up with a new product and then try and find a way of chucking it at the market and hoping it stuck. I think in the last 10 years in particular, companies have become a lot more efficient, a lot more intelligent about it. They look at the market, they look at what the market wants, where the gaps are, and then they start on the innovation process. And they end up with products which hopefully are perfectly suited to an unmet need in the market. So that market research, customer discovery is a vital part of the process. Before you start sinking significant amounts of money into sort of the development and commercialisation, you need to understand that because that help guide your subsequent research.
David Brühlmann [00:21:55]:
And what are some commodity products you think could still be interesting, but where you have a huge ecological benefit? What are you thinking about?
Tim Corcoran [00:22:04]:
From our point of view, biofuels is an area of strong interest. Now, cyanobacteria are able to make things like butanol, for example. Now, butanol currently isn't used as a biofuel because there isn't really a clean, efficient way of making it. But actually, as a biofuel, it holds great potential because it has a far closer profile to petrol and diesel than ethanol does. So if you can make butanol in a carbon-neutral fashion, it has great potential as a biofuel. Now, the challenge is butanol is currently, it's about $2 a litre, so it's cheap. And generally speaking, people don't want to pay a huge amount more for their fuel. So the goal is to be able to make butanol efficiently. Now, the thing that the triggers for us to be able to do that, and it's somewhere in the future, but we are going to be working on it further, is we need to get the yields from the cyanobacteria up. Now, the good news is for our cyanobacteria străin, the yields that we've already got are actually looking far more promising than we ever expected. So we actually think there are multiples of what we thought were achievable are now achievable. The cost of productions are much lower than we initially expected, and the technology continues to improve.
Scaling up to deal with a biofuel to make a significant impact on the petrol market or the diesel market or something like that, that's a somewhat intimidating prospect because you think about the scale of the petrochemical industry. But if you want to replace them, you do need to be able to scale it up. So if you want to have a photobioreactor producing butanol that isn't the size of a small country, the critical points will be that yield, getting a few grams per liter, perhaps 5 to 10 grams per liter into that photobioreactor, at which point it starts to look potentially like quite an efficient way of doing it. The environmental impact is sort of absolutely mind-blowing.
David Brühlmann [00:23:46]:
We have explored why cyanobacteria's unique biology, photosynthesis, CO₂ utilization and direct secretion finally makes commercial sense. In part 2, we'll dive into the strategic decisions that separate successful synthetic biology from brilliant failures. We'll talk about choosing hyaluronic acid over commodity fuels, navigating photobioreactor scale-up, and building toward a licensing model instead of capital-intensive facilities.
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 smartbiotechscientist.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.
Book a free consultation to help you get started on any questions you may have about bioprocess development: https://bruehlmann-consulting.com/call
About Tim Corcoran
Tim Corcoran is the Co-Founder and CEO of Deep Blue Biotech and an experienced business development consultant with over 25 years of experience guiding start-ups and scale-ups.
He specializes in growth strategies, investor relations, and building strong partnerships that create long-term business value.
Connect with Tim Corcoran on LinkedIn.
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
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.
Hear It From The Horse’s Mouth
Want to listen to the full interview? Go to Smart Biotech Scientist Podcast.
Want to hear more? Do visit the podcast page and check out other episodes.
Do you wish to simplify your biologics drug development project? Contact Us
Last time, we covered the biology of how raffinose works and the experimental journey that led to a 2.8-fold increase in high mannose glycans. Today, we're getting practical. I'm going to walk you through when raffinose works, when it doesn't, and the exact three-experiment protocol you can run in 8 weeks to validate it for your process.
Let's dive in.
This concept is discussed in greater detail in the Smart Biotech Scientist Podcast, hosted by David Brühlmann, founder of Brühlmann Consulting.
First, let's talk about scope. Because raffinose is not a universal solution, and I don't want you spending time and resources on something that won't work for your program.
✅ Use raffinose when you need to increase high mannose for biosimilar matching. Specifically, when your cell line's baseline high mannose is 1 to 3 percent and you need to get to 5 to 8 percent. That's the window where raffinose shines. You have room to move, and the effect size is large enough to hit your target.
✅ Use raffinose when you have analytical bandwidth to track Man5, Man6, Man7, and Man8 individually. If you're only measuring total high mannose, you're flying blind. You need to see the distribution because raffinose shifts the profile toward Man5. If your reference product is heavy in Man8 or Man9, raffinose won't get you there.
✅ Use raffinose when you're in process development—before you've locked your process for regulatory filing. Media optimization is expected at this stage. Regulators understand it. It's low risk.
Now, when should you not use raffinose?
❌ Don't use it if you need to decrease high mannose. If your baseline is already 10 or 12 percent and you need to bring it down, raffinose will make it worse. In that case, look at feed strategies or temperature shifts to drive glycan elaboration.
❌ Don't use it if your baseline high mannose is already above 10 percent. At that point, you have a cell line issue, not a media issue. Media tweaks won't fix a cell line that's fundamentally not processing glycans correctly. You need to go back and select a better clone.
❌ Don't use it if you need Man8 or Man9 specifically. Raffinose gives you predominantly Man5. If your reference product has a different high mannose distribution, you need a different tool. Kifunensine might be your answer, despite the cost and complexity.
❌ And don't use it if your titer is already marginal—below a few grams per liter. In that case, prioritize productivity first. Get your titer up, then worry about glycan matching. You can't afford to take a 20 percent titer hit when you're barely viable.
🔑 The key thing to understand is this: raffinose is tunable. The sweet spot for most processes is 15 to 50 millimolar. At concentrations above 65 millimolar—even with constant osmolality—you start seeing growth inhibition and titer hits. So you have a working range, and you need to find your optimal point within that range.
That's what the three-experiment protocol is designed to do.
Here's the roadmap. Three experiments. Eight weeks total. Clear go/no-go decision points at each stage.
1️⃣ Experiment 1: Dose-response screen in 96-well plates.
Test four concentrations: 0, 10, 30, and 50 millimolar raffinose. Do this in your current basal medium. Maintain constant osmolality by adjusting sodium chloride. This is critical—if you don't control osmolality, you're back to confounding variables.
Track three things: viable cell density, titer, and glycan profile at harvest. You need all three data points to make an informed decision.
Go/no-go decision: If you see at least a 2-fold increase in high mannose at 30 millimolar with less than 20 percent titer loss, proceed to Experiment 2. If you don't hit that threshold, stop here. Raffinose won't solve your problem. You'll need to revisit your cell line or explore other glycan control strategies like temperature shifts.
2️⃣ Experiment 2: Spin tube confirmation.
Take your top two concentrations from Experiment 1 and run them in spin tubes. Spin tubes give you better metabolic profiling than 96-well plates. You can sample every two days and track glycan evolution over the entire culture duration.
This is where you see if the high mannose increase is transient or stable. Some media additives give you a Day 5 effect that disappears by Day 10. You need to know if raffinose holds through to harvest.
Optional but insightful: measure intracellular UDP-galactose and UDP-GlcNAc if you have the analytical capability. This tells you whether raffinose is affecting nucleotide sugar pools, which would explain part of the mechanism. But if you don't have this capability, don't let it block you. It's not required for the go/no-go decision.
Go/no-go decision: If the high mannose increase is consistent across the time course and titer recovers by day 10 to 12, proceed to Experiment 3. If you see a glycan reversion after day 7 or if titer stays suppressed, you have a problem. Either adjust your concentration downward or reconsider the approach.
3️⃣ Experiment 3: Scale-up in bench-top bioreactors.
This is where you validate robustness. Take your lead concentration and run it in controlled pH and dissolved oxygen conditions—the environment your manufacturing process will actually see.
And here's a tip: challenge your process with stressed conditions. Run one batch at pH 6.9 instead of 7.0. Run another at 35 percent dissolved oxygen instead of 40 percent. Spike glucose on day 12 to see if metabolic stress affects the glycan profile. You want to know your boundaries before you commit to manufacturing.
Go/no-go decision: If all three batches hit your high mannose target and you don't see unexpected issues—aggregation, charge variant shifts, titer collapse—you have a robust process. Document it. Lock it in. Move to your next process development milestone.
Let me share three mistakes we made during this work—and how you can avoid them.
❌ Mistake 1: Waited too long to involve analytical.
We optimized media formulations in 96-well plates for weeks before getting our first glycan data back. We were measuring titer and viability, but we were blind to the quality attribute we were trying to control.
The fix? Get analytical buy-in on Day 1. You need rapid turnaround—ideally 48 hours or less—from sample harvest to glycan data. If your analytical team can't support that, this project will drag on for months. Build that partnership early. Make it a priority.
❌ Mistake 2: Didn't map the design space early.
Remember earlier when I said we tested raffinose at fixed pH? We never explored pH-by-raffinose interactions. We never tested temperature-by-raffinose interactions. We simply didn't check whether the raffinose effect would hold across different pH or temperature conditions.
The fix? Once you have a lead concentration from Experiment 1, do a mini design-of-experiments: raffinose by pH by temperature. Understa nd your boundaries. Know where the effect is strong and where it's weak. That knowledge will save you when you hit an unexpected process deviation at scale.
❌ Mistake 3: Didn't check feed interference.
We optimized raffinose in basal medium and assumed the effect would carry over when we added our standard bolus feed on day 7. We didn't test whether feed components might interfere with the raffinose mechanism.
Given what we learned about osmolality—that it can completely mask or confound the raffinose effect—feed interference could be equally substantial. Feed compositions vary widely and often contain components like manganese, galactose, or other supplements that could promote or inhibit glycan processing.
The fix? Test raffinose in your actual feed schedule from the start, and test higher and lower feed additions. Feed composition matters. Don't optimize basal in isolation and assume it will carry over.
These mistakes cost time. They cost materials. They cost credibility with your manufacturing partners. You can avoid them by planning more carefully upfront.
Here's what this research taught me, and it goes beyond raffinose.
Glycosylation isn't downstream of the process. It's not something you fix at the end after you've optimized titer and viability. Glycosylation is designed into the media from Day 1.
Most scientists optimize for titer first. They pick a cell line. They tune the feeds. They hit 3 or 4 grams per liter. Then analytical comes back with glycan data, and it's out of spec. Now they're scrambling. Temperature shifts, feed adjustments, maybe a late-stage media tweak. It's reactive.
The teams that win? They co-optimize titer and glycosylation from the first design-of-experiments study. They set up their 96-deepwell screens with glycan profiling built in. They track high mannose, galactosylation, sialylation, and fucosylation alongside titer and viability. They see the trade-offs in real time. And they make informed decisions about where to land on the productivity-quality curve.
Raffinose is one lever. There are others—we'll explore them in future episodes. Manganese, galactose, feed timing, temperature profiles. But the principle holds: your media is your glycoengineering platform.
In short, media optimization can be a powerful way—faster, cheaper, and less risky than cell line reengineering—to optimize the quality attributes of your recombinant protein.
If you lock that mindset in early, you'll avoid the late-stage scrambles. You'll hit your regulatory milestones on time. And you'll save your team months of rework.
If you want more details, you can access the full peer-reviewed paper in the Journal of Biotechnology, 2017, volume 252, pages 32 to 42. DOI: 10.1016/j.jbiotec.2017.04.026.
If you found this episode valuable, I'd love your feedback. The best way to share it is by leaving a review. It helps other scientists discover these insights and lets me know what's resonating with you.
Thank you for taking this journey with me into media-based glycosylation control for biologics manufacturing.
Until then—smarten up your biotech.
Book a free consultation to help you get started on any questions you may have about bioprocess development: https://bruehlmann-consulting.com/call
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
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.
Hear It From The Horse’s Mouth
Want to listen to the full interview? Go to Smart Biotech Scientist Podcast.
Want to hear more? Do visit the podcast page and check out other episodes.
Do you wish to simplify your biologics drug development project? Contact Us
🧬 Stop second-guessing your CMC strategy. Our fast-track CMC roadmap assessment identifies critical gaps that could derail your timelines and gives you the clarity to build a submission package that regulators approve. Secure your assessment at https://stan.store/SmartBiotech/p/get-cmc-clarity-in-1-week--investor-ready
Some years ago, I came across a study that stopped me in my tracks. Cyclists who ate pistachios before a 75-kilometer time trial performed worse than those who didn't. Not marginally—4.8% slower. Statistically significant. Why would a healthy nut sabotage athletic performance?
The culprit: raffinose, a trisaccharide in pistachios. During intense exercise, your gut becomes more permeable—and raffinose from the colon leaked into the bloodstream. Once there, it correlated with oxidative stress and leukotoxic effects. Your body was literally fighting the fuel you just gave it.
This concept is discussed in greater detail in the Smart Biotech Scientist Podcast, hosted by David Brühlmann, founder of Brühlmann Consulting.
I thought: if raffinose can slip through a stressed gut barrier and trigger metabolic effects in humans, what does it do to CHO cells under bioprocess stress? That question led to one of the most surprising findings of my PhD work.
Before we dive into that story, let me give you the roadmap for today. First, I'll walk you through why glycosylation matters for biosimilars and what happens when it goes wrong. Then, I'll show you the biology of how raffinose changes glycan processing. After that, I'll take you through the experimental journey—what we tried, what failed, and what finally worked. And I'll close with the real-world impact this had on actual development programs.
But let me tell you what this episode is really about. It's about media design that increased high mannose glycans 2.8-fold in CHO cell culture runs. It works in multiple cell lines. It doesn't require cell line reengineering or expensive glycosidase inhibitors. It's not a universal fix—I'll tell you exactly when it works and when it doesn't—but if you're 6 to 12 months from filing, this could save your timeline.
Before we go further, a quick primer for anyone who's new to glycosylation or needs a refresher.
Glycosylation is the process where sugar chains get attached to your protein as it's being made. Think of it like decorating a cake as it comes out of the oven—except the decorations determine whether your drug works or gets cleared from the bloodstream in 10 minutes.
This happens in two cellular compartments. First, the endoplasmic reticulum adds a core oligosaccharide structure—14 sugars arranged in a specific tree-like pattern. That's the starting template. Then, the protein moves to the Golgi apparatus, where the real action happens. Enzymes in the Golgi trim off some sugars and add others, sculpting that core structure into the final glycan pattern.
For monoclonal antibodies, glycosylation affects a lot. Half-life in circulation. Immune activation through Fc receptors. Protein stability. And most importantly for biosimilar developers: whether regulators will approve your product.
Get it wrong, and you're looking at 6 to 12 months of rework. Get it right, and you're on track for approval.
Now, back to raffinose and why it matters.
Let me paint you a scenario that's all too common in biosimilar development.
You've spent 18 months developing a biosimilar mAb. Your cell line is stable. Titer is great—3 grams per liter. You're hitting your productivity targets. The team is feeling good.
Then analytical drops the bomb. Your high mannose levels are 1.4 percent. The reference product? 6 percent. You're out of spec.
Now, you might be thinking: why does this matter? It's just a small difference in sugar composition.
Here's why it matters. High mannose glycans affect antibody-dependent cellular cytotoxicity—ADCC. They affect receptor binding kinetics. They affect serum clearance rates. And most critically, they affect regulatory comparability. If your glycan profile doesn't match the reference product within an acceptable range, regulators will ask for additional studies. Or they'll reject your filing outright.
So what are your options?
1️⃣ Option one is a temperature downshift to ~32–33 °C. It can push the glycan profile toward higher high mannose, but the productivity tradeoff is clone- and process-dependent.
2️⃣Option two: kifunensine. It's a glycosidase inhibitor that blocks mannosidase enzymes in the Golgi. It's effective—you get high mannose, no question. But it's expensive, hard to scale, and regulatory agencies scrutinize any process that uses enzyme inhibitors. You'll spend months justifying it in your CMC package.
3️⃣Option three: re-engineer your cell line. Go back to the drawing board. Select a new clone with better glycosylation characteristics. This works, but it adds 12 to 18 months to your timeline. If you're racing to market against competitor biosimilars, that delay could cost you hundreds of millions in lost revenue.
What you really need is a media-based solution. Something that scales. Something that doesn't torpedo your productivity. Something that regulators understand because it's just a media component adjustment.
That's where raffinose comes in.
Let me explain the biology of what's happening when you add raffinose to your cell culture.
Raffinose is a trisaccharide—three sugars linked together: galactose, glucose, and fructose. CHO cells can't metabolize it efficiently, so it accumulates in the culture medium and in the cell.
It turns out that raffinose competes with a specific enzyme in the Golgi: N-acetylglucosaminyltransferase, or GlcNAc transferase. This enzyme is responsible for adding the first branch to the core glycan structure. Think of it as the fork in the road where a simple glycan becomes a complex, multi-antennary structure.
When raffinose is present, it binds to the active site of GlcNAc transferase. It doesn't shut the enzyme down completely—it just slows it down. The result? Your antibody ends up with Man5—mannose-5—instead of the complex, fully elaborated glycans you'd normally see.
This is different from kifunensine. Kifunensine blocks mannosidase I and gives you Man8 and Man9—much earlier intermediates. Raffinose arrests glycan processing at a later step, giving you predominantly Man5.
We confirmed this mechanism with transcriptomics. When we looked at gene expression in cells treated with raffinose, we saw downregulation of galactosyltransferase—GalT—and other late-stage Golgi enzymes. The cells were adapting to the metabolic stress by dialing back their glycan elaboration machinery.
The key thing to understand is this: raffinose doesn't shut down glycosylation entirely. It arrests it at a specific step. That's why you get Man5 enrichment, not a complete block. And that's why it's tunable—you can dial the concentration up or down to hit your target glycan profile.
Now, knowing the mechanism is one thing. Making it work in practice? That's where things got interesting.
Let me take you through what we actually tried in the lab. Because the path to the breakthrough was not straightforward.
1️⃣ Attempt one: standard supplements.
We started with the usual suspects. Manganese chloride—known to affect glycosyltransferase activity. Galactose and GlcNAc at various concentrations—trying to push or pull the glycan pathway. We tested these in 96-well plates across a range of concentrations.
Result? Minor glycan shifts. Nothing reproducible. Batch-to-batch variability was all over the place. No clear dose-response relationship. We were tweaking the system, but we weren't controlling it.
2️⃣ Attempt two: osmolality manipulation.
We knew that osmotic stress affects Golgi function. So we tried increasing osmolality by adding raffinose at high concentrations—50, 75, 100 millimolar. The idea was to stress the Golgi and slow down glycan processing.
Result? Growth crashed. At 50 millimolar raffinose, cell viability dropped below 70 percent by day 5. Titer tanked. We thought we'd hit a dead end. Raffinose looked like a non-starter.
But then we had a realization. We were confounding two variables: raffinose concentration and osmotic stress. High raffinose meant high osmolality, and we couldn't tell which factor was causing the growth inhibition.
3️⃣ Attempt three: the constant osmolality pivot.
This was the key experiment. We adjusted sodium chloride in the medium to keep osmolality constant at 315 milliosmoles per kilogram—regardless of raffinose concentration. So when we added 30 millimolar raffinose, we subtracted enough NaCl to maintain constant osmolality.
Result? Growth recovered. Viability stayed above 90 percent through day 14. And now we could test raffinose concentrations up to 100 millimolar without killing the cells.
Once we isolated raffinose's effect from osmotic stress, the data became crystal clear. We had a dose-response curve. We had reproducibility. We had scale-up potential.
It turns out that the breakthrough wasn't in finding a magic ingredient. It was in controlling the variables so we could see what raffinose was actually doing.
Here's what worked.
50 millimolar raffinose increased high mannose 2.8-fold compared to the control. The effect was robust. It worked in two different cell lines. It worked in two different basal media. It worked at every scale we tested: 96-well plates, shake tubes, benchtop bioreactors.
The surprise? The glycan profile was predominantly Man5. Not Man8 or Man9 like you'd see with kifunensine. This told us we were hitting a different step in the Golgi processing pathway.
Now, I was fortunate to apply this approach in actual development projects. I can't share specifics—those programs are confidential—but I can tell you this: when you're staring at a glycan mismatch 8 months before your IND filing, having a validated media lever in your back pocket is the difference between making your timeline and explaining to leadership why you need another year.
One more thing about this approach that's often overlooked: it's regulatory-friendly. Raffinose is a simple trisaccharide. It's available as a GMP-grade material from multiple suppliers. It's not an enzyme inhibitor. It's not a genetic modification. It's a media optimization—something process development teams do all the time.
If you're pre-IND, this is straightforward. You're optimizing your process, and media composition is part of that. Document it. Include it in your development report. Done.
So we proved raffinose works. But here's the hard part: how do you actually implement this in your process without spending 6 months on design-of-experiments studies?
In Part 2, I'll give you the exact decision tree. When to use raffinose. When it won't work. And the three experiments you need to de-risk it before committing to your manufacturing campaign.
If you want to dig into the full methods and data, the paper was published in the Journal of Biotechnology, 2017, volume 252, pages 32 to 42. DOI: 10.1016/j.jbiotec.2017.04.026.
Thanks for joining me in exploring the biology behind raffinose and glycan control in CHO cell culture.
If you found this episode valuable, I'd love your feedback. The best way to share it is by leaving a review. It helps other scientists discover these insights and lets me know what's resonating with you.
See you in Part 2.
Book a free consultation to help you get started on any questions you may have about bioprocess development: https://bruehlmann-consulting.com/call
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
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.
Hear It From The Horse’s Mouth
Want to listen to the full interview? Go to Smart Biotech Scientist Podcast.
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A new era is emerging in cancer diagnosis and therapy—one that extends beyond common indications like prostate cancer to address notoriously difficult-to-treat tumors that have long challenged oncologists. Radiopharmaceuticals, with their unique ability to both detect and destroy disease, are rapidly redefining what is possible in clinical research.
In this episode of the Smart Biotech Scientist Podcast, David Brühlmann speaks with Bryan Miller, Director of Scientific and Technical Operations at Crown Bioscience UK, about how advanced preclinical models are used to help clients advance innovative cancer therapies toward the clinic.
I think we are also seeing radiopharmaceuticals developed for a wider range of cancers. We do have therapies available for prostate cancer and neuroendocrine cancer, but we are seeing this expanding—and this will further expand over the coming years, which I think is a really exciting prospect. I think particularly the value that Crown Bioscience brings is what we touched on before in terms of the value of the models that Crown has in the radiopharmaceutical field. We can now offer our platforms of preclinical models to our clients to run radiopharmaceutical studies.
David Brühlmann [00:00:34]:
Welcome back. In Part One, Bryan Miller walked usthrough his journey from cancer research toradiopharmaceutical development and explained why this therapeutic class is capturing the attention of oncology researchers worldwide. Now we’re shifting gears to explore how Crown Bioscience is scaling its preclinical capabilities to meet exploding demand, the strategic partnerships shaping the field, and the technological innovations that could define radiopharmaceutical development over the next five years. Let’s dive back in.
Now I’d like to touch upon a different part of the technology. There’s a lot of innovation happening. Many are saying that we’re entering a new era for radiopharmaceutical innovation. What makes this moment or season different, and how are you as a company positioned to help shape that evolution as this field scales?
Bryan Miller [00:02:44]:
Yeah, I completely agree. I think we are entering a new era for it. It’s quite exciting what we’re starting to see, and one of the things that is most exciting to me—I touched on it a little before—is the development of diagnostics. We’re certainly seeing increasing interest and excitement about the potential of radiopharmaceuticals.
We’re also seeing increased interest in the theranostic use of radiopharmaceuticals—this idea that you can use the same material as both a diagnostic agent and a therapeutic agent. There’s huge potential here, particularly for patient stratification and rapid movement from diagnosis to treatment.
We’re also seeing radiopharmaceuticals developed for a wider range of cancers. We do have therapies available for prostate cancer and neuroendocrine cancer, but this is expanding and will continue to expand over the coming years, which is very exciting.
I think particularly the value that Crown Bioscience brings is in the preclinical models we offer for radiopharmaceutical studies. Our platforms give clients the opportunity to run studies using very advanced, well-characterized models, which opens up a lot of possibilities for research and development in this field.
David Brühlmann [00:04:14]:
What kind of limits do these models have, and where do you see the development going? What kinds of limitations are we likely to overcome very shortly?
Bryan Miller [00:04:26]:
I wouldn’t suggest there are strict limitations as such. As mentioned, we have a number of different platforms, so we can literally take a study from two-dimensional (2D) cell lines to three-dimensional (3D) organoids, then into CDX in vivo or PDX in vivo. That gives a very strong workflow in terms of maturing a study over time. By the time you’re running a study in a PDX model, you’re working with a model that recapitulates the heterogeneity of human tumors and provides highly clinically relevant information, which can generate very powerful data.
David Brühlmann [00:05:04]:
Perhaps give a definition once again of PDX and CDX. What does CDX mean?
Bryan Miller [00:05:11]:
CDX is a cell line-derived xenograft. These are xenograft models where a human cell line is implanted into a mouse to form a tumor, either subcutaneously or orthotopically.
For PDX, that’s a patient-derived xenograft. These models are set up from patient tumor samples—they’ve never been cultured in vitro. The tissue is grown in animals, then cryopreserved from the animal tumors. This approach retains many features of the original tumor, so it provides a more physiologically and clinically relevant output than a CDX, where the cells have undergone selection and adaptation to culture. PDX models retain much more of the tumor’s original characteristics.
David Brühlmann [00:05:51]:
The power of using models, as you highlighted before, is that you can move faster. But another purpose is to have more predictive models to get closer to your targets. What strategies do you use to achieve that?
Bryan Miller [00:06:09]:
I would say there are two main strategies, depending on whether you’re at the in vitro or in vivo stage.
Our organoid models are incredibly valuable. They form 3D structures that begin to recapitulate features you would see in an organ. That gives a much more clinically relevant output than a traditional 2D cell culture model.
With PDX models, the key is that they retain many features of the original tumor. Crucially, they maintain heterogeneity, unlike a tumor grown from a cell line. This intrinsic heterogeneity means that the model’s response to therapy better reflects what we would see in a clinical context.
David Brühlmann [00:07:04]:
I’m curious, Bryan. What I’m hearing is that there’s a lot happening in the space—innovation, changes, breakthroughs. What breakthroughs are you most excited about?
Bryan Miller [00:07:17]:
For me, it’s theranostics. That’s something I find very exciting, particularly their applicability to treating cancers. Take PDAC (pancreatic ductal adenocarcinoma)—very difficult to treat. Current treatment options are limited, and the five-year survival rate is still very low.
What excites me is the development of radiopharmaceuticals with theranostic applications for these hard-to-treat cancers. I see a lot of potential here, and we are already starting to see more development in this space. I expect it will continue to advance significantly in the coming years.
David Brühlmann [00:08:01]:
And how do you balance, in your role, moving fast and innovating quickly while also working in an industry where everything will eventually be regulated? Even at early stages, how do you factor in regulatory considerations and ensure that patients will ultimately receive what’s being developed? How do you manage these two worlds?
Bryan Miller [00:08:26]:
Well, what I would say is that robust quality standards are always absolutely crucial. At Crown Bioscience, we’re dedicated to delivering scientific studies of the highest possible quality. In setting up our strategic collaboration with Medicines Discovery Catapult (MDC), we partnered with an organization that shares our values and commitment to quality.
Having these robust quality systems in place allows our teams to perform work rapidly to meet essential timelines while maintaining extremely high standards. There’s no conflict between high-quality research and speed. If you conduct a low-quality study, that will set your timelines back—poor quality prevents you from getting the answers you need and delays the entire research program.
It’s crucial to work with partners who uphold very high standards of quality and QC, and this is ingrained in the culture at Crown. Our clients know the standards we work to, and we consistently deliver on timelines while maintaining the highest quality.
David Brühlmann [00:09:35]:
Let’s make this practical. What advice would you give a smart biotech scientist who’s curious about radiopharmaceutical development? Where should they start, and what can wait until later?
Bryan Miller [00:09:53]:
I would suggest working with the right partners. Developing a robust strategy for your study is critical—how you’re going to target the tumor, construct your therapeutic, and select preclinical models. Drawing on the knowledge of experienced people in the industry is crucial, and that’s a lot of the value a CRO can bring.
At Crown, we have extensive experience helping clients in the preclinical space. We can advise on study development, help design your study, guide model selection, and assist with isotope choice and labeling strategy for your test material. Partnering with the right experts early on ensures you have a strong strategy to deliver a successful study.
David Brühlmann [00:10:48]:
How do you make a partnership like this successful? Entering into a relationship with a CRO—or later, a CDMO—is sometimes like a marriage. It's very similar. You have to select very well your partner. What is your approach there? Because I'd say not every company fits every CRO. There are differences and it doesn't always make sense for a company to go to one because it's the best or whatever reason everybody recommends. Sometimes it makes sense to go to another. Right.
Bryan Miller [00:11:19]:
I think people choose CROs on different criteria. At Crown, we do work a very wide array of clients with different needs and different interests. And we can always tailor a study to the individual client. One of the things that we always try to do is we do like to see ourselves as an extension of that client's lab. We work in close collaboration in the design of the study. And there's very open communication during the progress of the study as well. I think the success is seen by the amount of repeat business that we get. And we do form these close collaborations with our clients because we are really dedicated to helping them achieve the objectives of their studies. And we've had the feedback time and again that they start to see us as part of their team. They almost see us as part of the research team and they collaborate very closely with us in terms of delivering the study successfully.
David Brühlmann [00:12:14]:
Now I would like to look forward into the future, since there’s a lot of innovation going on. What is your picture? Where do you see this field in five years?
Bryan Miller [00:12:26]:
It’s a dynamic field at the moment. There’s already a lot of exciting progress, and there’s more to come. We’re certainly seeing rapid growth in interest in radiopharmaceuticals, and I expect this to continue in the coming years.
What excites me is the prospect of increasing the number of cancer indications for which radiopharmaceuticals are a viable option—for diagnosis and therapy. This is particularly important for hard-to-treat cancers, where current treatment options are limited. I think radiopharmaceuticals offer the potential to really advance new treatments in these areas. So I anticipate we will see a significant impact of radiopharmaceuticals in treating these challenging cancers in the years ahead.
David Brühlmann [00:13:18]:
Bryan, what is the most important takeaway from our conversation?
Bryan Miller [00:13:24]:
I think the most important takeaway is the level of excitement and potential in radiopharmaceuticals, especially for oncology. Radiopharmaceuticals also have applications beyond oncology in other disease areas.
As I’ve mentioned, Crown Bioscience is a strong partner for these types of studies. We have a fantastic library of models, both in vitro and in vivo, available for radiopharmaceutical research. In partnership with Medicines Discovery Catapult (MDC), we have the expertise to help design and deliver highly successful radiopharmaceutical programs.
David Brühlmann [00:14:09]:
Where can people get a hold of you and further have a conversation about your work?
Bryan Miller [00:14:15]:
People can contact me through LinkedIn and I'd be delighted to give them any more information that they need on breeder pharmaceutical programs at Crown or indeed any other services that Crown offers.
David Brühlmann [00:14:25]:
Fantastic. I’ll leave the links in the show notes on Smart Biotech Scientist. Bryan, thank you so much for coming on the show today.
Bryan Miller [00:14:33]:
Thank you, David.
David Brühlmann [00:14:34]:
And that wraps up our conversation with Bryan Miller.
The radiopharmaceutical revolution is just getting started, and the preclinical strategies we discussed today could reshape how these therapies move from concept to clinic. If you are navigating the complexities of biotech development—whether in radiopharmaceuticals or beyond—I hope this conversation sparked some new ideas.
If it did, take 30 seconds to leave a review on Apple Podcasts or wherever you’re listening. Your feedback helps us bring more insights to the biotech community.
Thank you for tuning in. Until next time.
For additional bioprocessing tips, visit 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.
Book a free consultation to help you get started on any questions you may have about bioprocess development: https://bruehlmann-consulting.com/call
About Bryan Miller
Bryan Miller is Director of Scientific and Technical Operations at Crown Bioscience, with over a decade of experience in oncology research and preclinical drug development. He earned his PhD in Biochemistry from the University of Leicester and completed postdoctoral training at the University of Toronto and the Beatson Institute, specializing in in vivo and in vitro models of colorectal and pancreatic cancer.
After moving into the CRO field in 2015, Bryan has focused on translating strong science into effective preclinical strategies for oncology programs. Since joining Crown Bioscience UK in 2019, he has played a key role in guiding scientific operations and supporting clients across diverse cancer indications and therapeutic approaches.
Connect with Bryan Miller on LinkedIn.
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
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.
Hear It From The Horse’s Mouth
Want to listen to the full interview? Go to Smart Biotech Scientist Podcast.
Want to hear more? Do visit the podcast page and check out other episodes.
Do you wish to simplify your biologics drug development project? Contact Us
Imagine treating cancer with something as precise as a guided missile—radioactive payloads delivered only where they're needed most. Radiopharmaceuticals are redefining both diagnostics and therapeutics, creating new momentum in oncology by pairing tumor-seeking molecules with potent radioisotopes. But what does it really take to develop these agents, and why are investors and scientists alike turning their attention to this field?
In this episode of Smart Biotech Scientist Podcast, David Brühlmann sits down with Bryan Miller, Director of Scientific and Technical Operations at Crown Bioscience UK, a Contract Research Organization (CRO) specializing in translational oncology and immuno-oncology drug discovery and development.
Radiopharmaceuticals are diagnostic and therapeutic agents. So they consist of a targeting agent—typically a small molecule or an antibody—and this will target the tumor. There’s also a radionuclide, and there’s a linker that connects the two. The radionuclide can act as either an imaging agent for diagnosis of cancer or as a therapeutic agent, where the radionuclide delivers a lethal dose of radiation to the tumor.
David Brühlmann [00:00:27]:
What if the next breakthrough in cancer treatment isn’t a pill or an infusion, but a precisely targeted radioactive payload that hunts down tumor cells like a guided missile? Today we’re diving into the radiopharmaceutical revolution with Bryan Miller, who is the Director of Scientific and Technical Operations at Crown Bioscience UK. From his early days studying colorectal cancer models to now leading preclinical development for one of oncology’s hottest therapeutic classes, Bryan is taking us inside science that’stransforming how we fight cancer.
Welcome, Bryan, to the Smart Biotech Scientist Podcast. It’s good to have you on today.
Bryan Miller [00:02:25]:
It’s great to be here, David.
David Brühlmann [00:02:27]:
Bryan, share something that you believe about early discovery research that most people disagree with.
Bryan Miller [00:02:34]:
So I’ve found that research progress is rarely linear or predictable. Over my career, I’ve seen the undruggable become druggable. I’ve seen false starts in some areas and surprisingly rapid advances in others. And I think that’s why I find it so dynamic and exciting—and why I love being a part of it.
David Brühlmann [00:02:51]:
Excellent. Draw us into your story. Tell us what sparked your interest in working on cancer models, and then what were some interesting pit stops along the way that got you to your current role?
Bryan Miller [00:03:03]:
Yeah, it’s quite interesting. So my PhD was actually in cardiac disease. So that’s where I started out. It was when I did postdoctoral fellowships—first at the University of Toronto and the second at the Beatson Institute (UK)—that really took me towards oncology models, both in vitro and in vivo. My postdocs were focused on models of colorectal and pancreatic cancer. And I think what motivated me at that point is exactly the same as what motivates me now. I was passionate about contributing to the development of new therapies for cancer and identifying new therapeutic targets. And really that’s what motivates me to go to work every day to this day. Being part of Crown Bioscience allows me to work across a large array of different cancer indications with a diverse range of clients. And it’s really motivating when you’re contributing to the development of new therapies. It’s fantastic when you’ve contributed to a research program that has led to a therapy going into the clinic.
David Brühlmann [00:03:58]:
Tell us a bit more about your current work. What does that look like when you’re developing these new therapies?
Bryan Miller [00:04:05]:
So we are a preclinical contract research organization, oncology focused, but we do work with a large array of different clients working on various therapeutic types. We have a range of advanced preclinical models available to our clients to run their research programs with. We work across most cancer indications and across most therapeutic types. So it’s a very diverse area of work that we conduct at Crown, which makes it really interesting. It’s very varied, it’s very interesting, and it’s absolutely fantastic to support this variety of client research projects.
David Brühlmann [00:04:42]:
And when you say it’s very diverse, that includes the various diseases you’re working on, and I imagine also very diverse companies with very diverse needs. Before we dive a bit further into radiopharmaceuticals, what is the main need companies have when they come to you? What is the main problem they want to solve?
Bryan Miller [00:05:04]:
They typically come to us with a target in mind and usually with a therapeutic that they wish to test. One of our main roles is to guide them towards the most appropriate preclinical model to address the question they’re asking. We have a range of different models available. We’ve got an excellent array of in vitro models, and we’re particularly well known for our organoid platform. So certainly at the in vitro phase, we have advanced models that can be very valuable. We’re also very well known for our PDX library. We have PDX models that cover most cancer indications, and we have genomic data associated with them. If you have targets in mind, we can guide you towards the most appropriate PDX model for your work. In addition, we have an array of TDX models, genetically engineered models, and humanized models. So really, while we’re cancer focused, for most questions around the development of cancer treatments—including neuro-oncology therapies—we will have appropriate models to support your research program and help you filter down to the most relevant ones.
David Brühlmann [00:06:08]:
When you say models, are these animal models, or are these 2D cultures, 3D cultures, or a combination of various models?
Bryan Miller [00:06:16]:
All of that, actually. So yes—2D cell culture, 3D cell lines, organoids, and various in vivo models. That includes syngeneic models, CDX models, PDX models, and humanized models. So it really is quite a wide array.
David Brühlmann [00:06:31]:
Excellent. So let’s dive into one specific area—radiopharmaceuticals. A lot of our listeners, I imagine, are not familiar with that. Can you start with the basics? What are radiopharmaceuticals, and how do they differ from traditional cancer therapies?
Bryan Miller [00:06:52]:Yeah, so radiopharmaceuticals are diagnostic and therapeutic agents. They consist of a targeting agent—typically a small molecule or an antibody—which targets the tumor. There’s also a radionuclide, and there’s a linker that connects the two. The radionuclide can act as either an imaging agent for the diagnosis of cancer or as a therapeutic agent, where the radionuclide delivers a lethal dose of radiation to the tumor.
David Brühlmann [00:07:18]:
Can you elaborate a bit more? Give us an example. How are they different from a traditional cancer therapy? Is it the morphology, the mechanism, or what exactly are the main differences?
Bryan Miller [00:07:32]:
I’d say there are probably two real advantages of radiopharmaceuticals. The first is safety, because you’re dealing with a therapeutic that can very specifically target a tumor. One of the early stages is to characterize the level of accumulation within the tumor and make sure you don’t have accumulation in other organs of the body. So they can have a greater safety profile than more traditional therapies. That’s one advantage.
The other thing that distinguishes them is the idea of theranostics. You can use an agent that combines diagnostics with therapy, using the same scaffold. You can use one radionuclide to diagnose a tumor and then switch to a second radionuclide to target and kill the tumor. Because you’re combining those within the same strategy, this allows for really good stratification of patients and very rapid progression from diagnosis through to therapy.
David Brühlmann [00:08:28]:
Okay, I see. So it’s faster, and there are a lot more things happening in parallel, giving you a much broader picture.
Bryan Miller [00:08:36]:
Yeah, and I think safer as well. A lot of them are much safer than traditional chemotherapies.
David Brühlmann [00:08:41]:
The radiopharmaceutical field has gone from a niche therapy to one of the hottest areas in oncology. What’s driving this rapid transformation, both on the scientific side and on the commercial and investor side?
Bryan Miller [00:09:04]:
That’s what we’re finding as well. There does seem to be growing interest in the area. It’s quite dynamic right now, and there are a lot of exciting things happening. I think it goes back to some of the advantages I just described, particularly the theranostic approach, which gives these therapies a considerable advantage.
I think the safety profile is another aspect that a lot of companies we work with find very valuable during development. And maybe the third aspect is the widening range of cancer indications that radiopharmaceuticals are being applied to. We’re starting to see more radiopharmaceuticals coming through that target a much more diverse range of cancers.
David Brühlmann [00:09:44]:
And the main purpose of all that is basically to make faster, more actionable, and more predictive decisions with all your models. I’m curious—on top of your models, do you add a layer of machine learning, AI, or advanced data-driven approaches? How does that work in your field.
Bryan Miller [00:10:05]:
In terms of model selection?
David Brühlmann [00:10:08]:
Yeah, and also in terms of interpretation of the data.
Bryan Miller [00:10:11]:
I would say that is certainly applicable to the selection of models. It’s absolutely crucial—you need to get your preclinical model right in order to have a successful research program. We have large datasets associated with all of our models. So certainly, if you’re looking for particular targets or particular gene profiles, we can help you with that. Our models are very well characterized, and that’s information we’re happy to share to guide you towards the most appropriate model.
We’re also very excited by the prospect of AI. I think that’s something that’s much more common now, and it’s something we’ll be incorporating into workflows as well.
David Brühlmann [00:10:51]:
Yeah, you’re making a very good point—you have to select the right preclinical model, because that’s the foundation, isn’t it?
Bryan Miller [00:10:59]:
Exactly. Yes. If you get the order wrong, you’re not going to have a successful program.
David Brühlmann [00:11:02]:
Yes. You’re going to answer the wrong question at the end of the day if you choose the wrong model. Besides that, what are other pitfalls when developing a new drug? What other choices or strategies really have to be right?
Bryan Miller [00:11:17]:
Yeah, particularly in the radiopharmaceutical field, it can be quite a challenging area. One early point is getting the targeting strategy for the tumor correct. That’s a very important aspect—you need high specificity in tumor targeting.
You also need to select an appropriate isotope and the correct labeling position and labeling strategy. Another important aspect is ensuring that you either have, or are working with someone who has, a reliable source of radionuclides. These materials have to be labeled fresh before dosing, so the supply needs to be reliable.
It’s also really crucial to have a robust labeling strategy and to ensure that proper and thorough quality control (QC) is performed on the labeled material. Nothing should be dosed unless it passes stringent QC tests. And, as we discussed, making sure that the model you select is the most appropriate one is critical to giving you the best chance of success.
These are all areas where we can assist—providing advice, guidance, and helping to design the most appropriate study design.
David Brühlmann [00:12:24]:
And compared to conventional drug development, what are the unique challenges associated with radiopharmaceutical development? You’ve mentioned quite a few things that need to be right. How different is radiopharmaceutical development compared to conventional drug development, and what are the unique challenges?
Bryan Miller [00:12:46]:I mean, obviously there are some commonalities. But I think the unique challenges are the need to prepare material fresh—you can’t make it in bulk and store it. You have to have fresh material that can be dosed almost immediately. There’s also the complexity of some of the strategies, particularly designing an appropriate radiolabeling strategy. Because this is quite a specialized area, you really need to work with people who have specialist expertise and can advise on the most appropriate way to label the molecule, the correct isotope to use, and, crucially, the linker. Those are all aspects of radiopharmaceutical design that are absolutely critical for success.
David Brühlmann [00:13:26]:
And how do you, as a company, manage all that and navigate these difficulties? What are some specific approaches you’ve developed?
Bryan Miller [00:13:35]:
One absolutely crucial element is the collaboration we’ve established with Medicines Discovery Catapult (MDC). We’ve recently launched this strategic collaboration, which brings together the range of preclinical models and preclinical expertise from Crown Bioscience with the radiolabeling expertise and radiopharmaceutical experience from MDC. It’s a really strong partnership, combining complementary strengths to deliver highly successful radiopharmaceutical studies for our clients.
David Brühlmann [00:14:10]:
And what kind of clients do you usually work with? Are they small companies, mid-sized companies, or large pharma organizations?
Bryan Miller [00:14:20]:
All three, actually. We work with a diverse range of clients—small, medium, and large. As we’ve alluded to earlier, there’s growing interest in the radiopharmaceutical field, so we’re seeing more and more organizations approaching us to discuss radiopharmaceutical development and appropriate strategies for further studies. That ranges from quite small companies through to larger pharma organizations.
David Brühlmann [00:14:39]:
I imagine their needs are quite diverse. Can you give us a sense of how those needs differ between small biotech and large pharma? What are the typical differences?
Bryan Miller [00:14:53]:
One of the main differences we see is the maturity of the program. Some clients approach us at a very early stage, without a defined radiolabeling strategy. In those cases, we may need to do significant optimization work—guiding isotope selection, developing the labeling strategy, and performing validation to ensure the material can be labeled effectively and is suitable for use.
Other clients come to us with more mature programs. They may already have an optimized labeling strategy and a defined protocol. In those cases, our role may be to perform the labeling through protocol transfer, rather than developing the process from scratch. So those represent two quite different types of client needs that we commonly see.
David Brühlmann [00:15:42]:
Since interest in radiopharmaceutical development is increasing on both the scientific and business sides, I imagine demand is growing rapidly. How do you ensure that you can scale your preclinical and translational capabilities to meet that demand?
Bryan Miller [00:16:04]:
We have a lot of experience in this area. Both Crown Bioscience and Medicines Discovery Catapult have worked in our respective fields for many years, and we’re accustomed to running a wide array of projects simultaneously. Scalability is something we’re very experienced with.
You’re absolutely right—we’re seeing increasing demand for these types of studies. But we approach scalability in the same way we do for other programs: scaling our in vivo and preclinical capabilities on the Crown side, and scaling the radiolabeling and radiochemistry capabilities on the MDC side. Both partners bring significant experience in delivering complex studies at scale.
David Brühlmann [00:16:43]:
That’s where we’ll pause for today. In Part Two, we’ll explore the specific platforms accelerating radiopharmaceutical translation and get Bryan’s predictions on where this field is heading. If you’re finding value in these conversations, please leave us a review on Apple Podcasts or your favorite platform.
It helps other biotech scientists like you discover the show. See you in Part Two.
Alright, 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 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.
Book a free consultation to help you get started on any questions you may have about bioprocess development: https://bruehlmann-consulting.com/call
About Bryan Miller
Bryan Miller is Director of Scientific and Technical Operations at Crown Bioscience. He completed his PhD in Biochemistry at the University of Leicester, followed by two postdoctoral fellowships at the University of Toronto and the Beatson Institute. During this time, his research focused on the development and application of in vivo and in vitro models of colorectal and pancreatic cancer.
Since 2015, Bryan has worked in the contract research organization (CRO) sector, supporting oncology drug discovery and development programs across a range of therapeutic modalities. He joined Crown Bioscience UK in 2019, where he leads scientific and technical operations, leveraging advanced preclinical models to help clients progress innovative cancer therapies toward the clinic.
Connect with Bryan Miller on LinkedIn.
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
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.
Hear It From The Horse’s Mouth
Want to listen to the full interview? Go to Smart Biotech Scientist Podcast.
Want to hear more? Do visit the podcast page and check out other episodes.
Do you wish to simplify your biologics drug development project? Contact Us
Our food systems face a monumental challenge: by 2050, the global population could reach 10 billion, demanding at least 60% more food than we produce today. This stark reality is one of the main drivers for innovation in agri-biotech. Traditional agriculture alone is unlikely to shoulder the burden, especially under the shadow of climate change, deforestation, and depleted resources.
In this episode of Smart Biotech Scientist Podcast, David Brühlmann steps into the lab with Steven Lang, Chief Technology Officer of California Culture. A veteran of both biopharma (and a former leader at Upside Foods), Steven is at the forefront of scaling plant cell culture for real-world impact.
Our future food systems have to incorporate new technologies because our population is growing. We're going to be 9 to 10 billion people on this globe relatively soon. And there are projections that we need to produce 60% more food than we're producing today by 2050 to support that population.
So what I like to say is that we need to continue with our conventional agriculture and supplement and add to it new technologies like what we're doing with plant cell culture and cellular agriculture, because there have to be multiple shots on goal to be able to feed our population. The alternative is malnutrition and starvation. To me, that's unacceptable.
David Brühlmann [00:00:46]:
Welcome back to Part Two of our conversation with Steven Lang from California Cultured. In Part One, we explored how plant cell culture works and the bioprocessing fundamentals behind cultured cacao. Now we're tackling the hard questions: Can this actually scale? What's the economic reality? And how do we move cellular agriculture from laboratory curiosity to commercial production? Whether you're in biopharma, considering a career pivot, or simply curious about the future of sustainable food, this conversation will change how you think about biomanufacturing.
On the taste part, because that's an important part for me. As a Swiss, I must say I'm pretty critical when it comes to chocolate. Producing cocoa that tastes well is quite a complex process because it's not just a plant. There is a complex fermentation process going on. How do you reproduce that in the lab to get as close as possible to natural cacao?
Steven Lang [00:03:03]:
That is a really important question. And I’d like to set the stage by basically giving a synopsis of how chocolate is made. The cacao pods are opened up on the forest floor at these small farms that grow cacao, and the beans are removed from the pod and then spread out on the floor to ferment. That develops some of the flavors. Then they dry those beans and go into the roasting process, followed by all the processing that goes into creating the cocoa nibs and extracting the cocoa butter to then recreate chocolate.
We’re starting with a different starting material because our cells are not analogous to the cocoa bean that's extracted from the pod, fermented, and roasted. So we have to take a food science approach and really think about how we can ferment our cocoa powder as well as roast it to achieve those flavors. The nice thing is that we can do that. In that process, we degrade some of the flavanols, so the astringent taste is decreased, and you can bring out some of the chocolate flavors.
Let me say to that developing great-tasting chocolate isn’t our primary goal right now, but it will be in the future—that’s where we’re heading toward the commodity market. Right now, we’re focused on scaling and commercializing, aiming to get onto the market in 2026 with our high-flavanol cocoa. Once we get there, we’ll have more time and bandwidth to build processes that allow us to pull levers to improve the sensory attributes of the cocoa powder to create really fantastic chocolate.
Once you understand the biology of those sensory attributes in the cell culture process, you can start building different varietals of tastes and flavors in chocolate. That’s really the exciting biology I’m looking forward to. And I think that will require, based on what we know about plant cell culture media optimization as well as improvements in bioreactors,…
David Brühlmann [00:05:05]:
What are the technologies you need to produce such high-quality cocoa products. Because you have the cell culture, and then you have the whole sensory area, which is highly complex—what do you need, and what kind of equipment do you need to use to make sure you get this high-quality product?
Steven Lang [00:05:24]:
That’s where I like to think that for cellular agriculture to be successful, we need to change people’s minds about it, not just overcome the technical challenges. We can take simpler processes like coffee or cacao cell culture to help explain the processes to people, which will create more consumer demand and actually pull the products from us.
With plant cell culture, we don’t use a lot of process analytical technologies. So we don’t control pH, there is no temperature control, and that’s essentially it. What we really need is macronutrient profiling at the end, flavanol concentrations at the end, and that’s essentially it.
Anything else relates to safety—microbial testing, for example. Speaking of safety, many people know there’s a heavy metal concern with most chocolates. Consumer Reports released a report showing that about one-third of chocolate products contain heavy metals above safe limits. The great thing about our cocoa powder is that because we can control all raw materials, we can produce products with essentially zero heavy metals. That’s a huge step forward when thinking about food safety and convincing consumers to try these products. Not only are they nutritious and healthy, but they’re also safer than conventional products.
David Brühlmann [00:06:50]:
This leads me to the bigger picture, because when we talk about cultivated meat or lab-grown coffee or chocolate, we hear a lot about climate change, deforestation, and environmental challenges, and you and other companies are trying to solve or at least alleviate these problems. How realistic is it that, maybe in five to ten years, we can produce enough in labs to reduce this burden? Or is this not realistic at all?
Steven Lang [00:07:22]:
No, I think this has to be the future. Our future food systems have to incorporate new technologies because our population is growing. We're going to be 9 to 10 billion people on this globe relatively soon. There are projections that we need to produce 60% more food than we produce today by 2050 to support that population.
What I like to say is that we need to continue with conventional farming and agriculture, and supplement it with new technologies like what we’re doing with plant cell culture and cellular agriculture. There have to be multiple shots on goal to feed our population. The alternative is malnutrition and starvation, which to me is unacceptable.
I am very motivated by using my cell culture background and everything I’ve learned in biopharma and at upstream biomanufacturing to really push the envelope. We need to ensure we’re improving human health, food security, and sustainability with the foods we eat in the future, rather than assuming that conventional industrialized farming will solve all our issues. Because frankly, that assumption distracts from the negative aspects of conventional agriculture.
David Brühlmann [00:08:40]:
And if we keep this future-focused lens, zooming out beyond coffee and cacao, what other lab-grown products do you see emerging? What are the hot technologies coming into this space?
Steven Lang [00:08:53]:
I think a lot of supplements as well as other food products could benefit. For example, one of my colleagues just started a saffron company using plant cell culture. Saffron is hugely expensive and difficult to produce, so if we can produce it in cell culture, it really reduces demand on the industry and also produces a higher-quality product. Other interesting products include ginseng, echinacea, and there’s even a startup trying to make cell-cultured wood. That one just blows my mind—it must be premium.
David Brühlmann [00:09:27]:
Wood must be very complex to make. I would imagine—you probably produce some cells in a bioreactor, and then you would need to assemble them to get your finished product at the end, right?
Steven Lang [00:09:43]:
Exactly. Very much like cultured meat. Wood probably has a lot of different components you need to recreate the structure. That’s where the complexity comes in. That’s why we need to start with simpler processes like cocoa or even cell-cultured wood—to build a foundation from which we can later be successful with cultivated meat and allow that technology to mature.
David Brühlmann [00:10:12]:
If one of our listeners thinks, “Well, this is interesting—cellular agriculture is great, you’re solving a big problem,” what advice would you give them as they transition into this exciting field?
Steven Lang [00:10:27]:
First and foremost, look for cell culture work outside of cultivated meat and biopharma. There are startups and companies using this technology—start thinking about where you can get involved. If you’re an entrepreneur, look for products that can be produced from plant cells, because those probably have the fastest route to market and are likely the most consumer-accepted.
The other thing to think about—and we discussed this back in 2023 for people coming from cell culture and biopharmaceutical backgrounds—is that you really need a safety and efficacy mindset. All the products we produce must be safe, and that’s paramount.
Next is efficacy. In drugs, we understand what an efficacious drug is. In foodstuffs or other products, it comes down to things scientists and engineers often overlook: texture, mouthfeel, aftertaste, packaging, and many other factors that are critical to consumers. If you build these considerations into your product intelligently, you can significantly increase your chances of success.
David Brühlmann [00:11:35]:
Before we wrap up, Steven, what burning question haven’t I asked that you’re eager to share with our biotech community?
Steven Lang [00:11:43]:
I’d like to highlight the collaborative aspect. One question I haven’t heard yet is: What does a team look like that can make this successful? I want to call out my technical team. They’ve done amazing work not only with cocoa, but also coffee and cocoa butter. With a small startup over a short period, they’ve developed cell lines capable of producing high-quality products.
We also recently brought in someone to help set up our data foundation. That’s near and dear to my heart. As a startup, setting up a data foundation and capturing all data in a way that can be used in the future is paramount. Many pharmaceutical or mature companies have siloed data systems, which prevents the use of machine learning or AI.
I really want to recognize my technical team, not only for their technical achievements, but also for how we’re building a foundation to implement advanced analytics—the kind of AI-driven insights that are rapidly transforming the industry.
David Brühlmann [00:13:02]:
What is the most important takeaway from all that we’ve discussed today?
Steven Lang [00:13:06]:
David, the most important takeaway is that cellular agriculture is much more than cultivated meat, and we need to start thinking about other processes using plant cell culture to produce products. I really encourage all of your listeners to explore opportunities where you’re doing non-traditional work and don’t be afraid, because cells and these technologies can be evolved to suit our purposes as we develop new products.
I really think about pressure-testing your systems and your assumptions about cells and what they’re capable of. I’ve been surprised throughout my 20-plus years working in cell culture at how far you can push a cell, and it’s amazing what they can do. So I encourage people to continue pushing and look for additional opportunities to help food security, human health, and sustainability.
David Brühlmann [00:14:02]:
This has been great, Steven. Thank you so much for helping us expand our horizons beyond traditional cell culture. It’s exciting what’s happening in that space. Where can people get a hold of you and also potentially taste this high-flavanol product or your coffee?
Steven Lang [00:14:22]:
Certainly reach out through LinkedIn. We’re hoping to be selling our product by the middle to late part of next year. We’re a B2B company, so we’ll be partnering with chocolatiers and hopefully co-branding, but that’s yet to be determined. I’d say definitely look for us in end-2026 or early 2027 in some chocolate products.
David Brühlmann [00:14:46]:
Fantastic. I’m also looking forward to that.
Steven Lang [00:14:51]:
As a Swiss, I’m sure you are.
David Brühlmann [00:14:52]:
Absolutely. Well, thank you, Steven, for these great insights, for expanding our vision, and thank you for being on the show today.
Steven Lang [00:15:02]:
David, I really appreciate what you do here on this podcast. It’s all about scientific communication and bringing people along with what we’re doing, which is very exciting and impactful. We just need more people to understand and get involved, so I truly appreciate the opportunity. Always good talking with you.
David Brühlmann [00:15:21]:
Steven Lang has given us a compelling vision of cellular agriculture’s potential to reshape food production while addressing real sustainability challenges. The bioprocessing fundamentals we discussed today apply far beyond chocolate—they’re principles you can use in your own CMC development work. If this conversation sparked new ideas, share it with a colleague and leave a review on Apple Podcasts or wherever you listen. Until next time, thank you so much for tuning in today and keep doing biotech the smart way. For additional bioprocessing tips, visit us at smartbiotechscientist.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.
Book a free consultation to help you get started on any questions you may have about bioprocess development: https://bruehlmann-consulting.com/call
About Steven Lang
Steven Lang is a biopharmaceutical executive with more than 20 years of experience across large pharma, CROs, and startups. As Head of R&D, Bioprocess, and Analytics at California Cultured, he leads CMC-driven development of plant-cell-derived cocoa and coffee products.
His expertise spans cell line development, process optimization, analytics, and regulatory strategy, with prior leadership roles at Genentech and Johnson & Johnson.
Connect with Steven Lang on LinkedIn.
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
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.
Hear It From The Horse’s Mouth
Want to listen to the full interview? Go to Smart Biotech Scientist Podcast.
Want to hear more? Do visit the podcast page and check out other episodes.
Do you wish to simplify your biologics drug development project? Contact Us
What if your daily chocolate or coffee could be brewed without farms—or deforestation—but straight from a bioreactor? It sounds like a technological fantasy, but plant cell culture is quietly remaking some of the world’s most beloved food staples. This episode cracks open the world of cellular agriculture, moving beyond the hype of lab-grown meat to explore how plant cells are ushering in a new era of sustainable food manufacturing.
Joining Smart Biotech Scientist Podcast host David Brühlmann is Steven Lang, Head of R&D at California Cultured. Steven is no stranger to ambitious challenges. After nearly two decades in biopharma with industry giants like J&J and Genentech, he pivoted toward cultivated foods, determined to go beyond the narrow focus of animal cell-derived products.
Cellular agriculture is using cell culture to produce agricultural products. And the frustration that I've had over the last three or four years is that everything that is considered cellular agriculture is actually synonymous with cultivated meat. And there's so much more to cellular agriculture than just meat.
I really want, through this venue as well as other venues, to drive home the message that cellular agriculture includes any type of cell culture product that can be derived from animal cells like cultivated meat, plant cells like cacao, or precision fermentation with microbial cells. And that broader definition of cellular agriculture is important to me because I see there is a resistance from consumers to adopt or try cultivated meat.
David Brühlmann [00:00:55]:
Imagine a world where your favorite chocolate bar doesn't require a single cacao tree, where coffee comes from a bioreactor, not a plantation. Sounds like science fiction. It's happening right now in California. Today we're joined by Steven Lang, who is the head of R&D at California Cultured, who left two decades in biopharma to revolutionize how we produce food. He's cultivating plant cells to create real cacao and coffee. No farms, no deforestation, no compromise on flavor. Let's explore the future of what we eat.
Welcome back, Steven, to the Smart Biotech Scientist. It's a pleasure to have you on today.
Steven Lang [00:02:52]:
It's great to see you again, David. I'm really pleased to have this conversation again and catch up.
David Brühlmann [00:02:57]:
Sure, Steven. Share something that you believe about bioprocess development that most people disagree with.
Steven Lang [00:03:06]:
Interesting. Well, since we talked last, the thing that I've really come to learn is that we need to walk before we can run. And that is not necessarily around bioprocess development per se, but it's more on the biotech industry and how we have to have stage-appropriate models to really kind of push this industry forward. We can get into more of those details, but that's kind of a nutshell of what I think—that we need to really look at simpler models that can help us answer some of these fundamental questions, not only on the technical side, but also on the consumer acceptance side.
David Brühlmann [00:03:39]:
I like that. Learn to walk before you run.
Steven Lang [00:03:43]:
Exactly. Yeah.
David Brühlmann [00:03:45]:
And I'm excited to have this conversation today on cellular agriculture. Let's start with you, because not everyone listened to our first conversation. So I'd love to hear your origin story—what sparked your interest in biotech and what were some pivotal moments, because a lot of things happened actually since we last spoke.
Steven Lang [00:04:05]:
So my origin story we kind of went into in the last podcast, so I'd recommend listeners go back and listen to that one. But just as a synopsis, I've got almost 20 years of experience in biopharmaceuticals with large, mature pharmaceutical companies—Johnson & Johnson and Genentech—as well as small CROs.
About four years ago, I decided that I wanted to do something a little bit different outside of the pharmaceutical arena. The opportunity came along to work on cultivated meat, which blew my mind, because using these expensive bioprocessing technologies to produce a commodity just doesn't make any sense.
As we spoke about back in 2023, that's really exciting for intelligent people—to have huge, audacious challenges to take on—and certainly cultivated meat presented that to me. That's what got me interested in it.
Throughout the biotech industry, there's been a lot of retraction and consolidation, especially in the food sector, which is more cost-conscious than the pharmaceutical sector. I was caught up in that and was laid off from UPSIDE Foods as part of a reduction in force, as they were consolidating their resources to extend their runway. I thought that was a little bit shortsighted, but I wasn't making those decisions.
I took about eight months off and did some introspection on what I wanted to do with the rest of my career. That brought me to wanting to have a larger impact on the world beyond just human health. That's where the opportunity came along to join California Cultured.
As we talk further, I hope to elaborate on how this cell culture technology can really have an impact on human health, food security, and sustainability—all of which are near and dear to my heart. Having the opportunity to work on something with that type of global impact was really compelling for me.
So I made the jump without much hesitation into California Cultured, where we're producing cultured chocolate (cacao powder) to begin with, as well as coffee. Those are the first products we're planning to get out the door.
This is a relatively small startup—about 18–19 people—founded in 2020, and we're building out not only plant cell culture products, but also the supporting biomanufacturing processes. We're actually developing new bioreactors for plant cells, which is fascinating work as well.
David Brühlmann[00:06:37]:
Yeah, I'd love to dive into more. It's fascinating, and I must say I'm a bit biased. As a Swiss, I love, love, love chocolate. And I ask some critical questions.
Steven Lang [00:06:49]:
Perfect, I'm ready for them.
David Brühlmann [00:06:57]:
Let's unpack it from the start because we have heard, or some of you listening have heard, the term cellular agriculture. But even to me, sometimes it's not clear what exactly is in that field. It's also evolving. So I would love to hear your definition. What is inside? Is even cultivated meat inside of that, or is it outside? Tell us more.
Steven Lang [00:07:16]:
No, that's great. Really good question. Because I think this definition has been evolving, and it's important for us as an industry to consolidate around a single definition. And I think that definition should be that cellular agriculture is using cell culture to produce agricultural products.
The frustration that I've had over the last three or four years is that everything that is considered cellular agriculture is actually synonymous with cultivated meat. And there's so much more to cellular agriculture than just meat. I'd also like to argue that the focus on cultivated meat has done us a disservice, because we have had some opposition to cultivated meat—political arenas, political grandstanding—where states and even countries have banned lab-grown meat even before it's available on the market.
So I really want, through this venue as well as other venues, to drive home the message that cellular agriculture includes any type of cell culture–derived products from animal cells like cultivated meat, plant cells like cacao, or precision fermentation with microbial cells. And that broader definition of cellular agriculture is important to me because I see resistance from consumers to adopt or try cultivated meat. So we need to get away from the singular focus on cultivated meat and move more toward these other products that people understand better and adopt more easily.
David Brühlmann [00:08:50]:
When you say precision fermentation is part of cellular agriculture, what comes to my mind—and this is a question—is beer production part of cellular agriculture or not?
Steven Lang [00:09:01]:
You could argue that, but it's traditionally been called fermentation, which is a stretch. You could call that precision fermentation.
David Brühlmann [00:09:08]:
Okay, fair enough.
Steven Lang [00:09:10]:
I think of precision fermentation as really using genetically modified microbes to produce a specific product, whereas beer and wine fermentation are essentially producing alcohol—which is important—but it's not as complicated as, say, producing lactoferrin from yeast.
David Brühlmann [00:09:26]:
Let's walk through the fundamentals of what you're doing. You're now growing cacao cells in a bioreactor. Tell us more. How does this work? Is it similar to a CHO cell culture? Is it very different, and more?
Steven Lang [00:09:40]:
I like to say cell culture is cell culture. What we do in plant cell culture is very analogous to a CHO cell line in cell line development or any type of cultivated meat, where you take a biopsy from the agricultural plant or animal, and you immortalize those cells and then expand them to produce biomass that is the product. So there are no differences there.
The differences are really about the terminology. With plants, what we do is take an explant instead of a biopsy. And plants are interesting because all of their cells are totipotent, so they can be differentiated into a full plant from any individual cell.
What we've done here at California Cultured, with our cell line development group, is take explants from a cacao pod. We aseptically open the pod, expose the beans inside, and take explants from those beans. Those explants are then put on solid agar media and induced to dedifferentiate. Those are called callus cells.
This technology has actually been around longer than a lot of animal cell culture, because it was historically used to propagate plants for the field. We can take those callus cells on the plate and use them as a cell bank, then screen and select the cell lines we want and adapt them to suspension culture, much like you would with animal cells, and then scale them up.
From there, once we go into scaled production, it's a very simple process—very much like cell culture. We're controlling the environment and the culture, running for a certain number of days, and then harvesting the bioreactor.
One big difference with the plant cell culture products we're working on is that there's relatively little downstream processing. Our downstream processing is dewatering, drying, milling, and packaging. Compare that to cultivated meat, where you take the biomass from the bioreactor and then have extensive downstream processing—such as scaffolding, maturation, or formulation with animal or plant-based proteins to create a meat analog.
With our plant cell culture products, downstream processing is very simple. And I think that alleviates some consumer concerns about cellular agriculture products because it's easier to understand. The products coming out of the bioreactor also really look like conventional cocoa powder or coffee. So it's easier for consumers to connect what we're producing with what they already think of as cocoa powder and coffee.
David Brühlmann [00:12:33]:
Regarding consumer acceptance, I think this cocoa product is much easier to sell because it's not a genetically modified cell, correct?
Steven Lang [00:12:43]:
Correct. We have not done any genetic modification to our cell lines or products. We're relying on the natural diversity in the genetics and epigenetics of cacao to select the cell lines we're interested in—not only based on growth parameters, but also the phenotypes we care most about, which are the sensory attributes and higher levels of bioactives that are important in cacao and cocoa powder.
David Brühlmann [00:13:11]:
Do you clone the cell or your cell lines as you would do in cell culture?
Steven Lang [00:13:16]:
Not necessarily. Since we're not doing any genetic modification, we don't need to ensure that our product originates from a single cell, like what the FDA requires for biopharmaceuticals. Essentially, we do perform clonal selection, but these cells tend to aggregate, so it's difficult to say whether the production unit is a single cell or an aggregate.
That said, we have strict quality control processes and specifications to ensure we're producing a safe, high-quality product.
David Brühlmann [00:13:46]:
And how do you manage the variability that comes from different cells? I imagine the taste will change, maybe the texture.
Steven Lang [00:13:55]:
There's not a lot of that. Right now, what we're finding is that if you control the environment very carefully for plant cells, you can control the consistency and quality of the product coming out. So we’ve been sticking with a very straightforward media and process, and we’ll talk more about that. The bioreactors themselves are pretty consistent, and that gives us stable production over time.
What we’ve demonstrated so far is stability over about six months at the lab scale. When we move to full scale, we’re hoping to translate that stability into a continuous manufacturing process.
David Brühlmann [00:14:30]:
I'm curious about the media cost, because that's a big challenge in the cultivated meat space. How does that work in cacao?
Steven Lang [00:14:38]:
Plants in the field just need fertilizer. And since we're growing them without sunlight, they also need a carbon source. Our media is relatively simple—about 18 components, compared to animal cell culture media, which typically has 40 to 60 components, including some very expensive growth factors.
Our components are mostly fertilizers—phosphorus, nitrogen—plus a carbon source and some relatively inexpensive growth factors that are already found in conventional food we eat today.
David Brühlmann [00:15:13]:
All of the components you're using are chemically defined, correct?
Steven Lang [00:15:16]:
Correct—chemically defined media. I should also add that all the components we’re using have gone through a GRAS (Generally Recognized As Safe) process and are totally acceptable for food production.
In addition to having fewer raw materials, the costs are dramatically different. Back when I was doing cell line development at Johnson & Johnson, we were paying around $40 per liter for media. I don’t know how much that’s changed, but in plant cell culture, we’re well below $10 per liter, and we expect to get below $1 per liter.
David Brühlmann [00:15:48]:
Wow. And what about the economics? Is it relatively easy to reach a point where the product is profitable?
Steven Lang [00:15:58]:
Yes, absolutely. And I should back up and describe our first product coming out the door, which is a high-flavanol cocoa powder. We’ve selected a cell line that produces higher levels of flavanols, which are bioactive compounds responsible for many of the health benefits of dark chocolate.
There was a very large clinical study called the COSMOS Trial, which included more than 21,000 participants, mostly elderly, and more than half had pre-existing conditions such as cardiovascular disease or diabetes. This long-term study supplemented diets with 500 mg of flavanols per day and found a 27% reduction in cardiovascular events. Additional analyses are still coming out of that study.
So we’re interested in improving not only flavor and taste, but also the health benefits of cocoa powder. Through our cell line selection, we believe we can do that. This allows us to enter the market with a premium product at a higher price point.
While we scale that product and generate revenue, we’ll continuously work on improving COGS and processes to reduce cost. That will allow us to move into commodity cocoa and eventually other products like coffee. So we start premium and then move toward commodity products.
David Brühlmann [00:17:38]:
That's an excellent strategy.
Steven Lang [00:17:40]:
Yeah. Other companies are doing this as well. I like to point out Gourmey, which has been very successful in France producing cultivated foie gras as a premium product. It really is the way to go—it’s more of the Tesla model, where you launch with a premium product first.
David Brühlmann [00:17:57]:
Yes, exactly. It’s a Tesla model.
Steven Lang [00:17:59]:
Exactly.
David Brühlmann [00:18:00]:
Before we go on to flavor, I just want to dive into the bioreactor side for a minute, because not everyone listening is familiar with plant cell culture. Can you describe how the bioreactor looks? What parameters are you controlling? How does a run typically work? Is it batch, fed-batch, or—you mentioned continuous—how does it work?
Steven Lang [00:18:23]:
With these cacao cell lines and our cocoa powder product, we’ve run the cells in both stirred-tank bioreactors and airlift bioreactors. They’re very robust and grow under a wide range of conditions, so we don’t have to control very much.
In one of your previous podcasts, you talked about Process Analytical Technology (PAT). For us, the main parameter we control is dissolved oxygen. These plant cells grow at ambient temperature, relatively low pH, and all they really need is oxygen and nutrients.
That’s not to say the processes are trivial, but they’re very flexible, and we can use different reactor modalities. Right now, we’re running batch processes, not fed-batch. A typical run starts with inoculation, and about seven days later, we harvest.
We use a higher inoculum than typical animal cell culture, but our cells are also much larger. We usually start with about 5–10% packed cell volume (PCV), and by harvest we reach 30–40% PCV. That yield is dramatically higher than what you typically see in even highly optimized animal cell culture processes.
So right out of the gate, the amount of biomass we can generate from plant cell culture is significantly higher than what animal cells can produce.
David Brühlmann [00:19:50]:
And how long does a run typically last?
Steven Lang [00:19:52]:
For seven days. And the seed train running up to that is your typical four- to five-day split ratio. Depending on the scale you're going up to, you'll need that time to get the inoculum ready for the final production vessel.
David Brühlmann [00:20:07]:
And what vessels are you using in the seed train? Are these shake flasks, spin tubes, the usual sub-specs, all that?
Steven Lang [00:20:14]:
Standard stuff—shakers and shake flasks, Fernbach flasks, the larger shakers—until we get into the bioreactors. At very small scale, starting at 5 and 10 liters, we keep them in a controlled environment, then scale from 5 to 10 liters to 100 liters, 500 liters, and then 2,000 liters.
David Brühlmann [00:20:34]:
How critical are these cultures with respect to contamination?
Steven Lang [00:20:39]:
The major problem with any scaled cell culture is contamination—how do you maintain a sterile envelope for the cells to really take off? The nice thing about plant cells, as I mentioned earlier, is that the culture media has a relatively low pH, which is not conducive to microbial growth. In addition, plant cells themselves produce antimicrobial compounds that help fend off contamination.
That said, we still deal with contamination, and that’s something we’re actively working through. As we talk about some of the bioreactor innovations we’re developing to create low-CAPEX, low-OPEX bioreactors, the sterilization strategy is a big part of that.
David Brühlmann [00:21:24]:
And you're using stainless steel tanks for the cell culture—it's not single-use, right?
Steven Lang [00:21:29]:
We’re not single-use, and we’re also not stainless steel, because we’re going after commodity products. One of the things that really attracted me to this company is that they’d clearly thought through the business model and understood they’re targeting commodities, so everything has to be interrogated for cost reduction.
Right now, we’re working with plastic bioreactors. The reason is simple: we can buy a 2,000-liter plastic tank for about USD 3,000. Try buying a 2,000-liter stainless steel bioreactor for less than USD 1 million. Right there, you can see we’re taking a very different approach—maybe even recreating the wheel in some cases.
But our cells are well suited to these low-cost bioreactors, which we can then scale out very easily. Another important part of the business model is that instead of scaling up beyond 2,000 liters, we scale out. That allows us to convert underutilized office space into laboratories where we can produce cocoa and coffee.
This is fantastic, because here in West Sacramento, where my labs are located, we’re using underutilized office space with very low cost per square foot, compared to what you’d pay for a GMP facility or a site designed for large-scale mammalian cell culture.
David Brühlmann [00:22:51]:
Yeah, that's interesting, because this model could also be very compelling for emerging markets. You could put this somewhere in Africa, Asia, or Southeast Asia. That works, and people there have the competencies to run it.
Steven Lang [00:23:10]:
Absolutely. And I’m really glad you brought that up. Not only can we co-localize these bioreactors because they’re so inexpensive, but we can also onshore production that historically hasn’t happened in Europe or the United States—particularly coffee and cocoa, which are restricted to regions around the equator.
In the U.S., the only places we can really grow coffee or cocoa are Puerto Rico and Hawaii, and that’s not enough. Our vision is to build not just the cell lines, but also the processes and infrastructure that allow us to deploy these production units anywhere in the world—co-localized with chocolatiers or manufacturers, right next to their facilities.
That also enables the creation of more biomanufacturing jobs. All of these are what I’d call positive externalities that come from focusing on low-CAPEX, low-OPEX biomanufacturing for products people genuinely want—and frankly, people are addicted to chocolate and coffee.
David Brühlmann [00:24:16]:
Yeah. And I think this is just the beginning, because you can produce all kinds of products in these cell culture systems.
Steven Lang [00:24:23]:
Yeah, absolutely. There are already plenty of precedents. Plant cell culture has been around for a long time. There are drugs being produced—at least four that I know of—from plant cell culture. There are also animal vaccines, as well as a wide range of nutraceuticals, cosmetic ingredients, and specialty compounds produced using plant cell culture.
David Brühlmann [00:24:44]:
That’s just the beginning of our conversation with Steven Lang. We've explored the foundations of cellular agriculture and the bioprocessing challenges of growing cacao in bioreactors. In part two, we'll dive into the economics, the scalability, and what this means for the future of food production.
If you’re finding value in this episode, please leave us a review on Apple Podcasts or your favorite platform. It helps other biotech scientists like you discover these conversations. We’ll see you in part two.
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 smartbiotechscientist.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.
Book a free consultation to help you get started on any questions you may have about bioprocess development: https://bruehlmann-consulting.com/call
About Steven Lang
Steven Lang is the Head of R&D, Bioprocess, and Analytics at California Cultured, where he leads the development of sustainable cocoa and coffee produced directly from plant cells. He brings over 20 years of experience in cell culture and biomanufacturing from the biopharmaceutical industry, including roles at Genentech and Johnson & Johnson.
Steven is passionate about applying scientific rigor and scalable bioprocessing to build more resilient and sustainable food systems.
Connect with Steven Lang on LinkedIn.
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
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.
Hear It From The Horse’s Mouth
Want to listen to the full interview? Go to Smart Biotech Scientist Podcast.
Want to hear more? Do visit the podcast page and check out other episodes.
Do you wish to simplify your biologics drug development project? Contact Us
For decades, biotechnology development relied on 2D cultures—cells grown as flat layers in petri dishes or flasks. While useful for many experiments, these models don't reflect the true complexity of living tissues.
In this episode of the Smart Biotech Scientist Podcast, host 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, about how 3D cell models are reshaping preclinical research and driving a fundamental shift in the field.
We have a breast cancer microenvironment model in which we include breast cancer cells alongside immune cell populations. We also incorporate stromal cells, namely fibroblasts, and we were studying antibody–drug conjugates (ADCs). These ADCs are very potent and can kill cancer cells quite quickly.
However, when we use a 3D model in which we reconstitute the tumor microenvironment, the response changes. The stromal cells—these fibroblasts—contribute to resistance to ADCs, and we can observe and study this effect directly in the 3D model. This is something you cannot—and would not—see in a flat, 2D culture flask.
David Brühlmann [00:00:46]:
Welcome back. In part one, Catarina Brito introduced us to the power of advanced 3D cell models that mirror the complexity of human tissues farbeyond traditional culture systems.
Now we’re going deeper into the immune microenvironment, the hidden factors that can make or break therapeutic success. From immunotherapy resistance in tumors to unexpected responses to gene therapy vectors, Catarina reveals how understanding innate immunity is reshaping preclinical strategy. Plus, she’ll share her vision for the future. Let’s continue.
Can you give us a concrete example of how modeling the tumor microenvironment in your system has revealed insights about specific interactions or mechanisms? How does that work?
Catarina Brito [00:02:53]:
There are different types of examples. One practical example comes from work we have published, where we developed a breast cancer microenvironment model that includes breast cancer cells, immune cell populations, and stromal cells, namely fibroblasts. In this study, we were evaluating antibody–drug conjugates (ADCs).
Typically, in 2D models, we culture HER2-positive breast cancer cells and test an anti-HER2 ADC. These ADCs are very potent and can kill cancer cells quite quickly. However, when we move to a 3D model, in which we reconstitute the tumor microenvironment, the response changes. The stromal cells—specifically fibroblasts—contribute to resistance to these ADCs. This effect can be observed and studied in the 3D model, and it is something you cannot—and would not—see in a flat 2D culture flask.
Another example comes from our work with neural models, which we use to study the early steps of immunogenicity to gene therapy vectors. In these models, we include neurons, glial cells, and microglia, which are the resident macrophages of the brain. Using this system, we were able to identify very transient but intense immune responses to viral vectors. These responses had not been detected in other preclinical models but were observed in patients. This illustrates how better reproducing human physiology can help identify factors that can later be used to improve therapies.
David Brühlmann [00:04:44]:
Where do you see these models evolving in the next few years? There’s a lot happening in the bioprocessing field—how we culture cells, how we maintain conditions, advances in analytical technologies, and now the integration of AI and machine learning. How will these technological advances affect the way you conduct your experiments?
Catarina Brito [00:05:16]:
I think advanced cell models combined with multi-omics data—multiple layers of omics information—and spatial information will be key. This is particularly relevant when we consider three-dimensionality and the multiple components of these environments.
This type of data will feed AI-based models, allowing a more accurate representation of human biology and pathophysiology. Until now, we have mainly been making observations and comparing them with human data. But to start making predictions, the integration with AI will be essential.
One starting point is thinking about digital twins of the models themselves, benchmarked against patient-derived data. From there, many things become possible: better tailoring treatments to biological patient profiles, optimizing dosing strategies, and designing drug combinations. Overall, this will be a major step forward for precision medicine and its meaningful implementation.
David Brühlmann [00:06:28]:
What is your advice to a smart scientist listening and wondering how they could implement these advanced models? We have many powerful tools available, but it can also feel overwhelming. Where do you start, and how simple can you keep these models while still gaining value from them?
Catarina Brito [00:06:53]:
I think the answer lies in focusing on the biological question you need to answer. I completely agree with what you suggested—we should aim to be as simple as possible to answer that question. The technology should not be the driving force; the question should lead us to define the biological endpoint, whether that is mechanism of action, potency, or safety.
From there, we decide on the level of complexity required. One risk today is overengineering systems too early, before fully understanding the cells and the question. That’s why I advocate for modular systems: starting simply with tumor or organ-specific spheroids, and then adding stromal or immune components only when the project demands it.
At the same time, we should avoid oversimplifying by treating these systems like regular 2D cultures. Factors such as mass transfer, cell source selection, and process control are critical. These are processes, and they require proper control to ensure reproducibility and standardization, which is often what feels daunting with these models.
David Brühlmann [00:08:17]:
At iBET, you collaborate extensively with pharmaceutical companies. I imagine you also guide them in how to use the models effectively. Can you describe the types of collaborations you have, how you run them, and how they shape model design and application?
Catarina Brito [00:08:42]:
That’s true—we collaborate extensively with industry. Over the years, we’ve been fortunate to work with several pharmaceutical partners who have helped shape how we operate. Pharma partners bring questions driven by translational needs: how to make models more predictive, more scalable, and more compatible with their development workflows.
These applied questions strongly influence model design and help us prioritize our research directions. They help ground the models in real-world use. A key factor for successful collaboration is alignment and transparency—being very clear about the biological question, the performance metrics, and the limitations of the system.
Open data sharing in both directions has been essential. This approach has helped move several of our platforms from proof-of-concept to tools that genuinely contribute to accelerating translation within companies.
David Brühlmann [00:09:49]:
What kind of companies do you generally work with?
Catarina Brito [00:09:53]:
I’ve worked mainly with pharmaceutical companies. Among our collaborations, we’ve worked with Boehringer Ingelheim, Merck Global Health—which is the social business of Merck KGaA, Germany—and AbbVie in the United States. These are large companies developing advanced and novel therapies.
David Brühlmann [00:10:14]:
Do you also work with smaller companies or startups?
Catarina Brito [00:10:18]:
Yes, we do. The collaborations I mentioned were long-term partnerships, often spanning several years, where we developed models from scratch to answer questions that were not addressable with existing systems. We’ve also worked with smaller companies and startups, typically on more focused questions related to their compounds, using models we already have established.
David Brühlmann [00:10:44]:
I have a question about potential pitfalls. As we mentioned earlier, there are many technologies available—so where do you start? What do you leverage? What is hype? What really makes a difference? Can you point out two or three pitfalls to watch out for?
Catarina Brito [00:11:03]:
As I mentioned earlier, one major pitfall is overengineering systems in a technology-driven way before truly understanding the cellular system, what you need the cells to do, and which cell types are actually required.
Another critical aspect is the cell source. Depending on your question, you may never get the answer you’re looking for from the cells you’re using—no matter how much you engineer them.
A third pitfall is insufficient validation and characterization. Moving too quickly to application without properly characterizing the system can be problematic. Thorough validation is essential before drawing conclusions or translating results.
David Brühlmann [00:11:45]:
Catarina, what burning question haven’t I asked that you’re eager to share with our biotech community?
Catarina Brito [00:11:52]:
I think we covered things quite thoroughly. It was a really good conversation—and you can probably tell how passionate I am about this topic.
David Brühlmann [00:12:05]:
Yes, absolutely.
Catarina Brito [00:12:07]:
And this also gives context to my work. My academic appointment is with NOVA University Lisbon, but my lab is also affiliated with iBET. It is through iBET that I collaborate with industry, because iBET is a partnering research organization that bridges engineering and biology to accelerate biopharmaceutical development.
This creates an ecosystem where we combine expertise ranging from cell line development, cell bioprocessing, and advanced analytics, and then close the loop with translational models under the same organizational framework. This setup gives us access to a highly collaborative environment and makes it easier to work with advanced therapeutics, from antibodies to gene and cell therapies.
David Brühlmann [00:12:59]:
This has been great. Catarina, what is the most important takeaway you want our listeners to walk away with from our conversation?
Catarina Brito [00:13:08]:
I think the key takeaway is that advanced cell models are here—and they are here to stay. They will play a major role in shaping translational research in the future, while at the same time driving transformation across the entire industry.
David Brühlmann [00:13:24]:
This was great. Catarina, thank you so much for letting us into the world of 3D cell models. Where can people get in touch with you?
Catarina Brito [00:13:33]:
I’m on LinkedIn, like most people, and also reachable through the iBET website and ITQB NOVA’s website. But I would say LinkedIn is the best way to contact me.
David Brühlmann [00:13:42]:
Excellent, smart biotech scientists—you’ll find all the links in the show notes. Please take this opportunity to reach out to Catarina. And Catarina, once again, thank you so much for being on the show today.
Catarina Brito [00:13:56]:
Thank you, David. It’s been a pleasure. Bye-bye.
David Brühlmann [00:13:59]:
That wraps up our conversation with Catarina Brito. Her work exemplifies the future of preclinical research, where complexity becomes predictability and where patient-specific insights move from aspiration to reality.
If this episode sparked new ideas for your own development programs, I’d love to hear about it. And please take a moment to leave a review on Apple Podcasts or wherever you listen—your support helps us bring more innovators like Catarina to the biotech community.
Thank you so much for tuning in today. Until next time.
For additional bioprocessing insights, visit us at www.bruehlmann-consulting.com. Stay tuned for more inspiring biotech conversations 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.
Book a free consultation to help you get started on any questions you may have about bioprocess development: https://bruehlmann-consulting.com/call
About Catarina Brito
Catarina Brito is Principal Investigator of the Advanced Cell Models Laboratory within the Animal Cell Technology Unit at iBET and ITQB-NOVA. Her research centers on the development of human cell models using induced pluripotent stem cells, patient-derived cells, and established cell lines, and on applying these models to investigate disease-associated alterations of the cellular microenvironment and their impact on therapeutic response.
Her key research interests include the innate immune microenvironment in cancer and neurological disorders, as well as gene and cell therapies and immunotherapies. Her laboratory is supported by funding from FCT (Portugal), the Innovative Medicines Initiative Joint Undertaking (IMI; EU & EFPIA), and the international pharmaceutical industry.
Connect with Catarina Brito on LinkedIn.
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
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.
Hear It From The Horse’s Mouth
Want to listen to the full interview? Go to Smart Biotech Scientist Podcast.
Want to hear more? Do visit the podcast page and check out other episodes.
Do you wish to simplify your biologics drug development project? Contact Us
Ever wondered what actually happens to human cells when you scale up bioprocessing from a petri dish to a bioreactor? Most scientists see it as a matter of bigger equipment and higher volume. But that shift isn’t just technical—it's biological. The rules that govern cell behavior change, sometimes dramatically, reshaping everything we thought we knew about cell therapy development.
Smart Biotech ScientistPodcast host David Brühlmann is joined by Catarina Brito, Principal Investigator at ITQB NOVA and Head of the Advanced Cell Models Laboratory at iBET and ITQB NOVA , Portugal, to talk about how 3D cell models are driving a paradigm shift in preclinical research.
I really believe bioprocess development starts with understanding cell biology at scale. Cells are social entities, and they sense each other. They remodel their microenvironment, they rewire their signaling cascades when things such as cell density, mass transfer, and mechanical cues change. When we are moving from the T-flask to the bioreactor, I think we are not just increasing volume; we are changing the entire context in which the biology of the cells operates. That’s why I think we really need to respect biology as a primary design input.
David Brühlmann [00:00:39]:
Imagine a world where we could predict how your body would respond to a therapy before it ever enters clinical trials. Today’s guest, Catarina Brito from ITQB NOVA and iBET in Portugal, is making that vision tangible. She’s pioneering 3D human cell models that recreate the complex microenvironment of human tissues—from brain and liver to tumors—revolutionizing how we test biologics and gene therapies.
If you’re tired of the limitations of Petri dishes and animal models, this conversation will reshape how you think about preclinical research.
Catarina, welcome to the Smart Biotech Scientist. It’s great to have you on.
Catarina Brito [00:02:35]:
Hi David. Thanks for having me here. I’m glad to be here.
David Brühlmann [00:02:39]:
It’s a pleasure. Catarina, share something you believe about bioprocess development that most people disagree with.
Catarina Brito [00:02:47]:
I think people are starting to believe it in the bioprocess industry—maybe not as strongly as I do, or not from the beginning. It’s a strong conviction of mine because I truly believe bioprocess development starts with understanding cell biology at scale.
Cells are social entities, and they sense each other. They remodel their microenvironment, they rewire their signaling cascades when things such as cell density, mass transfer, and mechanical cues change. When we move from the T-flask to the bioreactor, we are not just increasing volume—we are changing the entire context in which the biology of the cells occurs.
That’s why I believe we really need to respect biology as a primary (PR) input—media composition, oxygenation, and nutrient delivery—to keep biology within the right operating window so that we can successfully scale up. This means thinking about more than just equipment and volume, but really starting with biology as the foundation.
David Brühlmann [00:03:49]:
Scale-up is much more than “scaling up.” And you said it very well—there are so many different parameters you have to consider when scaling a process.
Before we dive deeper into today’s topic, let’s talk about you. Catarina, draw us into your story. What sparked your interest in biotechnology, and how did you arrive at the exciting field you’re working in today?
Catarina Brito [00:04:19]:
It all started during my PhD and was driven by the questions I was trying to answer. I was studying mechanisms driven by glycan–protein interactions, and these mechanisms are very different between murine and human cells. That was an early wake-up call—it made me really think about human biology and the accuracy of the models we were using, as well as the need for models that truly reflect human physiology.
The cellular processes I was studying involved neural cells and axonal outgrowth—processes that are highly dependent on context, particularly the extracellular matrix. Yet we were growing murine neurons on plastic surfaces, which are extremely artificial compared to what actually happens in the brain.
This reinforced the need for better models of the physical context and how it shapes signaling, morphology, and neuronal connectivity. And then there’s the cellular context—neurons are not isolated; many critical cues come from neighboring cells, particularly glial cells. The models we were using were monocultures, which was quite frustrating.
All of this led me to look for a postdoc where I could tackle these questions. My motivation truly crystallized when I had the opportunity to join iBET for my postdoc. I worked under the supervision of Dr. Paula Alves, who was already doing pioneering work on 3D culture systems and demonstrating that biology can—and should—be a primary design input for experimental models.
It was also a very exciting time: it was the first time human pluripotent stem cells were being used in Portugal. That experience was incredibly important and really set the direction for my career—building models that integrate human, multicellular complexity.
David Brühlmann [00:06:24]:
That’s fascinating. Let’s unpack this a bit, because not everyone listening today is familiar with animal models, 2D culture, or 3D culture systems—and there’s a lot happening in this space.
Let’s start with the traditional tools: 2D cell culture and animal models, which have dominated preclinical research for decades. What are the critical limitations of these systems, and what advantages do newer models offer?
Catarina Brito [00:06:53]:
Both. I should start by saying that, because we are often on the defensive. I’m always advocating for advanced models and 3D models, but all models have value, right?
2D cultures and animal models have taught us a lot about biological questions and pathological aspects as well. But of course, they also have limitations. And I think that understanding the limitations of each model is extremely important, especially when we’re trying to develop advanced therapies.
2D cultures are cells grown on a flat surface. Typically, they involve immortalized cell lines that are easy to culture. They offer a lot of control and high throughput, but they lack the structural and functional reality of tissues. Tissues are not flat. Some tissues are layered, but most tissues are three-dimensional.
Cell polarity is altered; diffusion of nutrients—and also of compounds with therapeutic potential—is different. There is no physical confinement of cells and no proper neighborhood effects. As a result, cell–cell interactions change significantly.
If we think about cells under these conditions, their receptor localization, metabolism, and overall phenotype change when moving from 2D to 3D, or from 2D to native tissue. So if we’re thinking about the development of biologics, for example, these molecules depend on receptor engagement, transport, and access to the microenvironment. There is therefore a major difference in both biology and therapeutic response.
When we think about animal models, they are still invaluable because they provide systemic biology—they represent a complete organism. However, they miss many human-specific aspects, particularly in the immune system, glycosylation patterns (as I mentioned before), genetic variability, and even disease etiology.
This can result in false positives and false negatives due to interspecies differences that can distort the readout. Of course, animal models remain useful and are part of a toolbox that should be as comprehensive as possible—but they do have limitations.
David Brühlmann [00:09:09]:
There’s been quite a push from regulatory agencies—especially the FDA—to reduce the use of animal models lately. What’s your take on this? Do you think we’ll ever reach a point where animal models are no longer used at all, or is that unrealistic? Will we always need a hybrid approach?
Catarina Brito [00:09:30]:
I think we are on a path that may eventually lead to the replacement of animal models, although a lot of validation is still required. There is a strong effort to develop multi-organ systems in which pharmacodynamics and pharmacokinetics can be studied. So far, what regulators have mainly pushed for is the replacement of animal models in types of readouts where we already know that the systemic component is not required. But I would say we are clearly on a path that could take us there—we just need strong validation.
There are also efforts from the European Commission, including dedicated calls and roadmaps, to move us in this direction. With support from regulators and agencies, we may eventually get there.
David Brühlmann [00:10:17]:
This will definitely be a paradigm shift for the industry—a very different way of developing drugs.
And speaking of different approaches, let’s zoom in on 3D models and advanced models. Tell us more about that. What exactly is a 3D model, and why is it called “advanced”?
Catarina Brito [00:10:35]:
The notion of “advanced” goes beyond simply growing cells in three dimensions. These models need to recreate key aspects of the tissue they are meant to represent. The tissue microenvironment shapes how cells behave, so the goal is to have a bioactive model in which cells influence the system and are influenced by it as well—ideally in a way that achieves reproducibility and robustness.
There are several important aspects. First, architecture—the three-dimensional structure is essential for cell polarity, spatial organization, and physical confinement. Then there is the presence of diffusion gradients. These are not only gradients of oxygen and nutrients, but also of signaling molecules, which are distributed in tissues and strongly influence biology. They also affect drug penetration, drug binding, and clearance.
Another important component is mechanical cues and the extracellular matrix. Cells sense stiffness and tension, which are crucial for survival, migration, and—for example—immune evasion, which is particularly relevant in cancer therapeutics.
Then there is multicellular complexity. Tissues are composed of different cell types that interact with each other. If we think about tumors, they interact with stromal cells and immune cells. In neural tissue, neurons interact with glia and microglia. These interactions are essential.
Advanced models aim to recapitulate biology more closely to what happens in the body, allowing us not only to study disease mechanisms but also to better predict therapeutic responses.
David Brühlmann [00:12:26]:
In those 3D systems, do people need to visualize this in a particular way? For example, if we take a liver cell type—do we reconstruct a mini liver organ in a bioreactor? Or is it more like having a large number of individual cells, maybe floating?
Catarina Brito [00:12:47]:
We try to recapitulate tissues by capturing this multicellular complexity—having the different cell types that compose the tissue interacting with each other.
It also depends on the tissue. In the liver, for example, hepatocytes are tightly connected through junctions. You also have endothelial cells with fenestrations—essentially “windows” that allow molecular exchange. Then there are macrophages, immune cells that move within the tissue space.
So the goal is not necessarily to reproduce the exact anatomical architecture, but rather to recreate the relevant cell–cell interactions and how they contribute to tissue function.
David Brühlmann [00:13:34]:
And how long can you keep these cells in culture? If you want to start a new experiment, do you have to start from scratch every time? Can you keep something like a cell bank—maybe that’s not the right term—but how does that work?
Catarina Brito [00:13:49]:
It depends a lot on the cell of origin. With primary cells, they are typically used for a limited time. They may last several weeks in the model, but they cannot be propagated extensively.
If we’re talking about pluripotent stem cells, then we can differentiate progenitors and at least bank those progenitor populations. This allows us to work in a multi-step way that facilitates reproducibility.
The duration of the model itself also depends on the culture system. We use a lot of bioreactor technology under perfusion, precisely to prolong the lifespan of these models.
David Brühlmann [00:14:37]:
And how do you handle diversity? You’re working with liver cells, neural cells, stem cells—many different cell types with different requirements in a bioreactor setting. How do you manage that? Do you change conditions, media, bioreactor size or shape?
Catarina Brito [00:15:16]:
It really depends on the tissue. Each tissue has its own requirements.
For example, neural cells are extremely sensitive to oxygen tension and mechanical stress. We use bioreactors, but the design has to minimize shear stress, and oxygen levels must be kept low and very stable. Tight control of process parameters is critical.
In the liver, oxygen requirements are completely different. There, maintaining functionality is key, and perfusion flow is essential to support metabolic competence. It’s also crucial to optimize the ratios of different cell types—not only hepatocytes, but also the so-called non-parenchymal cells. These ratios must be tightly controlled.
In solid tumors, heterogeneity is central. We need systems that allow extracellular matrix remodeling, which is a key feature of tumors. This enables the formation of tumor niches, including hypoxic niches, which are highly relevant. On top of that, we aim to incorporate immune cells and study immune cell infiltration.
All of these requirements are driven by biology. For each model, we carefully choose design variables to meet those needs. Across all systems, robustness and scalability are essential. We aim to design models that are as modular and bioreactor-compatible as possible, ensuring reproducibility and throughput.
Finally, we place strong emphasis on validation, to confirm physiological relevance and ensure that it is not lost during scaling throughput.
David Brühlmann [00:17:22]:
I’m just curious, and I may have missed this earlier, but the purpose of all this, as you said, is better reproducibility and, ultimately, faster development. So how do these advanced systems compare, for instance, to animal models? Why can development be accelerated so significantly?
Catarina Brito [00:17:42]:
The throughput is completely different. When you develop models in scalable systems, you achieve much higher throughput, and these models can be applied much earlier in the drug development process.
They can be introduced earlier in pharmaceutical development than animal models, which are usually brought in quite late. This allows for much more selection and decision-making earlier on.
Additionally, these models are increasingly being adopted because much of the relevant biology—particularly human biology—is not captured in animal models. Even in cancer research, many of the newer therapeutic modalities, such as cell engagers and multispecific antibodies, rely on biological mechanisms that are not reproduced in animal systems.
So even when animal models are available, there is still a strong need to bring human-based models to the forefront.
David Brühlmann [00:18:28]:
We’ve just scratched the surface of how advanced 3D models are transforming drug development. In part two, Catarina will dive into the critical role of innate immunity in predicting therapeutic responses and share her vision for AI-powered personalized medicine platforms.
If you’re finding value in these conversations, please leave a review on Apple Podcasts or your favorite podcast platform—it helps other biotech scientists discover these insights. See you in part two.
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 preferred podcast platform. By doing so, we can empower more scientists like you.
For additional bioprocessing insights, visit us at www.bruehlmann-consulting.com. Stay tuned for more inspiring biotech conversations 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 Catarina Brito
About Catarina BritoCatarina Brito is a Principal Investigator at ITQB NOVA and Head of the Advanced Cell Models Laboratory at iBET and ITQB NOVA in Portugal. Her research focuses on the development of complex human cell models to investigate disease microenvironments and therapeutic responses, particularly in cancer immunology and neuroinflammation.
By integrating fundamental cell biology with translational research, her work aims to accelerate the development of advanced therapies while reducing reliance on animal models. She has coordinated more than 19 research projects, authored 90 peer-reviewed publications, and works closely with pharmaceutical partners and clinicians to advance innovation in preclinical research.Connect with Catarina Brito on [LinkedIn](https://www.linkedin.com/in/catarina-brito-ibet/).
Connect with Catarina Brito on LinkedIn.
David Brühlmann is a strategic advisor who helps C-level biotech leaders reduce development and manufacturing costs to make life-saving therapies accessible to more patients worldwide.
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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