 The main challenge, it was how we can scale a micro environment that is so highly controlled and it's known for being useful in, for example, lab on a chip or an organ on a chip. So really small devices that allow you to create the conditions to make studies. Boom, what's up everyone? Welcome to Simulation. I'm really excited because we just finished up IndieBio demo day. We didn't get a chance to sit down with a couple of the companies so we brought them into studio to be able to explain what they're building and why it's important. With us, we have Stam Bio and we have both Shusho and Federico joining us, the co-founders and cousins of Stam. Thank you for coming onto the show. No, I did not know that. Make sure you bring the mic up if you're going to speak. Now, tell me about this journey because your cousins, you started a biotech company. You're from Argentina, Argentina. And so how did this happen? What were your careers that led you up to making this? Well, we know each other since we were born, basically, but what brought us to start this company actually was beer and our grandfather. So our grandfather taught us how to brew beer when we were really young and we saw an opportunity on creating a business out of selling beer. And we started working by starting to offer our product. We saw that there was also a vacancy on the providers of yeast for brewers. So I was studying agriculture engineer at the university at the moment and focusing on bioprocessing and bio-manufacturing. So I saw an opportunity of us being the ones that brewed that yeast, right? So we started the company as yeast manufacturers for brewers in Argentina and we designed a facility to do that yeast and we soon found out that it was really expensive to do so and even though we know how to brew yeast for the last 100 years, there was no one in our country that was doing so and it wasn't because they didn't know how to brew yeast but they didn't have access to the tools and that would cause that we didn't have any supplier for that product specifically. So we focused on trying to solve that problem by making linear infrastructure for doing biotech and that was the first pilot that we got. We built a small biotech facility to offer yeast for brewers but even when we did that we shrink the cost of that facility by 50x. Wow, 50x shrinking the manufacturing footprint of the facility for yeast. Yes, and reducing the team and making it more dynamic to production so you can offer different kinds of strains that work with more customizable orders for clients. But even when we got there we saw that there was this constraint regarding scaling of that kind of approaches and also gathering the team that it was necessary. So it's a really delicate process and if someone made a mistake by day five they were ruining a weak worth of work of the whole team. So once again at that time we got a little more of recognition from the ecosystem and we started being reached out by other industries saying that they had the same problem. So at that point we... Oh, interesting, for applications that are not yeast. Yes, exactly. That is what actually things started to become very interesting because it opened a new world of possibilities for us. It's like when you find the pain, we are told many, many times to find a pain and then you have a business. It's like we found a very, very big pain because we are going through this renaissance of biotech, right? And many, many startups what is happening right now they have these brilliant ideas that they come up with but they find out very quickly that the strings that they are developing they, you know, cells behave in one way when you are in the lab in a very, very small scale. But when you take those cells to a big bioreactor well, things are very, very different and companies are suffering that way. Many of them actually don't make it through the second year. So usually maybe they have this amazing idea they go through a seed round and they are not able to take it to the market. And oh well, I will pass the microphone to Xuxo. Yes and basically there is this knowledge that cannot be tapped in order to solve big problems mainly because we don't have the tools to make it happen. So that's what we recognize that there was this really big pool of knowledge about how to implement the technology biology as a technology and there's really big communities that understand how to do that very accurately but then there is all of this knowledge that has to do to actually scale that translate that knowledge to a product and make it to actually have a real impact. So there's a lot of new tools that you have to acquire really fast in order for your venture to be successful. Alright, so I got where you were at with grandfather and that being a crucial part of learning how to manufacture yeast and then starting to see these bigger facilities and being like why can't this be done in smaller facilities and also the dream is to make this very plug and play and very small manufacturing of whatever biomolecules you want. And okay, so the technology is microfluidics and robotics I want to talk about that as well. So let's go with just a little bit more on where was the moment for you when you were in Argentina in figuring out how did you bring the cost down 50X or the footprint, the size down 50X? Yes, basically we achieved that by reducing the size of the facility and basically integrating technologies that were off the shelf. So it was an integration of available technologies and trying to come up with a dynamic of work that would allow us to make it more efficient. But we saw that that wasn't enough. We needed to develop novel technologies that would integrate and you will solve these problems by the root. So something that was always really anti-intuitive for me is the way that we control cell behavior within our reactors. So we have these propellers and it's truly extreme to pull the flows to enable the gas exchange and the mass exchange required for the cells to metabolize and to deliver the product that we wanted them to. But as I told you before, I was studying agriculture engineering and I was particularly studying how microorganisms interact with plants and you can find that within plants there are plenty of bacteria that are living within the flow and some silimps of plants and that growth and that interaction and that delivery of molecules happens in laminar flow and it was really interesting because... Laminar flow. And what is that? So it's a regime of liquid fluid that is really slow velocities and you have these vectors of velocities of the flow that are really predictable. And that's microfluidics. So if you can have a predictable sort of flow then that can make processes much easier. And more predictable and more tunable. So the main challenge was how we can scale a microenvironment that is so highly controlled and it's known for being useful for example in lab on a chip or organs on a chip so really small devices that allow you to create conditions to make studies. But we saw an opportunity in that technology to be used for bio-manufacturing to be used in the industry. And the first thing that we saw is that we needed to find a way to scale those micro channels in a way that makes them compatible to how the industry requires products to be manufactured. Interesting, so where did the transition come from the yeast for brewing to the microfluidics? How did that happen? It happened because we found a problem that was compelling enough for us to shift our direction, right? Because there's no microfluidics for yeast, right? For bioreactors there are yeast that would be in microfluidic devices but there is no bio-manufacturing process that uses microfluidics as the way of growing cells and manufacturing products. Okay, and that's where you come in as the first? Yes, because this is a technology that is trying to solve the problem that we always wanted to solve. We started by saying there is no suppliers of yeast in Argentina and that's because there are no proper tools and by doing that we learned that that was a problem that happened across every industry that used microorganisms to manufacture molecules. So we see these... Microorganisms manufacturing molecules, interesting. So that was a problem that was across all the industries. And you're talking about the microfluidics inside of the microorganism. We are talking about the microfluidics that provide the microorganisms, the environment that is better suited for that intended reaction to happen. intended reaction to happen, yeah, okay. So then your microfluidics help the microorganisms' environment make it have an end process that you want it to have, which is making a specific biomolecule. And the first one was yeast that you were making. Yes, then we worked with bacteria. And how much yeast have you made with this process? Well, in Argentina, with this process, it's new because we have been working in the bioprocessor, that's how we call the machine that unites all these technologies together for the last 18 months, 20 months, right? That's a long time. It happened so fast, but the project of setting yeast in Argentina is longer than that. We have provided yeast for brewers for a long time. And we have done tests of productivity per hour. That's a way of saying how much product can we get from a volume size of a bioreactor every hour, right? So that's how you measure productivity in bioprocess. And we found that our microbioreactors are really efficient. And that's a way of comparing to other technologies. During the bio, we work with E. coli, we work with show cells. And we measure unprecedented increases in productivity that go from 70x to 100x of increase in productivity per hour. How much is growing in the bioreactor per hour? So now we're working with units that are 10 milliliters. And so you will get, for example, for bacteria, you will get 10 milliliters every hour. But the content of protein or the content of the end product is considerably higher as well. So we have found around 3x in titers of the protein. That's the concentration of the protein over the volume. And then the throughput that we can achieve is we are changing the whole volume of a bioreactor every hour. And that, in current technologies, it would be around 24 hours, 72 hours, in some cases, 14 days. So that's part of the benefit of being able to know where every cell is going to be at every time. So in that way, you can correct the microenvironment as the cell requires. Okay, so then the microenvironment has microfluidics. And what are the variables that you change in the microenvironment? The temperature, what are these variables? So the main two would be the availability of gas molecules and the availability of feed for the microorganisms to metabolize. Okay, so gas and feed, and then is gas pressure, is that what that is, or what do you mean gas? Yeah, it's like dissolved gases, like dissolved oxygen within the media. You're changing the composition of the gases inside of where the cell is. And then the other one is you're changing the feed that the cell is getting. Yeah, the concentration of feed available surrounding the cell. And we can do that really accurately. Then by doing that, you can also control temperature and control pH because as you have a gas phase that is interacting with the cell, the micro, and then you are adding also liquid, like the media. You have means to control the temperature and control the pH as the cell transforms the environment, right? As they are metabolizing that media, they are producing heat, they are changing the pH. Oh, so then you need... Oh, interesting, so the microorganism is causing the microenvironment to change over time and then you have to adjust the microenvironment. Then that's how you can get a continuous production of your desired biomolecule. Yes. This is what we call cool flow. Cool flow. Yeah, it's cool, right? Because you keep the microorganism in flow of the desired process. Yeah, we call it cool flow because it is cool what we've done and because it is CUL, which is continuous unidirectional and laminar flow. Ah, got it. So to put it into... CUL, cool flow. Continuous unidirectional laminar flow. That's cool. Yeah, and that is actually a very good thing to remind to understand it, continuous unidirectional laminar. That's a good acronym. Yeah, it is. Yeah, we were doing... We thought about saying the Luke, the L-U-C, but they say who is Luke? Cool. Yeah, no one is named Luke in the company, so it doesn't make sense. Let's go with cool. Yeah. If you compare it to the traditional way of scaling up and growing microorganisms, which is turbulent flow, right? The bioreactors think about the traditional bioreactor. It is like Xuxa said in the presentation right in the Mille, is we are putting these precious microorganisms, these factories inside a blender. Yeah, inside a blender. We prepare them. So try to imagine being a cell, trying to find food, trying to breathe, and you are going through sheer forces. In this system that we developed, there's no such thing. So it's actually like we said many, many times, it's a spa for a cell. It enables them to relax and do the one process that you want them to do. They are treated very, very well. They are treated very well. They have food availability at all times. So this is the spa for a cell. Yeah, and I think the key element of that is what happens when you design around the cell instead of putting the cell into our cell and trying to control what happens. So the exercise that we went through is that exactly how it's like to be a cell within a bioreactor. Yeah. And how come we improve that? How come we provide more tools for the users also now? Because sometimes you need cells to divide and then sometimes you need them to work. Then you need them to manufacture proteins. Yes. So you communicate that in different ways. Can you get the environment to enable the cell to only divide or to only manufacture proteins? Can you get it to do just one of those processes? Yeah. We have the capabilities of interacting in different stages. As we know, he said you need directional. So that's important because that means that if the cell is here now, eventually it's going to be in another place and you can know when it's going to happen. So basically you can design a process to say I want the cell to divide for this amount of time. That is going to be the time that it's going to take that cell to go from here to here. And then when it has arrived here, I don't want them to divide anymore. I want to induce the synthesis of protein. And I want to induce that synthesis for this amount of time. That's so interesting because then you can dynamically change the micro environment for the cell. That's great. So now in terms of sizing, ideally down the line, yes, very, very small. Where is it at right now, like the size of a table? How where is it at? So we did a presentation the other day and we presented one of the modules that we are using, our micro bioreactors. They have an equivalent throughput to a one liter bioreactor in turbulent flow. So they are this size. Maybe I can send you the picture and you can share it after us. But that's around, now we are in 100X of smaller sizes when it comes to the size of the bioreactor. Do you guys have it on the... Here, in the website now, we haven't updated yet. No, it wasn't on the... It's not yet on the website because of the IB strategy that we were dealing with like two or three weeks ago. But we're going to get it. So this, you say a micro bioreactor. So then the strategy then, I have a couple of thoughts. The strategy then is to get that to as many people that want to make their own biomolecules as possible and then have them make what they want. What are you seeing that people want to make with them? Like what's the number one or number two? So I think that there are real necessity in the industry for tools that allow companies to have more predictable manufacturing facilities and cheaper ones also or lower costs. Because now that's prohibited. It doesn't allow them to get there, to get to the market. But when we say micro bioreactors because they control the micro environment, not because they are small, right? So even they are small. They have this repeatability of the micro environment that is something that you cannot ask for a traditional bioreactor on turbulent flow as you scale. Every time you use larger vessels, you have to retune the process in order to correct for that changes of the design and the physical behavior that happened within the bioreactor. So when we say micro bioreactors because that micro environment, it can be always the same regardless you are working in a 1 liter micro bioreactor or a 10,000 liter micro bioreactor. So that's the key breakthrough here is that if someone has developed a process, let's say a really big corporation has developed a process in a 10,000 liter micro bioreactor, someone can replicate that process in a 100 milliliter scale and generally trying to achieve the same results and that will happen. So again, micro bioreactor means the climate that you are controlling inside the environment. The environment you are controlling inside. So that way if you are doing 100 micro liters or 10,000 liters that you can control the environments that the micro organisms are growing inside of. Interesting. So that's how it can be replicated out of these scales. So then how would you get a, how would your micro bioreactor, how would it attach onto a 10,000 liter one versus 100, would you sell the whole 100 micro liter one? Would you sell just an attachment for the big one? Yeah, and I think that that's one of the challenges that we need to solve in the near future to understand really how customers are willing to acquire this value that we are generating. So we have plenty of conversations with customers that they understand because they have to release new molecules to the market and they know that for every molecule that they have to release they have to build an entire new facility. So this is solving a big problem even for big companies. When do you put it that way? It sounds like a nightmare that to make a new footprint of manufacturing equipment every single time they want to make a new market. That's stupid, yeah. But on the other hand there is this opportunity of, this is a bio-manufacturing technology that has been always confined to really particular specific places in the world, right? And that's mainly because of the infrastructure that is required to go through this kind of manufacturing process. If we can create a technology that behaves equally in high volumes and in low volumes, all of a sudden there is a venue of innovation from highly trained and skilled groups that can develop knowledge and can develop technology but can now be implemented in a decentralized manner. Without the massive manufacturing facilities. So now you can ship this to the places in the still developing world where they can make whatever biomolecules they need. Okay, so which ones did we say are the most commonly used that you think are going to be most commonly used of biomolecules made? Yeah, I think in the beginning as every technology that is new it would be a choir for people that have really specific needs for manufacturing high value and low scale molecules for example. That's where we see the first adoption. Then there are other places where we see that there's problems when it comes to bio-manufacturing. For example, this can sound controversial but one of the big constraints to bring novel uses of biology to the industry it is bio-manufacturing and it's also the fact that the people that have the infrastructure to implement it don't know anything about bio-manufacturing. They affirm that every year they use this by stimulants to increase their crops, they know how to use the product, they understand the value of the product but they don't have the facilities to manufacture the product. So let's say that instead of having one big company manufacturing all the bio-stimulants in the world they can sell the information that is required to manufacture the product on site. So that today won't happen because the people that would be in charge of manufacturing that product, they don't have neither the tools, nor the skills or the training to do it. But if we absorb that complexity and we put it inside a machine that can read that information, that language of manufacturing and replicate it in a similar way, that's really convenient for all the parties involved because the company that has developed the product has to endure with the complexities and the logistics of manufacturing a product for the entire world but they will get paid for the knowledge that they have created. And on the other hand, the consumer... It's like a marketplace for the knowledge of how you turn a microorganism into a specific biomolecule produce the biomolecule. So then that marketplace people can just go and download that information, upload it into the STEM system. And by doing that you are multiplying the amount of people that are actually thinking about using biology or using biomolecules to solve problems. Because that's something for me that is central of the conversation. If more people know about the technology and how it works, they can see it as a way of solving problems nearby. And that is only... So far it's been only, I don't know how to say it, but it's only been possible for a really small group of people that has the privilege of working in one of these facilities. So by putting this technology in more people's minds, not only in their hands, we see a ripple effect of how we interact with biology as a way to solving real-day problems. And I think that's really powerful. Yeah, getting it in the hands of more people and also making a process that can... You're building the future of the process. You're not just making one tiny addition. You're completely changing the way that we do this process in a more efficient way. I love that. Okay. There's probably something else that's important to touch here that I think that you guys can explain. What does the... What is the recombinant protein monoclonal? What does that mean and how does that... What does that have to do with the... Does that have to do with the process of the microorganism making the biomolecule? Yes, it's different ways in which we use microorganisms to manufacture pharmaceutical products for treatment. Interesting. So you have this tear that has to do with molecules, particularly, and then other that has to do with cells. We use the microorganisms to build more microorganisms. That has the same capabilities. That could be seen, for example, in the clean meat industry, in the stem cells industry. In yeast, for example, we didn't use the yeast to manufacture a molecule because we didn't do beer. If not, we would use that yeast to manufacture alcohol. But what we sell is a number of cells. So our process was to take little cells, a really few number of cells, and take it to a large number of cells that would provide a service for the brewer that is actually transforming their malt into beer. So what I'm trying to say here is that the value of these microorganisms can be tied to the function that they provide as a microorganism or to the molecule that they manufacture as a product. Does that make sense? I think a little bit. I'm trying to follow it. At times it's so hard when I'm not able to fully grasp everything. You're multiplying workers. You have one worker that transforms sugar into alcohol, but you need a lot of them in order to make a lot of beer. So you use bio-manufacturing to increase the number of cells that will eventually transform that malt into alcohol. In the other cases, you have functional molecules that are proteins mainly that can target a specific cell or block a compound that is bad for you. So basically what you use bio-manufacturing to tell the cells and the microorganisms to manufacture that protein. Afterwards, you separate the microorganisms of the protein and you purify that protein. That's the end product that ends up going to the market. Okay. Then what does this look like in application in the pharmaceutical industry or in agriculture? What do the applications look like? We've talked about it a little bit, but give us some more. Anything that goes from medicines, the insulin is made this way, for example. Vaccines, treatment for stem cells, the personalized medicines, were they going to need your cells? This is all made this way. Everything is using these tools. Yes, using tools like this. So if we need your cells to treat you, we need a set of tools that are meant for the dosage that you require. Is this called molecular manufacturing? Is that what kind of the... Yes. Yeah, like the insulin and... Yeah. Interesting. This also opens a new world of possibilities in terms of business. Because when it comes to big, huge demands for a product, so there is a no-brainer, which is no problem. We go through with building $10 million facility because the demand, it allows it, right? It makes it profitable. But when you come, like you were saying, with very small and specific demands, there is not a possibility. But when you can build your own biotech facility for a small fraction of the money you would use to build a traditional facility, and that new facility, it fits inside of a regular office, then the sky is the limit, right? Yeah, and I wouldn't manufacture my own insulin, probably. I would let the main big dogs manufacture it because they have much larger... They already know. They are installed. They have other advantages. I had to do some logistics with regulations. But coming back to personalized medicine, for example, I believe that it would be really important for hospitals to have tools that would allow them to treat patients directly. And that's the leveraging this technology, biomanufacturing, I mean. And if we can be part of that, that would be amazing. But today that won't happen because the logistics require to get a sample from you and take it to an industry facility that can manage it that way. It may be too tedious or too expensive. So basically the end-up result is that we know how to cure you, but it's expensive, right? You have to be able to afford it. So that's not something that we can see today with novel therapies that are specifically expensive because of the skilled labor that they are required and the facilities. To make a new facility for the new treatment, the new personalized medicine, rather than be able to just compute the environment that it needs in order to make the treatment. Is that right? Yeah, it's like once you have an understanding how you do it, you can replicate it in a decentralized manner. So there's always been this part of you developing the process and understanding how it works. But eventually the big difference is how you create impact out of that knowledge. If you have to explain it to each person and to each country that you're working with how you have to do it, or you have to explain it to a machine, right? And you know how to talk to that machine because you have created that language and how a good process looks like to a machine. And then in egg, what is the agriculture? Yes, so we increasingly are using more microorganisms to control the environment that plants experience and we use microorganisms to promote growth and to provide capabilities to sustain growth conditions. And that's only going to get more demand for that. Yes, and more knowledge and intensity on those areas. So yeah, and there's other things, there's a lot of biological value in Arctic because there is where you have the plants, that's where you have the animals today. So there is a path to follow that is to rebuild the whole industry with new and more efficient technologies. The other side would be to leverage the current infrastructure in Arctic and to provide tools that will enable these high value technologies for cell-based, manufacturing cell-based meat, for example, to be performed by the infrastructure that is currently there. And there's a lot of value in that because you have local farmers that have a history with their cattle and a history about interacting with the environment that they live in. And there's a lot of knowledge, to my opinion, really valuable knowledge and identity linked to the rural way of living that could be preserved if we have tools that enable them to be part of the transition towards a more efficient technology. Right? So that's part of... Yes. I want to clarify this because I think this is important. When you have the different examples of either me purchasing the actual micro-bioreactor from you or you adding the micro-bioreactor onto an existing bioreactor infrastructure. So you will do both, do you think? Which one do you think you'll start with? Yeah, that's a good question. We are interacting with clients and customers and potential partners to basically to hear how they would use this technology. What we have found out is that even for big companies building facilities is a problem. So that's something that we didn't knew before coming to San Francisco. We thought that because of the high prices of some products that's not so important in manufacturing. There is this belief that manufacturing doesn't add value but actually adds a lot of constraint to the business model because someone could say it is already cheap but I think it's not cheap because you have to wait for years to build that manufacturing plant and one that is built is there to stay. And it's not that you can shift that into some other direction. You're there, you do all the regulations so you have to commit to that. So maybe someone would say that it's not that expensive but it is expensive for the decision making of pharmaceutical companies and biotech companies in general. And now you can't afford to have a narrower scope of decision making because the game is changing every year. New technologies are coming and that's where we believe that it's important to have a technology that is also dynamic. Totally. What is the most common gas that is being added? Is it oxygen, carbon? Yes, mainly CO2. Oxygen, nitrogen, CO2. Oxygen, nitrogen, CO2. And so then do you have then to have compressed oxygen, nitrogen, CO2 to be able to add to the environment over time? Yeah, that's a good question. We work with really low pressures but one of the good things about our system is that we have a lot of surface of contact between the liquid and the gas phase so we can provide a really good exchange of gas into the media working with high pressures. That is something that doesn't happen in the Korean industry. Basically you have a lot of pressure building up inside the reactor. You have really high shear forces as a side product of the propeller going at 30,000 rpms. You have a community of cells that are untraceable and that's a problem because you have a community that you don't know how long have been there. If you work with a continuous or semi-continuous approach some cells will leave the system but there are others that will stay inside and you don't know how long a cell has been there and that is detrimental for the production. Having a unidirectional path allows you to know the work life of that cell and when do you want that cells to go out from the system. Even if there is a lot of work to be done in that area that kind of capability is something that today you cannot control. There is no trace of cells. Being able to do that opens up a world of new possibilities when it comes to bio-manufacturing and how to create new ways of using cells to manufacture products. This is so amazing. It's very unique. I love it. We love it too. It's good because like I was saying earlier it's not just an addition. This is a completely new way of thinking about things with microfluidics. Robotics is very interesting. Is there something that we didn't cover that we should mention? That we wanted our technology to be used and we truly believe that that is a really neat for this and we would like also to hear what someone that could be looking at this might think about our approach. We are open for every insight and applications for improvements. We approach this problem willing to solve it so we can use all the headlights available and we are open in this conversation. Are you staying in the San Francisco Bay Area? Yeah. Good. We just opened an operation here in San Francisco in the Bay Area and although we have our alpha test told booked up after demo day so many startups approach us that we are considering opening it up again and maybe doing a larger alpha testing. Awesome. Everyone watching, we are super approachable. You can shoot us an email and we'll be in touch. Yeah. Awesome. That was very good. We have a lot to learn about the way that we can manufacture specific molecules and actually really tap into the... changing the variables in the environment so that we can optimize the production. This is brilliant. I love it. Good job, guys. Thank you. Thank you very much. Thanks for joining us on the show. That was a lot of fun and it was really fun to learn about that. Everyone that was watching, definitely check them out. stem.bio, s-t-a-m-m dot b-i-o, links in the bio. Also, give the comment below. Let us know your thoughts about the process and also about ways that you think it can maybe be augmented over time. Thanks everyone for tuning in and we'll see you soon. Peace.