Author: Trevor Mallo

Proteinea turns insect larvae into biofactories. Instead of cell-based biomanufacturing, their next-generation platform uses mass-reared insect larvae as fast growing, mini-biofactories to produce recombinant proteins of interest. From antibiotics to biosimilars to vaccines to aquaculture feed to growth factors and more, Proteinea makes valuable recombinant proteins affordable and accessible. And their Buggzy platform is just spinning up. We chatted with co-founder Mahmoud Eljendy and Abudulaziz Elgammal about the future of recombinant protein production. 

Proteins make every function you could imagine very fast and efficient. I dream of the day when we harness this power to make soft machinery.

CEO Mahmoud Eljendy

How did you two meet? 

Although we are originally from the same city 100 km away from Cairo, we only got to know each other from the entrepreneurial ecosystem in Cairo. Mahmoud had his previous startup, DeltaOil, where he built a success story that’s now Africa’s leading Used Cooking Oil (UCO) supplier for the Biodiesel industry in Europe. I (Abdulaziz, Aziz for short) was fascinated by the mission-driven and innovative approach he took to enable unprivileged communities to valorise an untapped source of income while making a good amount of money and saving the environment.

At that time, I was working with the leading accelerator in the Middle East North Africa region (Flat6Labs) and trying to build a community of science entrepreneurship enthusiasts. During one of our meetups for science entrepreneurs, I met with Mahmoud who was then raising insects in his own apartment and was looking for a technical cofounder. Funny enough, the place we first met years ago is now our own office and lab at Proteinea 🙂

What made you decide to start Proteinea? 

It was a convergence of efforts to make an impact in people’s lives through know-how and innovation. We started Proteinea with the aim to solve a very local problem that’s at the core of our food value chain. The principle was to use insects as a protein source for animal and aquaculture feed as Egypt imports 90% of its feed components. During this process, we borrowed technologies from aerospace to machine learning to biotech and everything in between to scale up the production very efficiently and very cheaply.

We then realized that combining the process we built and our previous background, we have created the perfect solution to a more pressing problem the world is facing — recombinant protein production.

What does “recombinant” actually mean? 

Something recombinant means it is made by recombination. As scientists, when we want to engineer a living organism, we usually start with engineering it’s DNA. By assembling a DNA fragment from smaller pieces so that they contain specific instructions for the cell, we build what’s called a recombinant DNA. In some cases, these new instructions tell the cell to produce a specific protein. In this case the protein is called a recombinant protein.

Why is a fly larva an optimal protein factory? 

Compared to cell-based technologies, insect larvae can perform much better in the production of our complex proteins. Very low capex and opex – we do not have culture media, our culture media is wheat bran, fast time to market – it can take as little as two weeks to have our protein of interest, and the scalability – we can produce hundreds of kilos of larvae from very small area & what happens in one larvae can happens in millions of larvae – that’s minimal risk in the scale up.

Seems difficult to get proteins to fold the right way – how does it work in the insect larva if you’re trying to do humanized or otherwise proteins? 

Insect cells have long proven to make complex proteins. They have complex cellular machinery to produce virtually any protein you might need. In many cases, they are the go to platform for expressing proteins that don’t work well in other systems, Virus-Like Particles (VLP) vaccines make very good examples here. Even some of the most complex proteins like full humanized antibodies have been produced in insect cells before.

At Proteinea we work with a novel platform which requires some work from our side to identify the proteins and pathways to make proteins stable to express, purify, and  humanize and we have success with it. Our AI-based computational optimization goes hand in hand with experimental validation to build the next generation soft bioreactor.

How big is your team?  How did you find all the talent?  What industries do they come from?  How hard is it to build a company culture so quickly? 

We are 22 team members between the US and Egypt. From the beginning, we are very keen to build a robust culture that can proliferate. We have built our manifesto in which we have our values and principles. We provide 4 things in Proteinea for our team members. A cool technology and science; a product could have a huge impact on our biomanufacturing thus bioeconomy; a robust culture with stunning colleagues; and fair financial compensation of salary and stock options. 

What is the biggest difference between working in STEM in Egypt and the US? 

Between Egypt and the US, you face a completely different set of problems. There’s not much competition over the talent pool in Egypt, so you get to build a very strong team easily. But, the support system in Egypt is still nascent when compared to the US. You don’t have many options but to build your own path. I remember when we started doing experimentation in Egypt, we got help from big research institutions because they want to help on the personal level not because of the institutional direction of supporting entrepreneurs.

Logistical challenges in Egypt are also a bit harder than the US. Because there are no local manufacturers of biotech supplies, things might take longer to arrive in Egypt. We mitigate that by proper planning plus we do some of the more advanced research in the US to cut time.

What’s your favorite biomolecule in the central dogma?  Favorite amino acid?  

I’m a protein guy, look at this one. It’s beautiful. I remember my fascination with the protein myosin moving a molecular cargo across the cell over a protein railway (cytoskeleton). Proteins make every function you could imagine very fast and efficient. I dream of the day when we harness this power and make soft machinery. We started this at Proteinea and built the world’s fastest biomanufacturing platform based on our soft bioreactor. Cysteine, disulphide bridges also have a special place in my heart.

The AltProtein space is abuzz, but lacking in products that engender the same finger-licking scrumptiousness of devouring a plate of tasty wings. Sundial Foods developed a novel processing technology for creating plant-based whole cuts of meat — complete with skin, meat and bone. The beauty is in how it ends up on your plate from only eight clean-label ingredients. Dr. Jun Axup, CSO of SOSV’s IndeBio sat down with co-founders Jessica Schwabach and Siwen Deng to reflect on Sundial’s journey of discovery.

The crazy thing about our wings is that all the texture and complexity – the skin, meat, muscle, and bone – comes from just eight clean ingredients.

Jessica Schwabach, CEO of Sundial Foods

Can you tell us a little bit about what the product you’ve created is?

At Sundial we’re making plant-based whole cuts, and the first thing we’re launching is chicken wings. So the basic premise is that for plant-based meats, there’s a single processing method, called high moisture extrusion, that’s used to create most of what you see on the market. It’s a really cool and versatile process, and can give you a nice protein base to work with, but then you are going to need more processing and some less pleasant ingredients — binders like methylcellulose for instance — to make a cohesive and meatlike product. Creating something like the complex cuts of meat that we are doing would require even more processing and assembly work.

So the process that we’ve developed allows us to have more of a one-and-done approach.  Like extrusion, we combine plant ingredients under thermal processing to generate a fibrous bite texture, but there are two key differences. First, we don’t have that shear, so we’re able to create a cohesive three dimensional product in one shot – no assembly required later. Second, we don’t just use the functionality of protein isolates to create these fibers — we use intrinsically present starches, fiber, and so on to our advantage when we’re trying to create this texture. Not only is the structure of our fibers and skin built differently, but once we’re done with this one thermal process, we’ve got a whole, cohesive, already delicious cut of plant-based meat. It’s much simpler.

And the reason we’re starting with chicken wings is just because people love them. It’s just a really nice experience — part of a chicken that’s genuinely fun to eat. Like seriously — Americans eat something like 1.4 billion wings over Super Bowl Weekend. But animal free versions are sorely lacking, and we know how to make them, so here we are.

And you’ve actually been able to make some and prototype them in stores and Europe. Can you tell us a little bit about the customer feedback and what you’ve learned?

Yes. So we did test them for two months in about 40 grocery stores in Switzerland last year, late 2020. And we got some super interesting feedback.  We asked a lot of questions. Probably the leading question is, is the concept of a whole cut with skin meat and bone made from plants something that’s just currently too weird for consumers, which we were worried about because when you look at the product, it’s a bit jarring or uncanny how much it looks like chicken.

What we found is that people are actually attracted to it by appearance.

People also liked that it was clean label and high protein, which comes from our process, so we were quite happy about that. Interestingly, the product was chickpea based and we thought this would be important because it’s a differentiator from soy or pea-based proteins, but consumers didn’t seem to care so much about that as long as it was healthy.

But the most interesting thing we learned about the product was that people really liked the plant-based skin. I know it sounds sort of weird because it seems like something that is just a strange concept, but it really takes things to the next level in terms of not only the initial appearance, but also the cooking experience and similarity to chicken. Or to put it more simply it just tastes good.

Looking at the cell based meat industry, with the first cell based chicken for sale being approved in Singapore, what do you see as the near future  — the convergence — between cell-based and plant-based meats? Where do you position Sundial?

Interesting question. 

The raison d’être for Sundial is that we need to provide center of plate protein options that are not derived from concentrated animal feeding operations because these operations cannot sustainably meet protein demand. If making protein taste like meat is what will make people buy it then we can do that, as long as we’re making sure it stays nutritious and is truly on par with or even better than meat in that regard. Also of course it’s gotta taste really good.

And cell-based meat has a similar purpose. And I think that both of them will take chunks out of the animal agriculture industry, but not necessarily out of each other. I guess it remains to be seen and everybody’s wondering, but I do feel that the consumer segments won’t overlap that much.

Innate Biology produces supplements to mimic the same cellular benefits you would get from fasting, without having to fast. Their formulation uses a unique combination of natural human molecules and has been clinically shown to produce the same anti-inflammatory, antioxidant, and cardioprotective benefits of fasting — so you can live life and thrive. Sibling founders Dr. Chris Rhodes and Caitlin Beatty share their journey to unleashing a healthier life below.

Using fasting as a roadmap to optimal human functionality we’re decoding and recreating our body’s innate “bio-programs” for cellular health and regeneration with the world’s first fasting mimetic supplement.

Dr. Chris Rhodes, CEO of Innate Biology

We’ve all explored ways to enhance our own health, whether diet, exercise, food, or drug — can you tell us what you are working on and how that led you to found Innate Biology? 

I’ve spent the majority of my scientific career studying human fasting at the University of California at Davis and can say first hand that fasting is one of the most powerful nutritional interventions out there for increasing human health. I can also say as someone who spent two years practicing alternate-day-fasting, that it can be a pain in the butt (if not impossible) to actually put into long-term practice and it’s definitely not for everyone.

While I felt the physical benefits of fasting, I also experienced a lot of social isolation and missed out on a lot of experiences that actually make life worth living. Until one day my sister (and now COO) asked me, “What’s the point of living longer if it means you have to live less?” and that was the big inspiration for me that there had to be a better way to get these amazing health benefits without sacrificing life in the process. And thus Innate Biology was born. Using fasting as a roadmap to optimal human functionality we’re decoding and recreating our body’s innate “bio-programs” for cellular health and regeneration with the world’s first fasting mimetic supplement. 

What breakthrough did you achieve during SOSV’s IndieBio program?

Our biggest accomplishment was pulling off a clinical study at UC Davis during the tail end of the pandemic. We were able to show that supplementing with our fasting mimetic was able to mimic the anti-inflammatory, antioxidant, and cardioprotective effects of fasting in human subjects even when they were eating. Best of all, supplementing with the fasting mimetic was able to increase plasma cholesterol efflux ability, which is the golden standard clinical marker of cardiovascular disease and directly related to the prevention of arterial plaque formation. Having clinical data showing that the fasting mimetic works to fight against the negative effects of eating and move a validated clinical disease marker was a huge win for us.

How does Innateness support human health over the long term?

Innate is a really unique company that takes a widely overlooked and undervalued approach to solving human health:  actually studying humans! Our fasting mimetics are designed exclusively from human research and are made of the same natural human molecules that the body produces during a prolonged fast. 

By recreating the regenerative and protective state of fasting through supplementation we are providing people with a whole host of beneficial effects from autophagy to cognitive boosts to reductions in cellular inflammation. Even better, we’ve shown that our fasting mimetic combination can provide holistic long-term benefits and extend the lifespan of model organisms by a whopping 96%.

Tell us about your team

We have a really robust team of scientists, serial entrepreneurs, academic professors, and business advisors in the supplement space. I’m a PhD in Nutritional Biochemistry and a nutrition influencer on TikTok with over 150K followers (@thatnutritiondr; like, follow, subscribe!). Our COO (and my sister), Caitlin Beatty, has years of startup experience in biotech and athletics (she’s a national champion in both field hockey AND tennis; nbd). Our third co-founder, Dr. Angela Zivkovic, is a PhD in Clinical Nutrition and a tenured professor in UC Davis’ nutrition department providing both academic expertise and clinical research capabilities to Innate.

Can you share how you are taking Innate to market?

We’re going to market as a direct-to-consumer e-commerce brand and leveraging my TikTok following as our early adopter customer base to drive enthusiasm and awareness around the brand. Our fasting mimetic is just our first product, with more supplement formulations on the way based on data from our clinical trials. We’re also teaming up with Hatch San Francisco which has done some legendary brands (SmartWater, Smashmallow, and Krave Jerky) to develop our visual identity and unique market positioning. 

What does the future Chris say to the current Chris? 

I would hope that I say something useful like, “Buy more Dogecoin!”, but in all honesty it would probably be something more cryptic and Yoda-esque like, “How is a raven like a writing desk?” just so I could laugh at my past self scrambling around trying to find the answer to life in a Lewis Carol quote. 

If you haven’t been following the trends in synthetic biology, just know that bio-based chemicals are the future. Capra Biosciences reimagined biosynthesis by developing a low-cost, continuous flow method that scales OUT without having to scale up. Pairing a proprietary continuous flow bioreactor with a novel biofilm forming organism, they are producing hyrdophobic products like retinol and performance lubricants, but without the petroleum.They do this using a fraction of the water required compared to traditional batch fermentation methods. Less water means less volume means less stainless steel. We sat down with CEO Liz Onderko and CSO Andrew Magyar to understand how Capra is upending the conventional wisdom that biomanufacturing is capex intensive. 

When we co-invented this technology… this was really something that I could see taking my love and belief in the power of biology and being able to turn it into something that could really impact the world.

Liz Onderko, CEO Capra Biosciences

The latest trends in synthetic biology point to a future of bio-based chemicals and materials that exceed performance specs. You’ve mentioned lubricants with improved performance specs, but during SOSV’s IndieBio program, you set out to make bio-retinol for the clean cosmetics market – what prompted this path? 

The decision to start with retinol – a small volume, high value cosmetics ingredient –  was influenced by the challenges the early biofuels companies faced. By starting out with retinol, we can fold our learnings back into our platform as we gradually scale up to larger volume products. 

The IndieBio team has helped us to learn a lot more about the cosmetics industry through both directly and through the program mentors they’ve connected us with. Through these interactions, we’ve been able to recognize some of the unique requirements for cosmetics products but also the tremendous market opportunity that clean retinol presents.

The novel organism you use naturally forms biofilms, and why is that so important?
Biofilms are really what enables our technology. A lot of people might not even have heard of biofilms before – I definitely hadn’t given them much thought before my postdoc! Biofilms are formed when microbes stick to each other and to surfaces. In a biofilm, microbes are more robust than if they are floating around alone in solution – this can make biofilms like dental plaque hard to remove, but this robustness is a great feature for our bioreactor. We’ve designed our bioreactor to work with biofilms – this combination is what allows us to operate in continuous flow as well as efficiently extract our product. 

As a bio-based chemicals company, how does Capra scale out?
The way our bioreactors scale is really different from how it’s done with conventional fermentation. By multiplexing our production scale bioreactors which are about 10 Liters, instead of making larger and larger bioreactors, we can avoid the productivity drop that is often seen when scaling up in the fermentation systems used today. You might think that multiplexing our bioreactors would increase our infrastructure costs, but the most exciting thing we learned from our technoeconomic analysis is that because our technology uses up to 100x less water, our capex costs actually go way down. 

Tell us about your team. What made you take the leap into entrepreneurship?
Andrew and I met when I was doing a postdoctoral fellowship at the Naval Research Lab and he was a principal scientist at Draper Labs. I was working on engineering biofilm-forming organisms and Andrew was focused on developing bioinstrumentation for synthetic biology – it was this combination of biology and instrumentation that led us to the idea for our bioreactor technology and the vision for our company.  

We both see a need for technologies that will drive down the cost of biological chemical manufacturing so it can become accessible for a much wider range of products and believe our bioreactor technology can play an important role in the future of chemical manufacturing.

What do you envision for the future of Capra? 

We envision a future where our proprietary biofilm bioreactor platform is the standard way to produce non-water soluble chemicals. In this future, Capra Biosciences has grown to become a large B2B chemical manufacturer selling retinol, specialty high-performance lubricants, and other hydrophobic chemicals, contributing to the replacement of petrochemicals with sustainable biologically-produced chemicals.

California Cultured produces sustainable chocolate from plant stem cells cultured to highlight the vast array of flavinols and functional compounds. Led by CEO and repeat founder Alan Perlstein, the team at California Cultured created the world’s first cell-cultured chocolate bar grown in a low-cost, high performance, food-grade cacao cell media. Or as Alan prefers — Chocolate that is simply better for the consumer and the planet. Dr. Jun Axup, CSO of SOSV’s IndieBio, sat down with California Cultured CEO and Founder Alan Perlstein to discuss his journey on bringing cell-based chocolate to market. 

Watch California Cultured unveil their first cell-based chocolate bar during SOSV’s IndieBio Demo Day on July 15th 2021 here

“The global chocolate industry is ripe for disruption. We can now make full bodied chocolate that reflects all of the global terroir — but without the deforestation and questionable supply chain.” – Alan Perlstein, CEO of California Cultured

Q: As a previous IndieBio founder, tell us a little bit about your journey of how you got into the food industry or what you’re really driven by and what you’re working on. 

About 15 years ago was when I first started to hear about cell cultured anything. I worked in one of the first labs in the US to work on cell cultured fish. And the more I learned about the reasoning of why making things cell cultured can be better, the more I fell in love with the field. I saw the challenges that the science has to go through as well as I think almost the writing on the wall when it came with both climate change, deforestation, overfishing, ethical issues for animals and people, and you combine all these different separate elements. Developing newer, better, healthier food systems started to make more and more sense.

And that sort of put me on my journey, working in different companies, working for different universities until today. But one of the major detours was one of my previous company. When we were looking to trade a product made with protein sweeteners, and I saw chocolate as a very serious product, but in itself, by looking through the supply chain of chocolate, looking through the health concerns or even the future of chocolate, I saw, wow.  It’s a giant industry. It’s I think right now $130 billion, it’s growing lightning quick over the past even year, there was a giant growth in chocolate because not only do people see it as healthy, but chocolate was one of the things that honestly got people through another day of a lockdown pandemic.

So I saw demand, a bunch of ethical environmental issues. I saw that I had the basic technical and business background. I looked deeper and I saw that all the talent to build the company, to do the science, and to scale up was literally right around me in Davis, California.

And, it just clicked. It made so much sense to work in cell culture chocolate. That we can make it healthier. We can make it tastier. We could make it a lot more cleaner,  and as the chocolate industry is going to go through severe disruptions over the next decade, we can provide a more, sustainable and ethical product for both the large corporations and the consumers who are looking for these things in the foods they are eating today.

Q: For those who aren’t familiar, can you tell us some of the problems with sourcing chocolate and the ethical problems as you mentioned?

So, the way how chocolate is made is close to stone age processes. It’s pretty similar to how it was done thousands of years ago where the seeds get planted, it takes half a decade or more before the cocoa plants may actually produce good quality pods and beans. And then the pods get picked by hand, they get split. They get put into fermentation pits, then they get dried and then ground up with other ingredients. And that is how most of the chocolate of the world is made. 

And this happens across thousands of tiny little farms all over the world from South America, Africa and Asia. Even the process to grow them, for many places, need to spray pesticides, antifungal agents, fertilizers that get them to grow. They need different light conditions whereas when they’re young, they need to grow in the understory, but when they mature, they need full light. 

Unfortunately that incentivizes many farmers to go clear cuts a lot of the surrounding forest areas, specifically the incredibly vital rainforests. Since it’s incredibly labor intensive, many farmers and other groups basically look for very, very inexpensive labor. And that usually either falls down to kids or the more unscrupulous farmer that would result in slave labor. Whereas in many countries in West Africa, there are cumulatively over a million child slaves all involved in the chocolate growing industry. And that’s besides for the amount of just regular kids helping their families grow chocolate. And even with all the claims by the giants corporates chocolate companies around the world, deforestation has increased, child labor has increased, the spraying of all these damaging and toxic chemicals are still continuing even more now at a frenzy pace than ever before, because there are more viruses and insects that are attacking the cocoa crops.

And these are just some of the problems I’m not even talking about mycotoxins in the chocolate or the chocolate itself. The reason why you get all these unique flavor profiles, it’s a bio accumulator. That means that it sucks up the heavy metals, many times lead, cadmium, and chromium in the surrounding soils. They accumulate in both the seed and the shell of where it goes into the chocolate making process.

So everything from the beginning to the end is incredibly problematic. And on top of that, all the chocolate companies that we’ve basically talked to have said, there’s just not enough room. There’s not enough farmers, not enough even region to grow the growing customer base, which is right now, very heavily, not only in the US and Europe, but increasingly in China and India who are just starting to really get a hankering for chocolate. And over the next five, 10 years, that demand is only going to increase massively.

Q: Let’s talk a little bit about plant cell culture. People have heard of people doing bacterial cell culture, people do cell culture with mammalian cells. Where does plant cell culture as a technique lie in that spectrum and what are some of the challenges for making this commercially viable?

Plant cell culture was originally developed the same time as animal cell culture around a hundred years ago. But it was still very primitively done for a very long time. And only in the past, maybe 20 or 30 years was there seriously some scientific advancements trying to figure out how to turn plant cells into production factories for food flavorings, for pharmaceuticals, or anti-cancer agents for dozens of different products and ingredients, but it’s not that widely known outside of a couple of core industries. 

One of the main reasons why was how these cells were grown. They were usually grown using undesirable synthetic chemicals that are also found in many other herbicides, for instance, one of the most powerful synthetic plant hormones is something called 24D. It sounds pretty innocuous, but it’s one of the main ingredients of Roundup weed killer. And the reason why it’s so effective, it makes weeds start accumulating nutrients fast. It basically overloads their internal circuitry and kills them. 

So, traditionally this was done in a very small amount of plant cell culture, but many different countries started putting very, very tight restrictions on the use of these chemicals in food and ingredients. And the entire field went static. 

And it really took, uh, some interesting companies and scientists and academics to really gently push it forward. And it sort of quietly chugged it along while the, the traditional fermentation such as yeast or microorganisms, or even the newer cell culture, food and ingredient products from meat are becoming well-known.

So what we’re able to do is take advantage of the many different metabolomic processes, as well as internal processes that are happening in plant cells. And we can make them not necessarily just produce one specific compound, but we can make them produce thousands of natural compounds all at the same time without changing the DNA of appliance cell or without putting in any undesirable ingredient and our thought was: imagine you could replace these synthetic ingredients with actual food grade ingredients, because there are many plants that we love and eat that have tons of natural plant hormones in them. But no one has actually looked at how useful they can be for plant cell agriculture.

So in essence, what we’re doing is a cross between clean meat and vertical agriculture. That’s how we tend to look at it. We basically have to give the cells food, we grow them in large tanks and you need to give them the right environment to grow and the right way that are flavors to develop as well. So for us, it’s sort of a learning process. And at the same time, we are going to be publishing some very cool scientific advances. So the world can understand a little bit better about the field of plant cell culture for food.

Q: What has been your biggest learning over the last four months at IndieBio and challenges that you faced?

Our biggest challenge was figuring out the best go to market. We came in to IndieBio with some specific assumptions of launching a product as quick as possible while at the same time developing the core technology. And by speaking with many different segments and investors, we saw that we needed to put some of our product launch on hold and just focus on derisking the initial technology as fast as possible. 

And by talking with many different customers, we saw that there was actually a very big need to make some ultra premium chocolate flavinols and high value compounds that are very, very difficult and expensive to retain in the industry. Usually they run for about a million dollars per kilogram. So that was our interesting discovery process.