Applications for San Francisco (Batch 12) extended through September 15th, 2021!

Carbix: Turning CO2 into Stone

To meet the challenge of our climate crisis requires humanity to reinvent industries on a global scale. Eliminating emissions as fast as possible is critical, and it has become clear we also need to pull CO2 out of the atmosphere, as well as prevent more from collecting. As we do this a new question emerges, where do we put it? Carbix is working on a solution for long-term carbon storage while simultaneously decarbonizing cement, a notoriously hard to clean up industry. I sat down with Quincy, their CEO, to find out how.

 Enhanced Weathering is a term that more and more people are learning about as climate science goes mainstream, yet its geological nature feels so distant to human timescales. How are you learning from nature to take on the challenge of producing carbon negative cement?

 Nature has perfected the capture of CO2, but over timescales that are far beyond the urgency of humanity’s climate crisis. We know from extensively studying the natural carbonation cycle of minerals like calcium silicates and olivine that certain conditions must co-exist in order for CO2 to turn to stone. At Carbix, we have distilled this biological process to engineering parameters optimizing heat, pressure, mixing rate, UV-C and CO2 injection.

We don’t have to pipe CO2 underground near hydrothermal veins to achieve optimal heat and pressure for carbonation. To further speed up the process we learned from the chemistry of the upper atmosphere that UV-C light energy can enhance carbonation reactions at lower pressures than what may be possible on Earth. The Big Reactor in the Sky (Sun + upper atmosphere) has taught us the role that UV-C light plays in generating hydroxyl radicals (OH) to accelerate the carbonation process.

Our X1 reactor has been designed from day one to give us control of these key variables.

 Can you tell us about the X1? What does it look like to potentially deploy in the world to meet the incredible scale of construction?

The X1 reactor scales up to about 150m3 (cubic meters) to meet the demand of the cement and concrete industry. In operation we need a few inputs. Certain minerals, like olivine, have the greatest carbon sequestration potential so we’ll be finding sources with the smallest carbon footprint possible to ship in. The other critical input is CO2, which we can get by partnering with direct air capture (DAC) technologies or at lower concentrations through direct smokestack effluent. While effluent has lower CO2 concentrations, it actually is still a good feedstock since we then forgo DAC costs and capture other pollutants which otherwise end up in our air and lungs. We also will need energy and water, which we hope to get from renewable sources and lower costs with water recirculation and energy recovery devices.

 Ooh sounds sci-fi!

The X1 reactor looks like something out of an “Alien” movie series so I guess that makes it Alien tech hahah.

The design keeps in mind that size and speed matters when it comes to tackling the emissions from cement making, which accounts for up to 8–10% of GHG global emissions! It’s a huge climate issue, and a huge market as cement and concrete products are a nearly $330B annual global market. The use of concrete, as well as heavy CO2 emitters, are distributed across the globe so the X1 can be deployed as a single unit or scaled to multiple to match the rate of emissions or concrete production needed.

 You’re a young company, yet already in deep conversations with large companies about working together. Can you share more about the appetite in industry for climate solutions?

 The interest is strong from the industry to reduce their GHG footprints. The public and private incentives are expanding but already moving the industry in our direction. The US and other major governments have incentives through the 45-Q and LCFS standard (California) to help pull the industry in. The call to action — in a country like Japan for example, are mandates that require cement companies to reduce their GHG footprint by 30% by 2030, no exceptions.

These incentives are important because the scale we’re talking about is so big. One potential customer, Dangote-West Africa as the example, processes nearly 6000 metric tons per day of clinker at one plant!. That’s an annual rate of nearly 2.0Mt (megatons). Other cement plants have production rates of about half that at 1MM(megaton per year), like Mitsubishi.

We’re in talks and even sharing ideas on which product makes sense to pilot. Dangote proposed the idea of creating tiles with carbon negative carbonates and oxides so that every one of their customers can buy carbon negative products. Imagine that — individuals and businesses can beautify their homes and offices and become climate champions while effortlessly installing tiles. We think it’s an amazing idea as it lets consumers vote with their dollars to act on climate change.

 Finally, tell us about yourself and your team. What inspires you all to work on this problem?

 We’re all passionate about protecting our natural environment (and the humans in it) and have been so for most of our lives. It’s an internal drive. We’re also technologists. So for us the pathway to healing the plant comes through technology, like the X1 reactor. Inspiration to take this direct path to removing CO2 from the atmosphere and creating products like cement and concrete is driven in part by the scale of impact we can make. What we’re doing works in parallel with the transition to a clean energy infrastructure by giving the planet some “breathing room“ until the transition is complete.

Myself, I have over 10 years in clean energy design engineering, with a previous finance background. Dr. Vintit Dighe has also been in the cleantech space. He is an expert in fluid dynamics, wind energy, and machine learning. He‘s developing fluid and chemistry solvers to guide enhancements to the X1 reactor kinetics. Samip Desai has a clean energy and finance background in cleantech and is actively working in business development to bring in multinational cement and concrete ready mix producers.

 

AsimicA: Raising the Bar for All Biofermentation

In May 2020, a McKinsey report found that the global bioeconomy is slated to become a $4 trillion gold rush as synthetic biology’s promise to make high-quality, sustainable products gains traction. These products range from food to textiles to medicines, and biofermentation is the manufacturing process that makes all of it instead of having to extract them as natural resources. Today, we sit down with Nik Mushnikov, CEO and co-founder of AsimicA, whose technology promises to solve the bane of biomanufacturing: low yields that formerly could not compete with traditional manufacturing methods. Using his invention, dubbed “microbial stem cells,” Nik thinks he can achieve multi-fold yield increases in product, and keep the bioreactors running longer.

Ok first off, what is a biofactory, and why is everybody talking about them?

Microbial biofactories are basically reactions in which we use microbes (like a bacteria or yeasts) to make the product we want. This was a solution when the product itself was biological, like insulin, and we didn’t know how to engineer a synthetic process that is smarter than a living cell.

Now with genetic engineering, biofermentation is becoming more popular as we are learning how to make other products that aren’t even biological in nature. For example, we used to make plastics with petrochemicals because it was cheaper and more efficient, but the synthetic biology field is learning they can engineer microbes to make specialized plastics.

Wow, so do you think that biofermentation will be used to make everything?

I think petrochemical or chemical synthesis is still more efficient, but it comes with problems like relying on oil as a feedstock and toxic pollutants as a byproduct.

Microbes, on the other hand, have the potential to produce any chemical compound in a sustainable manner, using renewable resources, if you can engineer it correctly. If you factor in the externalities, I think that traditional chemical synthesis is starting to lose its edge, especially when it comes to specialized products.

Why isn’t everyone using biofermentation right now?

Microbial biofactories can’t operate non-stop. As they divide, every generation becomes less productive and you have to restart the entire batch. Every restart is expensive in terms of expensive, specialized labor and downtime. We’re talking several days. Economically this doesn’t fare well, and we need to find ways of making them more efficient and more productive.

People have tried ways to make the microbes live longer or more resistant, but evolutionary genetics eventually catches up and drives the population to become sickly and unproductive. The solutions in the past have been… lackluster.

So I guess that’s where you come in! How are you solving this problem of low yields?

Instead of trying to make the microbes live longer, we found a way to repopulate and replenish biofactories with a fresh generation of microbes during the batch. We’re doing it using our innovation of “Microbial Stem Cells.”

In our bodies, our stem cells essentially replenish the cells in our tissues so that they stay functional for decades, much longer than individual functional cells can live.

Our idea is similar to that — microbial stem cells are constantly replenishing the fraction of productive microbes in the bioreactor. It is a way to bring up new young and strong “workers” to the factory, so to speak. We’ve published mathematical models that show that this replenishment strategy would result in a 2–4 fold higher number of productive microbes in the bioreactor, which translates to higher productivity per reactor, and longer batch runs.

The effect that microbial stem cells can provide on bioreactor productivity can significantly increase the profitability of bio-manufacturing.

How did you come upon this insight? Was this always something you engineered with biofermentation in mind?

I was always very intrigued by the potential of biofactories for manufacturing all sorts of chemicals: pharmaceuticals, fuels, advanced materials, and so on. And I wanted to be involved in designing new strategies for bio-manufacturing using microbes.

When I started my PhD, I had a couple of projects, focused on increasing yields of microbial fermentation. The idea of realizing stem-cell-like behavior in industrial strains of microbes came out from previous fundamental research insights made by my advisor, Dr. Grant Bowman. He was studying a phenomenon of asymmetric cell division in some unique bacterial species. Sometimes their cell division diagram resembles the division of stem cells. Certainly, these species are not applicable to the industry. And molecular mechanisms underlying their asymmetry are way too complex to just copy them.

What we’ve done is that we identified a minimal set of key components that can induce asymmetric division in other species. We borrowed them from several different bacteria and transferred them into E. coli, and our Nature Chemical Biology paper demonstrated that we can indeed induce asymmetric cell division and program differentiation in different cell types.

What kind of products are you able to make and is there any limit to what yields you can increase?

We just got results last week that we are able to make several products from pharma, food, and the cosmetics industries. These are just proof of principle experiments to demonstrate how versatile our platform is. We’re thinking of experimenting with fuels next which are highly toxic products for microbes to make — again, just to flex how broadly applicable our “microbial stem cell” technology is.

Everyone who does biofermentation is dealing with the exhaustion of microbes, and I don’t think there is a better solution than ours to improve yields and lengthen batch reactor runs.

So the sky is the limit in terms of products, but what about the cells? Are you limited to E. Coli?

That is a very good point. Of course, not all biofactories are using E. coli cells as their workhorse. We see a fairly straightforward way to transfer out technology to other species of bacteria. We’re already working with Bacillus subtilis, which is what most of our industrial partners are using. Transferring our ideas to eukaryotic microbes, yeast, and fungi, would be a more R&D extensive project but we’re confident we can get there.

How does a potential partner incorporate their technology into their existing manufacturing process?

Biotech companies won’t need to change much in their manufacturing processes. What we do is a strain engineering service, which changes how the culture of cells in the bioreactor behaves, enabling microbial stem cell properties. But it doesn’t change the production process itself. Simply speaking, our partners would do the same things they were used to, but their strains after AsimicA modified them would have higher productivity.

Why did you study microbiology?

I started to learn about the broad potential of microbes back in high school and my interest kept growing throughout college. Each microbiology course taught me that the potential of microorganisms is unlimited. My first research project was in yeast genetics. I’ve learned some methods and practices of working with microbes, but the research scope was rather fundamental and driven by the needs of clinical biology, whereas I was more interested in applied microbiology.

I finally found The Bowman Lab in Wyoming to do my PhD, where my interests were more aligned with applied bio. There, I could perform my research studies, keeping in mind that we’re creating new tools, new technologies that can be directly applied to the industry. That research dynamic is closer to my heart, and launching AsimicA where I can take the application to industry has been one of the most rewarding experiences I’ve ever had.

What good would this do for the world?

The world needs cleaner economics. Humanity is facing existential challenges, and although we are getting closer to solving those challenges we still have a long way to go and perhaps what will move the needle the most is to change the way we make things — using renewable resources, reducing pollutants, and dropping down our emissions. Our technology can facilitate biofermentation in becoming the primary method for the production of the vast majority of chemicals. Just imagine how much dirty production we can push out if we can increase yields by 2–4 fold across the entire industry. That’s what I think AsimicA could do for the world and that’s the future that I want to help build for us.

Kraken Sense: Pathogens Have Nowhere Else to Hide

A considerable amount of effort is taken to make sure that the water that is used to process and rinse your produce is clean and clear of pathogens like salmonella and legionella. Even with all the regulations that are imposed on our food supply chain to prevent such outbreaks, we are still not impervious to these bacterial threats. The affects not only public health, but also environmental, as millions of pounds of food are thrown away because of the scare. The primary reason is that the current methods for testing are too slow and too cumbersome to alert us fast enough. We sit down with Nisha Sarveswaran to talk about her innovative platform to disrupt the water testing market.

How did you first become interested in water safety? What life experiences led you to this?

Water quality has always been a passion of mine. I was born in Sri Lanka and I knew many people who didn’t have access to clean water, so I have always been conscious of the importance of safe water access. Our continuous progress is only ensured if we can properly manage our basic resources, and having safe water is critical to everyone.

I learned about the importance of water testing while doing research on pathogen-related illnesses and food recalls. It became clear to me that the present testing methods, developed more than fifty years ago, cannot meet the water and food supply challenges of 21st century.

Why not?

The current best practice is to take a sample of water, culture it in the lab for three days and have a trained technician examine the results to determine the presence and the extend of the contamination in the original sample. With our just-in-time logistics network, the produce collected and tested today may already be in the grocery store three days from now, so the current testing methodology takes too long and too limiting in scope.

With our real-time detection methodology, we can identify the contamination issue at the source and prevent the costly recalls that we are always hearing about on the news.

What’s special about your technology?

Ours uses a system based on antibodies on a carbon nanotube, which are tiny materials with very interesting properties. With our specific treatment and manufacturing methods we are able to create thin, narrow, electrically conductive strips with embedded antibodies specific to certain bacteria and even strains. When exposed to water samples that contain the target bacteria, the electrical signal changes in a very unique way, and that allows us to detect the presence and concentration of the bacteria that we want to detect.

Because we are measuring the signals immediately as water is passed through, we can essentially detect pathogens in real time. The only limit is how fast we can concentrate the water, and how fast the antibodies bind to the pathogens to get a noticeable change in our signal. This real time signal means that you can catch pathogens before the food even leaves the door of your facility. Compare that to having to get a water sample, and literally shipping it to a testing facility.

Incredible, that must really save a lot of time and money!

Yes! People need to understand that it’s not just about how many people get food poisoning. Just think about how much perfectly good produce out there gets thrown out because of a bad apple in the market (pun intended).

How do you mean?

For example, once a bad batch of romaine lettuce leaves a facility, it’s hard to track where all of it goes after, and once a few people get sick from it, the entire industry panics and avoids romaine lettuce, which kills the prices and puts the entire romaine market in shock (for good reason). This scare translates to hundreds of millions of dollars of food wasted, which is not only an environmental waste, but also a waste considering how many people are currently food insecure.

Interesting! So this isn’t just about people getting food poisoning, you’re saying this is a much bigger supply chain efficiency problem?

Food consumption is growing rapidly with our rising population and increasing prosperity. Our resources and supply chain will become more strain and will require modern solutions to identify the potential contaminations in real-time. The sensors that are able to detect harmful bacteria, in as little time as possible, are becoming more and more important to ensure food safety.

Moreover, by detecting contamination early, we are not only able to prevent costly recalls and associated health implications, but can also significantly reduce the food waste by providing alternative utilization for food that is no longer fit for human consumption. Currently the food waste from the supply chain accounts for 6% of the total greenhouse gas emissions. Our solution will ensure that the food that is distributed is safe and thus will also reduce the food waste that happens in the supply chain due to recalls.

You’re not a one-trick pony are you? I assume you can test for multiple pathogens?

We are building a multi-pathogen lab-on-a-chip system that can detect multiple pathogens simultaneously in real time. The remarkable advantage of our approach, other than the real-time capability, is that if there are antibodies available for a certain pathogen, we can build a sensor that can detect it and add it to our list of capabilities.

This work however goes beyond simply creating new sensors. In order to ensure that the results can get to the right hands in as little time as possible we have also developed automated water sampling systems and AI based machine learning algorithms running on our cloud platform that can interpret the sensor data and send the results in seconds.

Looks like you can cover a really broad spectrum of pathogens, but how fast can you make a test for other pathogens?

We can develop a new sensor in under 2 months, for example having developed the E. coli sensor we have spent some of the time at IndieBio developing Legionella sensor. This process will only accelerate as our first sensors enter the market and the process of creating new sensors becomes more established.

So is the speed at which KrakenSense is testing going to be the new standard for water testing? Are we going to see you guys across the entire supply chain?

We are working on developing protocols to help increase food safety testing and establish our methodology as the new standard for water testing. We really think that the water testing market won’t be the same after a few facilities can test in real time.

It’s like Amazon’s 2-day shipping: Once people start to get used to the speed, they just can’t imagine going to a much slower system… likewise, we think once we have a few pilots and customers, the rest of the market will start to find their conventional way of testing really outdated, and will want to come to us. In the near future, we see our solutions being present across the supply chain from early detection on the farms, to critical supply chain points that are highly susceptible to contamination.

So what’s on your roadmap now?

We are raising the seed round to further develop the lab on the chip system, expand our detectable bacteria capabilities, and pilot our solution with several key customers that will demonstrate the concept to the industry in general. At the same time, we are developing a suite of tools that will be used in tying it all together with blockchain technology so that every supplier has constant traceability in their food supply chain in real time.

Reazent: Powering Organic Agriculture

Despite the demand from consumers and environmental benefit, organic agriculture accounts for less than 2% of global agricultural land. Reazent is on a mission to change this by providing biologic products to supercharge plant growth and crop yields. Despite being a young company, they extensive field trials showing the benefit and consistency of their product, with more planned for late 2020 and early 2021. I caught up with Sumit Verma, their CEO, to learn more about their progress and the state of the industry.

CEO and co-founder, Sumit Verma

Alex: What inspired you to start Reazent, and what was the genesis of your idea?

Sumit: I worked in the chemicals industry for over a decade, and as an insider I encountered first hand some of the biggest challenges the industry faced. Companies grappled with how to reduce the carbon and toxicological footprint of the materials that consumers, industrials, and agriculture use, while retaining their effectiveness and performance. This problem was most evident in agriculture.

Agriculture directly affects human and planetary health, so sustainable agriculture — one that employs organic alternatives rather than synthetic petroleum-based ag-inputs — is beneficial for everyone. However, we learned farmers don’t want to adopt organic alternatives and organic agriculture because they consider it inefficient and leads to reduced income. My scientist colleagues and I had a shared passion to change this. While I was seeing this problem from a practitioner’s point of view, my scientist colleagues were working on developing sustainable alternatives for field applications.

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Quote from Earl Butz, US Secretary of Agriculture in 1971

Alex: So how are you replacing chemical ag-inputs?

Sumit: Reazent has developed a patented technology to increase crop yield and control plant pathogens in a wide range of crops such as soybean, peanuts, wheat, kale, and lettuce. Our approach is based on the effect of metabolites produced by soil bacteria. These metabolites up-regulate plant defense and root growth genes, as well as other members of the soil microbiome who in turn produce metabolites which help the crop.

We learned how to do this by studying unique genomic loci present in certain bacterial strains which increase the range and quantity of metabolites produced. We have over one hundred uniquely genotyped strains and hence we can create plant growth and disease control effects in many crops critical to the global agricultural supply chain.

Alex: You’ve been running field studies this year in several crops, tell us about what you’ve found.

Sumit: We have demonstrated the efficacy of our product in increasing both crop yield as well as plant pathogen control in bench-scale, greenhouse, and field scale trials in legume crops such as soybean and peanuts. The results we have obtained so far are fantastic — up to 400% increase in soybean root nodules, up to 30% increase in peanuts above-ground biomass, and up to 35% increase in peanuts pod dry weight. In these trials we are putting our product up against industry benchmarks of synthetic and organic products.

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Soybean root nodules from a greenhouse trial. Control on top, Reazent below

We have several other greenhouse trials underway — including soybean, kale, wheat, and tomato — and are very excited to be getting results by mid November to December. Next, we will be running extensive field trials in soybean in North America, Brazil and India during the next growing season.

Alex: In the chaos that is nature, how do you ensure consistency and predictability for farmers? This seems like a challenge, at least in perception, versus traditional chemicals.

Sumit: Farmers have had mixed experiences with ag-biologicals over the years. Often what works in the greenhouse fails in the field. Moreover, their performance varies in different environmental conditions and geographies.

Knowing this we have focused on meeting the needs of farmers in any geography from day one. Unlike conventional biologicals, our system has a very long shelf life. Secondly, they are highly resistant to adverse environmental conditions. This is because our biologics are based on unique bacterial species that form durable spores — a form that allows them to withstand adverse environmental conditions. When condition are right the bacteria activate and start to have their beneficial effect.

Additionally, we have designed our biological system in a manner that allows them to colonize plant roots and soil effectively. This adds to their consistency and predictability.

Alex: There are a growing number of approaches to biologics in agriculture. What makes you different?

Sumit: A few startups involved in this space are tackling the problem of sustainability through synthetic nitrogen fertilizer replacement. Their biologics can directly fix atmospheric nitrogen, providing an alternative source of nitrogen to the plants. Although this mode of action, if successful, would work on crops that don’t fix nitrogen themselves, it won’t work on leguminous crops like soybeans that fix nitrogen themselves through their root nodules.

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Early corn trials. Three untreated roots on left, three Reazent treated roots on the right

We have shown our product increases the number of root nodules significantly in soy, which leads to increased yields. With our library of beneficial soil bacteria we can also work in crops without root nodules, like corn. In these crops we increase immunity, root growth, and vigor of plants through the bacterial secretion of metabolites.

Alex: Regenerative Agriculture is getting a lot of attention as a potential solution for climate change. What’s your take on the role of agriculture, and how do you see Reazent being part of that?

Sumit: Paradoxically, agriculture is a well-known contributor to climate change. This is because a large amount of carbon is released back in the atmosphere due to various farming practices. Therefore, sustainable farming practices such as no tillage farming, crop rotation, and enriching the soil microbiome help in reducing carbon emission from agriculture. If less of carbon in the soil is made available for release in the atmosphere by better utilization of that carbon in the soil itself, the carbon emission from agriculture would come down.

Like the human microbiome in human health, the plant microbiome plays a crucial role in soil health. Recent studies have shown that a rich soil microbiome contributes to improved Carbon Use Efficiency (CUE). This means resident microbes are taking up and retaining carbon in their biomass rather than losing it during respiration. The increased CUE means more carbon is stored in the soil for longer, more beneficial microbes propagate, and plants thrive. Healthy living soil thus benefits humanity by storing more carbon and providing us with healthy nutrient rich crops.

Alex: Finally, tell us about your team. Who are the people building Reazent?

Sumit: I am very proud of my team. They are some of the best business and scientific minds in the sector.

Before starting Reazent, I worked in the chemicals industry for over ten years in a wide range of functions that included innovation, operations, marketing, and sales. Most recently I was with Ashland, a globally renowned specialty chemicals company, where I handled its regional innovation for Asia Pacific. Over the years, I grew to understand the limitations of the chemical industry from the demand side, and what it took to introduce a new product.

Dr. G L Rao is the CTO of Reazent. He is a plant biotechnologist with experience in plant biostimulants. He understands how to translate science into product through his work as a formulation specialist for Tinyfarms-Modgarden where he was involved in the optimization of soilless media and liquid nutrient formulations for greenhouse and indoor gardening. He also co-founded Plasma Agriculture Solutions where he developed cold plasma to treat seeds for improving seed quality and provided services to Argo-industries to perform product trials. Before this he was a post-doctoral Fellow at Faculty of Agriculture, Dalhousie University and at Earth Institute, University College Dublin, Ireland

Our advisory team has experts from the industry and academia.

Dave Warner, a former executive of Indigo, Corteva, and Monsanto advises us on go-to-market strategy and has helped us in building partnerships with potential distributors. Dr. David Mulla is an expert in soil science and precision agriculture. He is helping us build soil expertise that will provide us a competitive advantage in the market. Professor Srienc has three decades of experience in bioengineering and biomaterials. He developed technology to optimize bacterial fermentation and his expertise will help us in product scale-up.

To learn more about Reazent check out their pitch at IndieBio Demo Day on October 28th! To get in touch visit their website at http://reazent.com.

If you’re a startup solving challenges in human and planetary health interested in the IndieBio accelerator, let us know at www.indiebio.co/apply

Khepra: Renewable fuels from waste

Khepra is building continuous flow reactors that deploy high-intensity ultrasound frequencies to take waste — everything from unrecyclable plastics to biomass to cardboard — and even mixed waste — and break the chemical bonds in the waste. The result is upcycled renewable chemicals and fuel components.

Today, I sat down with the founders to learn a bit more about the field and also about their personal motivations to run Khepra as they get ready for demo day. Below is a paraphrased and condensed version of a long discussion we had.

How did you guys get into this field?

Madeleine: Growing up in California, seeing solar panels all around, you start thinking solar panels are some be-all, end-all solution. Over time, I learned how without renewable energy storage the potential of solar cannot be realized. You know the infamous duck curve — the timing imbalance between peak demand and renewable energy production — leading to us literally throwing away solar energy. The sun shines the most when we don’t need it. I was working as a systems integration and testing engineer at Lockheed Martin, when Julie, who is my childhood friend, told me about this project, where she planned to put this excess solar energy to use, to breakdown waste into renewable fuels. I was in.

Julie: Yeah, I had been obsessed with renewable fuels for a long time. And obsessed with sustainability for even longer. My dad took me to see the movie, ‘Inconvenient truth’ when I was eight and that messed with my brain chemistry if I can put it that way. Sustainability was also a key theme for me throughout my education career. Reading a lot about space and going to school at the University of California San Diego, right in the neighborhood of pioneering companies such as Sapphire Energy, making algae-based biofuels by harnessing high energy, high pressure.

Fascinated by the idea I started reading a lot about these high-pressure, high-temperature methods in the field. I got very active in the cleantech community at UCSD when I got hooked to the concept of cavitation. There’s large amounts of energy stored in a cavitation bubble and a large amount is released when a bubble bursts. At its core, Khepra uses that energy to break long-chain organic polymers into shorter chain molecules, which are potentially higher value aromatic ingredients or precursors to fuels and/or fuel precursors. With the idea in mind, we started charting the concept more with waste as a feedstock.

Madeleine and I, staying true to our silicon valley origins, started tinkering in her garage. We played with cheap transducer units ordered from amazon and catalyst combinations, even accidentally burning stuff in Madeleine’s oven! The oven survived but we did have to brave some rank odours. Haha!

We were ultimately able to get access to a warehouse space in San Francisco, enabling us to prototype a bit more and hash out a solid blueprint of the tech-stack and file a provisional patent around the process. That’s around the time we spoke to you guys at IndieBio and started putting together a de-risking plan and budget against those blueprints. Going from theory to reactors in less than six months and that too during a pandemic!

Sustainability has become a buzz-word, rightly so in my opinion, yet this is not the first time cleantech startups are taking a shot at the problems the earth faces. As you must have seen with so many San Diego cleantech startups, they are no longer operational, unfortunately. What’s new; how is this time different?

Julie: There is an abundance of waste. Both waste in the traditional sense of the word — the mountains of trash out there — and that of renewables as Madeleine mentioned. Using renewable energy transforms our unit economics. Acting as a pontoon against the waves of commodity prices. Cost parity against commodities aside, failing to achieve margins was a big factor leading to the sad demise of the first wave of cleantech. By co-locating with refineries with installed CAPEX, collecting tipping fees on waste, monetizing offsets from progressive corporations, and finally selling the valorized waste gives us multiple revenue sources; We’ve created a two-sided marketplace. Which is what is new and exciting here.

Madeleine: I’ll also add that from a tech perspective, our use of high intensity focussed ultrasound for waste pyrolysis (breakdown) is completely new. This technology has a high energy efficiency from electrical to acoustic energy. Because our method is powered by renewable electricity, it has a positive EROI (ratio of energy returned on energy invested).

Now you may think there are many moving parts here, which there are. But the good news is that many of these parts have been de-risked by earlier cleantech or the refining industry. We specialize in orchestrating all of it together. That’s also where a good portion of our IP lies.

That’s super exciting. I like how renewable energy-powered ultrasound is helping you connect the waste and commodity markets. Respectfully, I do have to ask, how do two undergrads catalyze change in such entrenched industries?

Julie: IndieBio opened doors to a lot of corporates, we have been made full use of the network and been actively reaching out to incumbents. To our surprise, we learned how corporates and oil and gas companies, juggernauts of emissions, understand the impact they have on the world, and they also understand the tipping points climate change will hit and how that will come back to hit their businesses. They are also incredibly practical and have already begun adapting their models. For example, for oil & gas, extraction drives a lot of the emissions. So many oil & gas companies are adapting by transferring a lot of their extraction budgets to venture capital arms. This has just started happening and shows you how they need something new, not just what they have, and had no incentive to change all these years. And these venture arms are very results-driven, you have to show them a product, not just projections. That’s been motivating us to prototype and scale rapidly. The impact multiplier with their distribution channels is manifold. With renewable chemicals and fuels that come out of our reactors, we see our company as a means of facilitating change for industries looking to add circularity in their processes.

Madeleine: In this process, a big learning has been to leverage the wealth of expertise out there. I am no longer afraid to reach out to and ask experts for help.

I learned how our process is so novel and exciting for many experts in the field, who know so much more than us and want to help because they love what they do, and now see a chance to make an impact.

One example is our chemical process design consultant, Kieth Gazda. With 30 years of experience, Kieth can design a reactor in his sleep. He’s been interested in our company even before we had a prototype. Skeptical at first, till he saw more data points and preliminary data from the small experiments we did where we were breaking down organic polymers with ultrasound. He is in a unique position in his career and can work on a lot of projects, but chose to work with Khepra as he sees the environmental impact we can create.

Julie: That’s a very good point Madeleine makes. Valuing experience beyond just effort and skills. I don’t fall for the mythology of the genius visionary founder. Getting top talent and mentors excited and on-board early is important to us. Creating value and therefore disrupting trillion-dollar industries can only be done if we aggregate experience and bring on people who know more than us. Kieth is an excellent example of the role experience plays in accelerating impact. I am excited, as CEO, to make Khepra into a platform for talent, from many disciplines to create impact through renewable fuels and circular products.

Team-building as a means of disruption. I love it! Let’s talk about where you are now. Recently you revealed your prototype to the world during an interview with our MD, Po Bronson. Where do you fo from here?

Julie: Khepra plans to scale up to a 500-liter reactor by the end of our Series Seed and add catalytic refinement capability to enable higher-value fuels. Looking very far out we want to get to 70 tons/day which is the waste output of a small city.

Madeleine: And scale is one dimension, as a pre-seed company we have had to tradeoff some complexity for budget and speed. We have been learning by breaking. With our Series Seed, we are also excited to optimize our process flow and demonstrate proof of concept of processing varying feedstocks. Going into demo day we are also looking forward to gathering insight around techno-economic analysis that shows the economic performance as a function of the inputs and economic value of our outputs. Really exciting times!

IndieBio’s Demo Day is October 27–28, with the New York batch on Tuesday the 27th at 10 am, and the San Francisco batch on October 28th at 10 am. Please follow this link to Eventbrite to RSVP. A single registration will grant you access to both days’ events.

Liberum: Automating Protein Production

When we think of synthetic biology, we often think of synthetic DNA. However, the purpose of the DNA is often to make protein. Today we can order DNA overnight for cheap, but producing protein takes at least two weeks of lab work with various instruments and techniques. Liberum aims to free researchers from the tedious task of turning DNA into protein and make experiments faster and cheaper. I chatted with Liberum’s CEO, Aidan Tinafar.

How important is protein for biological research and production?

When most people hear the word protein, they immediately think of food. Proteins are far more than food. They are used as therapeutics, industrial catalysts, biomedical research tools, materials for manufacturing and additives in consumer goods just to name a few. Insulin is a protein. Chymosin, the enzyme that enables cheesemaking is a protein. Silk is two proteins combined.

Imagine if you could come up with a type of material that you could design with vastly diverse physical and chemical properties for a whole host of applications. Ideally, you would want this material to have three properties. First, you would want to be able to make the material from a small set of inputs that are readily available. Second, you would want to be able to control the properties of the material in a tunable or programmable fashion. And third, you would want the production process to be sustainable and capable of being integrated into pre-existing environmentally-friendly modes of production. Protein is that type of material.

Proteins are strings of building blocks called amino acids that are folded and held together such that they enable certain functions. Combinatorial combinations of 20 amino acids give rise to all the breathtaking diversity we see in nature. The type and order of amino acids are generally encoded within the DNA of an organism. A single cell such as an E. coli bacterium requires a couple thousand different proteins to carry out its biological activity. These proteins can act individually or in concert as networks.

One way to take advantage of proteins is to piggyback on an existing living organism. For example, we can use yeast to make beer without having to deal with its proteins on a granular level. We can also benefit from extracts, secretions or purified proteins from organisms found in nature.

In the 70s, we began gaining a grasp on being able to mix and match these wild-type proteins between organisms through somatic fusions and recombinant technologies. During the same decade, chemical synthesis of a complete gene was demonstrated for the first time. Shortly after, in the 80s, polymerase chain reaction (PCR) was invented allowing us to make billions of identical copies of these chemically derived sequences. Together, these technologies enable us to go from a digital DNA sequence stored on a computer to a designer protein within weeks. At Liberum, we significantly speed up this process, so that we can create better products faster.

These breakthroughs have already brought about the synthetic biology revolution with a total market size worth hundreds of billions of dollars and rapidly growing. For example, the size of the recombinant therapeutics market alone is now over 100 billion dollars. There are two factors that have hidden this revolution in plain sight. Firstly, cultural taboos surrounding genetically modified organisms (GMOs) have incentivized many to categorize these products as natural rather than engineered ones. More importantly, the wide range of applications of these technologies make the market appear highly fragmented. End products include anything from extracts and purified proteins to small molecules, cell lines and other goods and services that use these as intermediates. While apps of the internet revolution came to most through their screens, proteins that lead the synthetic biology revolution touch people’s lives in so many ways that make them hard to categorize as a single class. Massive shifts are often harder to observe.

What are the bottlenecks in creating protein today and how is your technology solving those bottlenecks?

Making protein using biology is hard. For every idea, for every iteration, you have to re-engineer the genetics of living cells, grow them, break them open and purify. This process is very hands-on. You need to keep coming back to it over a week or two. The process also requires expertise and expensive equipment that take up a lot of space. Even if you outsource the work to a contract research organization, you are still bound by similar timelines, plus the duration of shipping. Liberum speeds up and automates the protein manufacturing process in a miniaturized device without having the need to re-engineer any living cells. We do it all in a cell-free system that contains the same powerful enzymatic machinery used by cells.

Now you may wonder, why can we not chemically synthesize these proteins; what is so special about using biology to accomplish protein manufacturing? The problem with chemical synthesis of proteins is really two-fold. First, the error rate for state-of-the-art chemical amino acid incorporation hovers around 1%. This means that for an average bacterial protein of 320 amino acids in length, only about 4% of the final mixture would contain the correct sequence. More importantly, proper folding of amino acid chains into functioning proteins tends to be trickier in chemical systems. A system that more closely resembles biological conditions, such as a cell-free protein expression system, can avoid these problems.

Technical challenges of making proteins aside, there is a deeper conceptual issue at play. We can certainly make a protein of a specific function starting from a working DNA blueprint, but designing that blueprint is far from trivial. While rational and modular protein designs can be highly informative, they are rarely strictly prescriptive. One often needs to screen sizable libraries of designs to optimize for a specific function. Even if we take wild-type sequences from organisms in nature, there is still room for validation and screening of homologues. Unless and until we have computational means that can predictably design for functionality in silico, protein prototyping remains an indispensable tool for protein engineering.

How might your company change the way we produce protein?

We want to enable protein manufacturing at small scale with minimal time and capital investment on the part of our customers. The key insight for our business model is that we have separated the fermentation process from the act of protein production. This allows us to operate as a utility company that delivers protein production capacity to our clients on-demand. Our device and cartridges are merely the last mile. The infrastructure we build to enable this capacity is where much of the value we provide will be generated.

Once our customers have ordered and amplified their template DNA, they can simply place it inside one of our cartridges and produce their desired protein with a push of a button. Having the capacity in their own labs will allow them to optimize the desired conditions. It also provides control and rapid turnaround to enable more bright ideas to see the light of day.

What lessons have you learned transitioning from scientist to entrepreneur during the IndieBio program?

Put the customer first. Science is just the tool we use to serve our customers and the community at large. The value of our company is a function of the value we create for our customers and other stakeholders in the community.

What does the next year look like for Liberum?

Rapid iteration cycles to loop in customer feedback has been in our company’s DNA from the very early days. Our goal over the next year is to build our infrastructure such that we can bring the power of cell-free protein expression to thousands of labs around the world at very affordable prices. We will continue to build upon enhancing user experience through further iterations of the device and cartridges. Our goal is to wrap up alpha and beta testing as soon as possible so that we can launch our product within the next year.

Ivy Natal: Turning Skin Cells into Eggs

The future of our species depends on procreation, but today the world is at an all-time high in infertility due to disease, stress, and the decision to delay having kids. But what if we can generate healthy egg and sperm from your skin cells? Ivy Natal is attempting just that using stem cell technologies and CRISPR. I talked with Ivy Natal cofounders, Colin Bortner and Jeff Hsu.

How did you get interested in the fertility field?

COLIN:

That definitely started with Jeff. We are pursuing a revolutionary solution to the problem of the fragility and scarcity of human eggs. Right now, many women can only have children using donor eggs, which has many challenges and obstacles, and donor eggs still don’t allow patients to have a genetic child.

Our solution pulls together different innovations in synthetic and molecular biology and genetics and genomics to solve this particular problem. Jeff became interested in the problem while working at a pre-implantation genetic diagnosis startup, which was his exposure to the application space, but the underlying approach stems from his interests during his PhD and postdoc research.

For me, when Jeff and I started talking about the idea, I was very excited by the potential for patients and for society as a whole. Women have always born a disproportionate share of the costs of having children, which has shaped society. Now, effective contraception has been a revolution in giving women the ability to choose to not have a child, but our company has the potential to provide women certainty in their ability to choose to have a child. It’s the flip side of the same coin.

The science of turning stem cells to eggs has so far only been demonstrated in mice. What bottlenecks do you see for making this possible in people? How do you plan to address those bottlenecks?

COLIN:

Yeah, as you say, this has only been done in mice. About four years ago, a team based in Japan published the landmark result in this area. They successfully differentiated stem cells into egg cells, and then they essentially completed IVF cycles with their mice, and those mice gave birth to fertile offspring.

For a couple of reasons we’re taking a different approach. The first is that a direct translation of the Japanese group’s approach to humans is a non-starter because that would require ovarian tissue from a human fetus. Ovarian tissue from a mouse fetus was a key component of their results. So, part of our motivation is solving that issue.

So this is a kind of bottleneck, which is legal and ethical but also technical. What we mean by technical is that we don’t have a great way to systematically answer the question: what is the mouse ovarian tissue doing to differentiate the stem cells into egg cells? If we could easily answer that question, we could just emulate whatever variables that matter and get the same results, and by extension we could do the same for humans.

Now, without getting too deep into the details, our approach works from the inside out instead of from the outside in. Essentially, we’re using different kinds of sequencing technologies to understand the internal state of egg cells, like which genes are being expressed, and then we’re using new tools to directly change the internal state of skin cells to match the internal state of egg cells, and in doing so transforming the skin cell into an egg cell. We’re still in the early stages of proving out this approach for egg cells, but it has worked with a bunch of other cell types.

The specific engineering challenges in our approach are discovering the genes to turn on or off in order to “reprogram” our skin cells into egg cells, and developing a “safe” tool to do the reprogramming, which eliminates any risk of genome changes. But here we have a huge advantage in that we can work systematically, using sequencing data and computational methods to discover targets and leveraging the synthetic biology ecosystem to do safe reprogramming.

We already have solutions in place for these challenges, and we are now applying them to a proof-of-concept of our approach, but even if we have setbacks, the long term trends are all working for us. Sequencing is getting better and cheaper, the synthetic biology ecosystem is developing rapidly, and the computational methods we’re using are improving almost monthly. We’re making progress quickly, but even if we did nothing for a year, we’d still end up with more data, lower costs, and better tools.

If successful, how might your company change the future of childbearing?

JEFF:

We’re very focused on the immediate goal, which is helping women who would otherwise rely on donor eggs to have genetic children for the first time. That is a super meaningful problem for us, and reason enough to pour everything into this company. That said, our long term goal is to ensure that every person and couple has the choice to have genetic children. There are hurdles along the way, or problems to solve, but this includes women and men of any age, including those with many conditions which currently complicate reproduction, as well as same-sex couples.

What lessons have you learned transitioning from scientist to entrepreneur during the IndieBio program?

JEFF:

One of the big attractions of becoming an entrepreneur is the freedom to work on problems and solutions you are passionate about. The valley is willing to take a risk on founders with plausible solutions to big problems whereas as a scientist you are often constrained to projects and funding that are often related to your previous work in very obvious and straightforward ways, whether that’s in academia or large corporate research organizations.

What Ivy Natal is trying to do would be life-altering for many prospective couples and families. That type of impact you can’t measure by publishing metrics or impact factors, and that’s in many ways shifted my own frame of thinking. Since we are developing a process that not only will work but scales to meet the demand of the market, I’ve learned that it doesn’t matter if we execute a protocol myself or work with partners and vendors. What matters is cost, reproducibility, quality of the results, and ability to scale.

Now, the biggest challenge for me has been transitioning from a fully resourced institution like the Cleveland Clinic to setting up a startup lab in the IndieBio basement. It’s just very different working without the existing physical and human infrastructure of a major research center. In some cases, we’re rebuilding that infrastructure for ourselves and in other cases we’re partnering with vendors to use their infrastructure, almost like cloud computing. For the human infrastructure, we’ve been tapping our existing networks for advice and insights that our team doesn’t have and also working to grow our networks.

We have the additional complication of relocating and starting up our lab work during the pandemic, but we’ve been able to make a huge amount of progress despite that!

What does the next year look like for Ivy Natal?

COLIN:

Right now, we’re completing a proof of concept for our approach. This involves producing a progenitor of egg cells called primordial germ cells, which will prove out a lot of our core hypotheses and de-risk our business. We want to complete this in Q4 of this year, and next year focus on egg cells. Our timeline for egg cells, how far we’ll get in 2021, depends on some of our ongoing work on our proof of concept. After we have data from those experiments and results from our scaling up partnerships, we’ll have a clearer picture of our progress in the next year.

Cybele Microbiome: Skincare Through Precision Prebiotics

Nearly half of society has some sort of skin sensitivity. Cybele Microbiome is the company behind a new direct-to-consumer skincare brand. Cybele’s unique products trigger the natural skin biome to secrete skin restoration compounds. Today I sat down with Cybele’s CEO and Founder, Nicole Scott PhD. Nicole is a geneticist who became fascinated with the interaction of skincare products and the skin biome. Cybele was born when Nicole discovered how to gain precision control of microbes through the use of functionalized prebiotics. She thinks of cosmetic ingredients as first and foremost “food for the microbiome.”

Q. During IndieBio, you ran a small pilot study with your skin serum formulation and got some exciting early results. Tell us about what was seen?

Just two weeks into the study, I got a bunch of excited phone calls, because many of our volunteers were noticing the results right away. We provided the photos to a dermatologist who is highly experienced in reading skin conditions on photos, and he confirmed there’s notable decreases in scaliness, flakiness, hyperpigmentation, papular eczema, eczema, psoriasis, and even a decrease in a precancerous lesion. We knew that one of our long-chain ceramides is a known anti-melanoma compound– but these early results after just 2 weeks have us floored.

Q. Your prebiotic ingredients trigger the skin biome to create only long chain ceramides and no short chain ceramides. Why is that so important?

There are huge differences in the bioactive function of short chain and long chain ceramides. The long chains are the good ones. The short chains actually harm your skin, competing with, and fighting against, the good ceramides. Your typical skin care products that advertise ceramides don’t make this distinction, and can be doing as much bad as good.

From skin serum we can round out that product line with moisturizers, toners, and eye creams.

But we aren’t a one trick pony. What is also really exciting is that we can get your skin biome to make hyaluronic acid — the most common ingredient in anti-aging cosmetics. These advances come from our platform to identify and formulate new prebiotics for other uses. This allows us to create a suite of related and complementary products. We also will customer’s skin biome assessments and input to help craft the additional products.

Q. How do you manufacture the prebiotic ingredients, and how does this affect Cybele’s margins in the early years of the company?

Our prebiotics are the output of fermentation. At small scale, we can purchase our prebiotics. They are not expensive. As we scale up, we can use any standard contract manufacturing organization to produce them for us — so no capex needs to go into ingredient manufacturing.

Ceramides are normally expensive to add to skincare products — and every bit added to a formulation hurts margins. In our case, not only is our product more effective, but we aren’t paying for ceramides. The skin biome makes them. So we have a much higher margin — estimated at 88% for our serum product.

Q. Tell us about your team.

Our team includes James Lamoureux — a microbiologist that received his PhD with Dr. David Low at UC Santa Barbara — and Hui-Ling Seow, who helped develop and carry out the marketing strategy for a HR platform Epic Quest Games, and Liz De Ruyter, who lead the Amazon On-Campus Store, launching products like PuraVida, Red Bull and Aveeno at UC San Diego. We are currently expanding the team by actively recruiting a Chief Marketing Officer right now.

 

Advanced Microbubbles: Drug delivery across tumor and brain barriers

Getting drugs through the tumor barrier and across the blood-brain barrier is a well-known, major challenge for medicine. Many clinical trials are underway using chemotherapy co-administered with diagnostic microbubbles, energized by ultrasound at the site of the tumor — but these are performing poorly, with inconsistent acoustics, because the bubbles are highly-varied in size.

Today, I sat down with Dr Jameel Feshitan, CEO and Connor Slagle, CTO of Advanced Microbubbles from our current class to learn more about not only the field but also how their product compares to the existing solutions out there. The conversation below is a paraphrased version of our interview.

How did you get into this field of microbubbles?

Jameel: In college, in my final year, I took an elective class on medicinal chemistry which proved to be among my favorite classes. I was fascinated by the design of drugs. The different ways we can engineer poisons into life-saving drugs and how entire drug classes such as, say,statens are found. That started a fire that stayed with me all the way till grad school, at Columbia University. There I had a chance encounter with Dr Mark Borden, he was the first person I met during orientation and he introduced me to the use of microbubbles in medicine. The rest is history.

I learned while there are many applications of bubbles in medical imaging, producing uniform sized bubbles in a reproducible manner was a big problem for the field. You cannot control bubbles of varied sizes. For bubbles to realize their potential for drug delivery they had to be uniform. Uniformity leads to consistency, an essential feature to control the dosage of the drugs our bubbles would enable. My first big project — to make bubbles uniform for their use to deliver drugs — turned into Advanced Microbubbles over time, the only company in the world currently offering uniform size-controlled microbubbles. It was also during my time at Columbia University, that I got to translate this work to that of other labs at Columbia University working on the use of microbubbles to deliver drugs across biological barriers and tumors.

Connor: Similar to Jameel, I had a chance encounter with bubbles. Got introduced to the company via a job-board posting for a chemical engineer to scale microbubble production. Dr Mark Borden, who at that time, was an Assistant Professor at my alma mater at Colorado University Boulder, where I studied Chemical and Environmental engineering, acted as the glue. He provided me with supplemental materials and some of the research on the field; that got me hooked. After going through the research and work done by the company thoroughly, uniform microbubbles emerged as a strangely commonsensical solution. Uniform bubbles and the use of ultrasound to trigger them was such an elegant solution not just for medical imaging but also for drug discovery, where controllable as well as localized response is key.

For you, it might seem commonsensical, but for the readers who are new to the product, injecting bubbles into the body is somewhat terrifying, no?

Jameel: When we talk about injecting bubbles people start thinking about embolisms and clots. It is, in reality, a very well characterized, commonly used and sophisticated engineered product similar to other prevalent delivery methods such as liposomes — which are spherical vesicles with lipid layers — used to deliver a range of drugs into the body. Our proprietary microbubbles are similar to liposomes, engineered on a microscale, except with a gas core. The gas core makes them reactive to ultrasound and they are precisely engineered to last for 30 minutes in the body.

Connor: And to give a bit more context, our bubbles can be easily co-administered with existing clinical protocols for the most part. They are injected systemically, using IV, which is already used in chemotherapy clinics and for most indications they can be triggered in a highly localized manner using conventional ultrasound machines. Our bubbles are designed with the clinic and the patient in mind. It is only for specialized indications of the brain that we look to R&D and partnerships with specialized ultrasound machines.

Now that we understand the concept, how will Advanced Microbubbles impact the space?

Connor: Delivering precise amounts of drugs in a precise space is the holy grail for oncology — really motivates me to work towards this goal. Our lofty goal is to pair our size-isolated microbubbles with promising drugs that can’t get to cancer or are injected at such high doses that cause debilitating side effects to the patient.

One example that comes to mind is glioblastoma, a notorious cancer of the brain that can’t be challenged well today, and a lot of it is due to the blood-brain barrier making it hard to deliver drugs with consistency and safety. With our technology, we have preliminary mice data showing that we can temporarily disrupt the blood-brain barrier. This data is published in a study Advanced Microbubbles did with NIH- NIDA, that showed dramatic improvement in delivery to the brain compared to non-uniform bubbles. And off that study, a dozen partners have interest in using AMB’s bubbles instead of conventional bubbles. Of course, the data is not in-human / clinical data, but offers promise to one day deliver the payload across the barrier and then the barrier heals for normal biological purposes.

Jameel: Couldn’t agree more. I see the potential of Advanced Microbubbles to enable a new standard of care in the field. The standard of care for chemotherapy hasn’t changed in hundreds of years.

With chemo, we have to poison the patient to hope to cure them. Advanced microbubbles can really impact the life of a lot of patients by making chemo less toxic and more efficacious.

Where are you currently in this process?

Jameel: We have been hard at work to get preliminary in-vivo data during IndieBio. Despite the pandemic and limitations of being a pre-seed startup, we were able to work with an excellent partner lab at the University of Texas. Led by company co-founder Dr Shashank Sirisi. Dr Sirsi has been with the company since it’s origins at Columbia University. There he was the key liaison between laboratories for the execution of microbubble development and therapy experiments.

Thanks to his support the team was able to get preliminary results in animal data. In “n of three”, small cohorts of neuroblastoma mice models — a tumor and rare disease that develops in adrenal glands. We are excited to showcase the data this demo day where we demonstrate not only proof of delivery, relative to control, with a commonly used chemo-drug. But more importantly, we show efficacy, a 1mg/Kg effect at significantly lower doses. Sending a strong signal in support of our thesis of low-dose efficacy without chemo-like side effects.

Excited to see this data this demo day. Looking beyond demo day, what does the next phase look like for Advanced Microbubbles?

Jameel: Work in mice models can always go wrong. Demonstrating reproducible and consistent results in-vivo, and in outcompeting non-uniform bubbles is where we are going next. This would mean running larger cohorts. We plan to show the efficacy of the platform in Neuroblastoma and pancreatic cancer animal models by the end of next year.

Looking beyond next year we want to show the versatility of this platform in more than one indication. Extending in-vivo proof of concept in a wide range of chemo toxic drugs expanding the market to other cancers such as breast cancer, prostate, and lung cancer. Showing we can take existing chemo toxic drugs and achieve higher efficacy at hopefully lower doses also plays into our business model to partner with Pharma to enable the efficacy and safety of their old and new drug classes.

With clinical trials coming next, should we be preparing for a long wait to see your product commercialized? Curious to learn more about your regulatory strategy and some learnings in this process?

Connor: At a very high level this data helps us gather more safety data points, setting us on a trajectory to get to IND and therefore, into the clinic in two year’s time. We do realize that there are many indications and potential drugs we can partner with.

Bubbles can go so many places, but at IndieBio, we learned that focus will set you free.

Jameel: Totally. To piggyback off that comment, focus is key. Bubbles have been used in ultrasound imaging, tumor ablation and other medical uses as an approved product for many years. IndieBio emphasized the value of tying key scientific milestones and data to a good go to market strategy. Starting with hard and rare diseases to drug tumors and then opening up to broader markets as we gather more performance and safety data.

Delving into regulatory strategy, early-on, was also a big learning that came out of the program. We didn’t wait instead the regulatory strategy helped us focus on our experiments. We learned how we can leverage the existing safety profile of bubbles and use an accelerated FDA pathway, the 505 (b) 2 to speed up going to market. An eye-opening experience to learn the role of the regulatory process in go-to-market decisions. Furthermore, based on advice from industry experts, we plan on combining this pathway with the orphan drug pathway can cut our time to market to 3 to 4 years.

Connor: When I come to think of it went from the mode of optimizing the best bubble and researching methods to do so in the lab to operationalizing the company to scale and sell the best bubble coming out of that research. In doing so we learned there is a new set of skills one has to code-switch to. Acknowledging this mindset shift is important as there is a stigma of moving too slowly in the lab. It is also exciting as we face a new set of challenges.

Jameel: In all this, I must say, IndieBio network really helped get a sense of the bigger picture and conveying that to a different set of audiences. We are gaining a sense of pitching the company to a rare disease investor versus a platform investor. How to engage different stakeholders and get people excited about what we are doing. We will continue to advance our relationship with regulatory experts and mentors we gained through the program. Look forward to keeping the momentum going around demo day and recruiting post-doc scientists to help speed up our preclinical data package.

IndieBio’s Demo Day is October 27–28, with the New York batch on Tuesday the 27th at 10 am, and the San Francisco batch on October 28th at 10 am. Please follow this link to Eventbrite to RSVP. A single registration will grant you access to both days’ events.

Spintex: Sustainable Materials Powered by 300 Million Years of R&D

Friends and labmates who trained together in the Oxford University silk group, Alex Greenhalgh and Dr. Martin Frydrych are tackling climate change one silk shirt at a time.  From their lab in Oxford, Alex answered some of my most pressing questions around the environmental damage fashion manufacturing is inflicting on our planet, Spintex’s unique take on a material that’s been used for millennia, and how a 300 million year-old technology can be new again.

[Interview has been edited for length, but not the British spellings.]

Pae Wu: First things first, how do you pronounce Greenhalgh?  

Alex Greenhalgh: Green-hal-sh, very soft on the s. But everyone has their own idea on how to pronounce it!

PW: Silk seems to be all the rage, but Spintex is coming at this in a totally different way than other venture-backed start-ups in the silk game.  What’s the key difference and what are the implications? 

AG: I think there are really three aspects to our approach which set us apart. Firstly, we produce a feedstock which has the key attribute of a natural silk, ‘shear-sensitivity’, which means it can transform from a liquid to a solid, just from a physical force, such as rubbing your hands together. . .if you pull it in the right way, the nanofibrils inside the solution start to orientate in one direction and form bonds between themselves, and you get a fibre

Crucially, we can produce this feedstock without bioreactors, which although it is an impressive technology, has seemingly struggled to replicate the size and complexity of the silk protein. This reduces our costs dramatically, whilst also allowing for a completely different form of spinning machine. 

Our spinning machines . . . instead rel[y] on the liquid to solid transition from force, meaning that the feedstock is actually self-assembling into the fibre. This is a direct mimicry of the spider’s approach, and is what gives us our impressive energy savings and material performance.

PW: Energy savings – I like the sound of that.   

AG: Compared to the traditional silk process that relies on heating huge vats of water and caustic chemicals to boiling temperatures to reel the silk from the cocoons, we can expect to produce our fibres with at least 50% energy savings, by removing the need for any heat inputs, which represent the vast majority of silk’s impact. I’m expecting once we run the numbers further, the energy reduction will be even greater, due to removing several of the more environmentally damaging chemicals from the traditional process, and an expected decrease by 100x in water consumption.

Even compared to other alternative silks, we expect to see a good reduction in energy requirements, as bioreactors commonly have to run above room temperature for their microbes, and require protein purification and freeze drying steps that are very high energy input.

PW: How will Spintex scale-up and disrupt the silk industry? 

AG: Our scaleup is somewhat easier to achieve than might be expected for a biotech company. We don’t need to invest heavily in large bioreactors, which are a serious drain in capital and very costly to run 24/7. Furthermore our consumables are all very cost-effective, and can be mostly sourced renewably

Our scaleup mostly comes from increasing the quantity of our feedstock [using] readily available machinery and automation, and increasing the throughput of our spinning process [by running] more [of our low-cost] spinning machines . . . in parallel.

Spintex spinning silk (say it fast 3 times)

PW: You say this is backed by millions of years of R&D – how’s that?  

AG: Silk first evolved in spiders around 300 million years ago, and . . . the versatility that silk provides to the spider . . . orb web, cobweb, natural diving bell[s], parachute[s] for young spiders to travel immense distances, demonstrates [its] value and usefulness.  

Interestingly, the approach to producing fibres through a low-energy spinning, is so effective that . . . it has evolved independently multiple times, in multiple arthropods, including bees and glowworms, arachnids and even a mollusc species. 

However when we look specifically at material properties, particularly toughness which is the combination of the strength and stretch of a material, spider silk reigns supreme. Although the underlying feedstock between species share many characteristics and attributes, it is the process that a spider uses to spin that seems to be critical to the performance. This is why we looked to spiders as our template for our spinning machinery.  

PW: Why is alternative silk such an appealing planetary health play?  

AG: The drive to reduce costs of clothing has seen many synthetic materials used, which we now know can have real impact, first in the energy or resources for their creation, to microplastics produced during washing, to problems with end-of-life

PW: Earlier, you described the immense energy and environmental cost involved in traditional silk production, too. 

AG: That’s right, it doesn’t mean natural materials are inherently better.  Traditional silk . . . doesn’t suffer from microshedding and can biodegrade, [but] takes a huge amount of energy for its production. The huge vats of boiling water . . . represent 50% of the total energy in silk’s production, and is the primary source of its large CO2 emissions. 

So even when using a natural product, we can’t seem to avoid having a negative impact on the environment. I think this is why alternative options, and new, sustainable technologies are so desirable, and really tackle some strong pain points for the industry.

PW: During IndieBio you’ve made some great progress with customers – what have been the highlights in customer development?  Any unexpected learnings? 

AG: For me, the real highlight has been the industry’s willingness to support innovation through a variety of means, including providing market and industry data, to supporting testing projects. I’ve been really impressed by the genuine commitment from them in seeing new developments that tackle sustainability issues in fashion, and even in other markets, where environmental issues are increasingly being taken very seriously. We’ve seen potential for collaborations and projects together, with real commitments for working together, beyond even LOIs.

An unexpected lesson for us, was not every value proposition is actually valuable for your customers. For example, we demonstrated some new dyeing possibilities using our fibres, that we thought would be exciting for reducing the environmental impact dyeing has. But most of our customers print directly onto the woven fabric, so they had no need for this!

PW: Elephant in the room, can folks test Spintex’s fibers?  

AG: From the very start we knew that the performance of our fibres would be critical. You can’t easily supplant an existing material, if you have grossly inferior qualities. So much time was spent on perfecting the feedstock and spinning processes to produce a material that can at least match a traditional silk. And what we found is that through our process, we can actually improve some properties, particularly toughness, to levels not seen in traditional silks, but in spider silks. 

We have had quite some interest in testing the fibres, particularly from performance and advanced material companies, which we have been happy to supply. The results closely matched our own testing, clearly showed the potential for the technology, giving unique possibilities in natural fibre textile spinning. These discussions are ongoing, but so far the reactions have all been positive. 

PW: What inspired you to start Spintex? 

AG: I’ve always loved science, but increasingly I found myself wanting to see research turn into an actual solution, that changes something, rather than just being an interesting footnote in an academic paper. With our work, we saw a real opportunity to provide a tangible benefit to the world. I’m especially excited about the possibility of reducing CO2 production in fashion, as the COVID pandemic has shown, even with personal changes to travel and working, we can only drop emissions by a fraction of what is needed to prevent devastating climate change. Manufacturing and the power generated for it are still by far some of the largest producers, so it’s crucial we start moving towards low energy methods for manufacture of the materials we need.

PW: What’s your biggest lesson from spinning (ahem) up Spintex during a global pandemic? 

AG: You never have enough of everything, so stock up! But also that tough times can be stressful and unpredictable, but if you keep pushing ahead you can weather nearly any storm.

PW: Finally, let’s play a little word association: What’s the first thing that comes to mind when you hear the term “butt rope”? 

AG: For me it’s a birthday card that I have received many many times from friends and family.  

Check out Spintex at IndieBio’s (virtual) Demo Day on 28 October!  Register here for the two-day event (27-28 October 2020).   

Microgenesis: Restoring the Fertility Biome

Through the development of a simple swab-based test combined with personalized nutraceutical solutions, Microgenesis is helping women facing fertility challenges forge a path to pregnancy and motherhood.  Building off their impressive initial patient results in Latin America and Spain, the team just landed (literally!) in the US to begin offering their infertility solution to the American market.  I wanted to dig a little deeper into Microgenesis’ offerings, upcoming clinical trials, and their future plans.  Here are excerpts from my conversation with co-founder and CEO/CSO, Dr. Gabriela Gutierrez.

 

Pae Wu: Gaby, your team really caught our attention with your impressive clinical data from Argentina that predated IndieBio.  Out of 287 women that had previously failed at least 4 IVF procedures, 75% of them got pregnant within 6 months!  

Tell us, what are you most proud of accomplishing during this pandemic edition of IndieBio?   

Gabriela Gutiérrez: During IndieBio we studied 15 alpha testers that are at the beginning of their fertility journey and 14 of them are already pregnant!

 

 

PW: What motivates you to tackle such a tough challenge?    

GG: Yes, we have worked with the hardest cases of infertility.  I have spent 15 years helping women that already failed IVF treatments. Women that are desperate and looking for a test that can help them to understand the real problem and how to fix it. We intend to replace the painful classic fertility journey of women by focusing on women’s health. 

PW: But you’re not solely working with women who are undergoing IVF, is that right?  

GG: Because we can anticipate the real problem using our test we can treat the patients before they start IVF.  We also work with women who are just starting their fertility journey and couples. 

PW: What’s the customer journey like?  Is this a one-size-fits-all solution?

GG: We send the woman a non-invasive test and we guide her through nutraceutical recommendations that improve her fertility potential while preventing inflammatory diseases.  

Our test is able to identify 64 different infertile biome phenotypes and we have developed 53 different treatment combinations to provide the right solution for every woman.

PW: There are so many fertility tests on the market today – traditional tests through ob-gyns, and newer direct-to-consumer options.  How does Microgenesis’ solution differ?  

GG: The traditional test is based on the evaluation of 5 hormone indicators of ovary function. This information is oriented to determine if a woman with low ovarian reserve/function should go for assisted reproduction. Our test brings information about the real problem and it is actionable. Our fundamental insight is that infertility is associated with an intestinal condition which also can affect ovary function. 

There is no other test in the market oriented to study intestinal microbiome disbalances affecting fertility.  We focus on women’s health, we restore key components to treat inflammation and the reproductive senescence associated, and we get women pregnant during the process.

PW: You’re now in the Bay Area!  Welcome to the US – what’s on slate for Microgenesis here?    

GG: In the next 3-4 months, we will focus on our Seed round to go to the US market next year. 

We have launched our alpha test in the Bay Area with women who are asking about their fertility potential.  We will send them the sample kit with a swab and lancet for a blood drop test.  They can send us the samples to our CLIA lab in Oakland.  They will receive the report by e-mail and we can send them nutraceuticals and customized probiotics for a 90-day treatment based on the results [and] we will work with them through conception and pregnancy. Please refer potential customers to gabriela.gutierrez@microgenesis.net

We also will repeat our proof-of-concept with 86 infertile couples and 20 fertile couples in a clinical trial at Wayne State University with Professor Gil Mor, the chairman of the Clinical Research Center at Wayne State University and president of the American Society of Reproductive Immunology. I have been a member of this society since the last 15 years. 

PW: For your alpha test, you are poised to bring in early users and ship your product — who are you partnering with to make this happen? 

GG: Our partner in the CLIA lab is Renegade Bio, our partner in digital marketing is Bullmetrix, our supplier of probiotics is Sacco System, and the supplier of our customized private label nutraceuticals is Equinox. 

PW: You talk a lot about a couple’s fertility, not just a woman’s.        

GG: We are planning to study male partners during the clinical study at Wayne State.  We know that the markers we hunt for in our test can impact fertility potential in women, and they can also be exchanged by fluids. So we want to test the expression of these markers and restore missing key components of the fertility biome in a male partner, too.  

We also have a scientific collaboration with a pediatric gastroenterologist that will run our study with autistic and celiac infants.  We intend to track the expression of our markers in the family and prevent early onset of diseases associated with microbiome disbalances like autoimmunity.

Check out Microgenesis at IndieBio’s (virtual) Demo Day on 28 October!  Register here for the two-day event (27-28 October 2020).  

Diptera.ai: Fighting Mosquitoes with Mosquitoes

Diptera.ai combines computer vision and deep biological knowledge to fight mosquitoes and their diseases. We spoke with CEO Vic Levitin about Diptera.ai’s solution to the mosquito problem.

Watch and read an abbreviated version of the conversation below.

What is the mosquito problem?

Mosquitoes are the most dangerous animal alive: they kill nearly a million humans every year and infect 700 million more with diseases like Zika virus, malaria, and yellow fever.

The mosquito problem is a spreading one. Thanks to climate change, the mosquito-friendly habitat is expanding. By the year 2050, half the world’s population will be living among mosquito infected areas. 

There are no vaccines or treatments to most of the mosquito-borne diseases, and the solutions to control mosquito populations depend mostly on pesticides; this uses chemicals that are toxic to both humans and the environment. These are quickly losing their productivity because the mosquitoes are becoming resistant to these insecticides.

Why has Sterile Insect Technique failed to address the mosquito problem?

Sterile Insect Technique, or SIT, relies on one beautiful fact: male mosquitoes mate repeatedly while females mate only once. Based on this concept, when you release large quantities of sterile male mosquitoes, they mate with wild females and there are no progeny, diluting and depleting the population.

This is the core of the technique, but it isn’t new; SIT has been around since the mid-1940s. It’s been widely used for other types of insects, but there’s been a major bottle neck with implementing this technique for mosquitoes: you want to be very precise to release only sterilized male mosquitoes. Only the female mosquitoes take bloodmeals; if you release any females, they can still bite and transmit disease. You want to be as close to 100% accuracy in releasing only males.

Another problem is the sex sorting of mosquitoes at the adult stage, which is what is currently done. Adults are fragile and have a short lifespan, so they are difficult to ship. You need a facility to grow, set, and ship, which is why this technique, although very promising, is not being widely implemented. It’s just super expensive at the moment.

What has Diptera.ai innovated in mosquito sex-sorting technologies?

We developed a technology to sex sort mosquitoes much earlier, in the larval stage. At this stage, the mosquitoes are much more robust, and they have about 2 weeks prior to becoming adults. That’s 2 weeks that we could ship all over the world.

Sorting at the larval stage allows us to introduce a new business model to the industry, where instead of having to build your own facility, we can ship sterile mosquitoes to you and use sterile insect technique as a service.

How does your team have the unique ability to build this technology?

I’m fortunate to be joined by 2 co-founders that are exponentially smarter than I am. Each of them brings along more than 15 years of experience in their own fields. 

Elly Ordan has been working with insects for his entire adult life, so he really knows his stuff when it comes to insects. He brings a unique knowledge of how to recognize differences between males and females at the larval stage. Ariel Livne is an expert in automation and optics, and he translates Elly’s mind into an artificial intelligence and an automated machine. 

Who will Diptera.ai’s customers be?

The current annual spending on mosquito control in the US is $2.5 billion dollars. The private market spends $2 billion, and half a billion is spent by mosquito control districts. Because existing solutions are toxic and inefficient, we estimate a $15 billion untapped market in the US alone.

This estimate is based on the fact that out of 80 million households with private lawns, half of them already have a mosquito problem, and only about 2 million households are buying mosquito control. The rest have basically given up on their outdoors during the mosquito season.

We offer an effective and sustainable solution at a comparable price. Our strategy is to start from the mosquito control districts, as they have both successful experience with SIT for agricultural pests and immediately available budgets. To that end, we have an LOI from a major US mosquito control district. We’ll then expand to the residential market, where we have signed an LOI with one of the largest mosquito control companies in the US.

How do you imagine Diptera.ai will grow as the SIT technologies matures?

At this point, we’ve spoken to dozens of experts from all around the world: from the U.S., from Asia, South America, South Africa and the Gulf Coast. For us, it’s clear that SIT will be implemented widely and will be a default mosquito control solution. It’s important to say it won’t be a silver bullet: you still need other methods as well, practices like eliminating still water, and educate the community not to leave open water containers, and so on. But it’s really not a question of if SIT will be implemented, it’s a matter of when and who will do it. We believe we hold the key to unlock scale for the sterile insect technique and essentially create this industry.

See Diptera.AI pitch at IndieBio New York’s Demo Day here.

Cayuga: Treating All Forms of Bleeding

Cayuga Biotech is a preclinical therapeutics company whose lead compound, CAY001, shows promise to change the way that severe bleeding episodes are treated. We spoke with CEO Damien Kudela, who explained the science and path forward for Cayuga.

Watch and read an abbreviated version of the conversation below.

How did you transition from academia to biotech entrepreneur?

I had never envisioned an academic route for my career and by the time I was done, I was looking for a new way to apply my scientific knowledge. Cayuga was seeded by a conversation I had in my 4th year of my Ph.D., where someone said that there was a real need for this technology and I should think about creating a company to advance it. Since we’d already been in the early stages of patenting my thesis and the CAY001 drug, I figured ‘I’ve already been a starving grad student; why not go be a starving entrepreneur as well?’

How do platelets work with polyphosphate to promote clotting, and where does CAY001 fit in?

If you think of a clot as a brick-and-mortar material, the platelets form the bricks. There’s a second compound called fibrinogen which is the mortar. That constitutes the physical clot. 

The problem becomes how to get that brick wall to plug the wound. Polyphosphate is produced by platelets and is essentially a catalyst for clot formation, a molecule whose job it is to speed things up. Adding polyphosphate helps the clot to form more quickly, which enables the clot to shut off the bleeding more quickly.

Bleeding causes a lot of negative outcomes for patients, so stopping the bleeding has many benefits. Not only are you saving their lives by reducing blood loss, but you can actually reduce the time it takes for them to heal as well. 

Bleeding causes a lot of negative outcomes for patients, so stopping the bleeding has many benefits. Not only are you saving their lives by reducing blood loss, but you can actually reduce the time it takes for them to heal as well. 

 

How does CAY001 differ from other pro-clotting drugs available?

Typically, many currently available drugs are recombinant factors that are either direct mimics of endogenous proteins or slight alterations of these same proteins. 

The issue with bleeding and clotting is that they are two sides of a seesaw. Typically, a patient is balanced flat but when they get injured, and start bleeding, the seesaw tips toward the dangerous effects of too much bleeding. Unfortunately, what can happen with recombinant drugs is that the balance remains out of whack; they can tip the seesaw in the other direction and they can have the dangerous effects of what’s called ‘throwing clots.’ 

This is a huge problem. All the drugs that treat bleeding currently have a black box label warning because of that. And doctors have to weigh a crucial decision in treating patients, asking whether the patient is critical enough to warrant the safety risk.

Using polyphosphate as a catalyst differs from these drugs because it has an effect on the rate, but it doesn’t affect the specific clotting factors present. For example, polyphosphate has its biggest effect on the clotting factor, thrombin. The patient doesn’t produce more thrombin. Polyphosphate has a more limited effect, so you can hopefully use it in a safer way.

What data support your hypothesis?

We’ve been looking at different tissues, specifically the lungs. This seems to be where a lot of nano-based drugs fail. Obviously, the liver is also a concern, because it plays such a huge role in clotting. And of course, the blood-brain barrier. 

What we’ve done is compared CAY001 to saline in a pig model. Pigs are hyper-clotters, so there was some evidence of clotting, but it was the same in both the saline and CAY001 drug-treated animals. That was likely the results of the pigs’ natural clotting cascade, but obviously, safety is the number one concern, especially in this field. The first question we’re always asked is, “is it safe?”

“Is it effective” is always the second question. We’re on the pathways and have very promising data that we’ve seen so far to lead us through safety, and the remaining IND-enabling studies as well as our clinical trials.

 

What will your clinical trials focus on for the first indication?

Until IndieBio, we were fully funded by DARPA and the Army. Obviously, bleeding is a huge problem on the battlefield and causes about 50% of deaths. There’s also a huge problem with bleeding here in the U.S., especially as patients age and may need to be prescribed anti-clotting drugs such as plavix or coumadin. The problem is that these patients are already in the clotting phase; they’re given anti-clotting drugs and they go back to a risk of bleeding. A lot of it is done because there is no treatment for bleeding.

There are other conditions where patients may benefit from a drug like CAY001. We’ve been focusing recently on platelet dysfunction. This could also benefit patients on chemotherapy who end up with thrombocytopenia, as well as patients who have congenital platelet disorders. We’ve identified a hemophilia-like genetic disease that affect platelets, as opposed to Factors 8 or 9. There’s a wide range of people who may benefit.

Obviously, everybody thinks the quantity of life is a major benefit, because bleeding can kill very quickly. Stopping a bleed also importantly enables patients to have a better quality of life, so they don’t have to worry about shaving or having an accident, whether the kitchen will be fatal. You can really help to give patients their life back.

 

Who is the Cayuga Biotech team?

I was at UC Santa Barbara, and the sole graduate student who really did any animal experiment at UC Santa Barbara was Kyle Ploetze. Kyle actually has a very good story of the first time we med; I’ll let him tell it another time. I ended up working with Kyle to test our new drug, and we hit it off while doing the test. The data worked well, and we got along well. Kyle and I jokingly refer to CAY001 as kind of our baby.

We were the two initial co-founders; in 2019, we needed to add a third person to do a lot of our quality controls. We were working on our manufacturing, and Nate, a postdoc at UC Santa Barbara, interviewed and we thought he was excellent, so brought him on board. It’s been excellent working together.

 

What are the next major milestones for Cayuga on the road ahead?

We had our first meeting with the FDA in May 2020, so we’ve gotten feedback. What we really need to do is finish our PK/PD and tox studies. These will help to figure how the drug is cleared and its toxicity; are there any adverse effects from the drug, what doses are safe, what doses are effective. Really, we need to determine it’s safe enough to move to human trials. We’re excited to present our data at Demo Day.

Learn more about Cayuga Biotech and all of IndieBio New York Class 1 companies at Demo Day.

BioFeyn: Making Eating Healthy Fish Sustainable

BioFeyn is a company that aims to make farmed fish a truly sustainable practice. We spoke with CEO Timothy Bouley to learn more about how nanotechnology can create better fish. 

Watch and read an abbreviated version of the conversation below.

What are the problems with current farmed fish practices?

There are many ingredients used in fish feed; the kind of fish that we eat most frequently are ocean predators, things like salmon. Salmon naturally eat other animals and so salmon feed often includes other fish; the fish in this feed is often caught from the open ocean, depleting wild populations and contributing to overfishing. The FIFO, which is the “fish in, fish out” ratio, for a species like salmon, that can be more than one. By putting more fish into the system than you’re producing, the system is not efficient.

There’s also an incredible amount of waste associated with this process due to the excess nutrients that are dumped into the fish pens, which then goes into the environment. Additionally, a lot of fish die, adding to environmental contamination.

BioFeyn is taking the latest science from human biomedicine and applying to the space of aquaculture, or farmed fish. Our team is unique in that each of us come from the world of human biomedicine—I’m a medical doctor, my cofounder Umberto is a nanotechnologist and our other cofounder Marie-Christine Imbert is a molecular biologist—and we are taking some of these latest technologies and simply applying them to the word of aquaculture, where there’s ample opportunity to scale up these biotechnological developments.

What can you tell us about your Feyn products?

Essentially it’s a capsule, on the nanoscale, that encapsulates existing ingredients, such as nutrients or medicines, that can be used in aquaculture to greatly increase their efficiency and improve overall sustainability in the field. Our Feyns are made of all natural ingredients, all already approved ingredients in this space.

We’re focussing on high-value ingredients that are already in fish food but are delivered very inefficiently. One example is omega-3 fatty acids; everyone knows that these are why we eat fish, to get the omega-3s and gain cardiovascular health and brain health. The problem is that salmon get omega-3 fatty acid by eating other fish. We can encapsulate it and include it in salmon feed, increasing feeding efficiency by an order of magnitude, tenfold. This increase in omega-3s is passed on to a customer that eats BioFeyn-treated fish feed.

We’re looking to encapsulate many different ingredients, part of how we determine what the characteristics of a successful Feyn. Number one, we look for things that are expensive. Number two, ingredients that are marine-derived that have a secondary, more sustainable means of production. 

For example, previously omega-3s have come from smaller fish to the salmon, but the natural environmental source of omega-3 fatty acids is in fact algae, and the smaller fish that eat algae pass that up the food chain, eventually reaching salmon. New ingredient companies are farming algae, and these omega-3s can be taken directly from algae and inserted into the fish feed, bypassing the need for wild-caught fish. The problem is that these omega-3s can be very expensive, and our method increases the efficiency tenfold. We can make it cost effective to use an ingredient that benefits fish, farmer, and consumer.

We can make it cost effective to use an ingredient that benefits fish, farmer, and consumer.

How will BioFeyn get its product to the fish?

There are many different ways to address this, one of which is going directly to feed producers; these folks have global reach to the farmers of the world. There are many, many tens of thousands of fish farmers, shrimp farmers, crustacean farmers around the world, and there are many, many fewer feed producers. Working directly with the feed producers is the most efficient way to reach as many farmers as possible.

That said, there is a path to working with farmers either individually or through trade organizations that represent a number of farmers and developing specialized products for farmers. 

What other products might BioFeyn use its technology to produce?

We have a roadmap for how our platform technology, where our nanocapsules can encapsulate a number of different ingredients. That includes probiotics, essential oils, that includes medicines that are approved in aquaculture. This is really key: there are a lot of medicines that work for some of the trickier fish diseases that are heavily regulated and can, of course, cause environmental pollution; with our technology, we can massively increase the efficiency and reduce the amount needed.

Down the horizon, in the future, we imagine encapsulating antigens as well, with some potential to developing vaccines. So you know, basically the spectrum of aquatic animal health that we think can be addressed with our encapsulation technology. We anticipate the technology will reach a point where it is fully modular and we have recipes for any challenge in this space, whether it be nutritional or infectious.

The ocean is the lifeblood of all life on Earth. All humans are three-quarters salt water. We came out of the ocean and there’s so much that can be done with understanding the marine environment and combining it with the latest biotechnologies that can be used for human and oceanic health.

Learn more about BioFeyn and all of IndieBio New York Class 1 companies at Demo Day.

Biomage: Making Single-Cell Sequencing Data Accessible to Research Biologists

Biomage is a computational biology company with a unique software that allows scientists to explore the multiverse of human cells through single-cell sequencing. We spoke with CEO Adam Kurkiewicz about the ability to turn every biologist into a bioinformatician.

Watch and read an abbreviated version of the conversation below.

How is single-cell transcriptomics changing biomedicine?

Single-cell transcriptomics, or single-cell sequencing, is a relatively recently discovered method, and is used to really understand what’s happening inside living organisms at the level of individual cells. This is something I like to compare to the invention of the light microscope when scientists were for the first time able to look at individual cells. Single-cell sequencing gives us the ability to look at individual cells, from the inside. It’s a unique capability that has only emerged in the past couple of years.

This technology is not specific to just one type of biomedical researcher, but is used throughout many fields of biology, including prominently cancer research, cardiovascular research, and developmental biology.

What problem in bioinformatics is Biomage solving for researchers?

One of the biggest challenges in applying single-cell transcriptomics is that it will be difficult to scale the technology to every biologist who wants to use it. At Biomage, we make it possible for every biologist to analyze a single-cell dataset without having to develop the really, really elite expertise that has been required so far to carry out such analysis. 

We do this by effectively removing a step: the process where the files created from analysis of a sample of tissue are normally first worked on by a research bioinformatician. We remove that step entirely by automating the research bioinformatician and making it possible for biologists to become the bioinformatician themselves. This benefits not just the cost efficiency, but it’s also quicker: quicker to iterate, quicker to test the hypothesis directly. It also removes the potential issues with miscommunication and knowledge transfer between 2 different fields, biology and bioinformatics. 

What are the benefits of empowering biologists to analyze single-cell transcriptomics?

We are significantly cutting down the amount of time required to carry out such analysis. Typical single-cell analysis using a bioinformatician working part-time takes between 3-6 months to deliver the level of insight that is required for a publication in a high-profile journal. Our aim as a company is to bring that process down to a week or two of hand-on analysis by the biologist directly with the software. 

The bulk of the cost savings is specifically eliminating reliance on a consulting service or partnership with a qualified bioinformatician. There is some additional cost reduction in how we handle the data and how we can process the data by a close integration with the core facilities where the sequencing actually happens to make it more cost effective to process the data and carry out the computational aspects of the analysis as well.

Scientists need excellent software. It’s often treated as an afterthought or something that is only a small part of research grants.

Who will your initial customers be, and will this change as you iterate the product?

We’ll work first with core facilities. Those at core facilities are happy to partner with us because working together, we can actually deliver the biggest value to their customers: the researchers. We can free the core facilities staff for work on the truly creative and difficult aspects of the field. In a core facility, there are typically bioinformaticians who are taking care of as many as 50 projects; they really need the ability to cope with the analytical needs of that many projects efficiently. By bringing the time down to 1-2 weeks, we make it possible for bioinformaticians to effectively do their job, so they’re very happy to partner with us. 

On both sides of the Atlantic, both in the U.K. and in the U.S., the core facilities have been overwhelmingly positive and we expect these partnerships to further expand into other core facilities and to grow stronger by closely integrating together.

The bulk of the users and the real impact of the software that we’re building is going to most likely come from other sectors, including pharmaceutical research and biotechs. Our plan is to initially target the academic customers as a way to validate our technology and get an initial beachhead and enter into this space. For the next stage, we’re going to target biotech and pharmaceutical companies—they’re the next customer.

What provided you with unique insight into this problem?

My journey started on the other side of programming, computer programming and mathematics. I worked a short time in Skyscanner, a software company where I understood what social engineering is like and understood how software can be used to solve real-life issues and help people to accomplish major tasks.

The biological side came a bit later. To have a really impactful professional life, I wanted to come at it closer to human health and so I enrolled in a Ph.D. program at the University of Glasgow, where I ended up doing bioinformatics. I managed to find a way to merge my scientific interests with my software engineering interests! While a Ph.D. student, I realized that there was a really big need for bioinformaticians among biologists I worked with, so I started offering such analysis as a consulting service. 

With my co-founders Marcel and Iva, we quickly realized that it would be impossible for us to cope with the demands. The most impactful way to allocate our efforts would actually be to build a software solution to solve the difficult problem of the alignment biologists to understand single-cell data. 

Scientists need excellent software. It’s often treated as an afterthought or something that is only a small part of research grants. Through conversations with senior colleagues and in academia, I realized the best way to realize the mission of building really great software that can help was by creating a company.

What does the future hold in store for Biomage?

We would like everybody to be able to use Biomage as their solution of choice for single-cell data analytics and expand into other technologies such as spatial transcriptomics. We hope to dominate the landscape for single-cell data analytics.

Learn more about Biomage and all of IndieBio New York Class 1 companies at Demo Day.

Brightcure: Reviving, Restoring, and Replenishing a Woman’s Intimate Microbiome.

Brightcure is a company dedicated to improving women’s health. We asked Brightcure CEO Chiara Heide questions about the first product, a bioactive cream that promotes a healthy microbiome in a woman’s urogenital tract. 

Watch and read an abbreviated version of the conversation below.

Your personal story lends a lot of motivation. Will you please share it?

I personally suffered from chronic urinary tract infections, caused by harmful bacteria that enter the bladder and cause an infection. However, I’m not alone; every second woman worldwide suffers from these infections, and many are my friends and family.

I was super frustrated with the treatment situation because urinary tract infections are basically treated by antibiotics. There aren’t validated alternatives available and antibiotic resistance is now much more common. What that means is that many women experience a vicious cycle, to constantly contract infections and subsequently constantly take antibiotics. 

This is not a sustainable solution; it’s bad for the immune system and the natural microbiota. Antibiotics destroy the microbiome of your vaginal flora, and create many side effects, including making it more likely to get another infection because you don’t have the good bacteria in your intimate area anymore. Because of my frustration with this situation, I used my scientific background to look into new solutions. 

Tell us about Brightcure’s unique solution.

It’s very exciting: we basically found a good bacterium and we can use a good actor to fight the bad bacteria. Our bacterium is one that naturally exists on some healthy individuals and animals and can also be found in nature. There is nothing externally introduced.

This bacterium specifically fights the bad bacteria, but it does not affect the good bacteria of the urogenital tract, so it’s perfect for the intimate care area, because it balances your vaginal flora.

By fighting these bad bacteria, it gives the good bacteria room to colonize the vaginal area. This is what balances and promotes the good bacteria in the intimate area.

Is there risk of resistance developing to this solution?

There have been decades of research conducted with this bacteria and there is no associated risk with it. There has been extensive animal research around it and also testing in different human cells, and it has been in no way negative at all. 

This good bacterial strain basically eats the bad bacteria that cause these recurrent urinary tract infections. These normally travel from the rectum to infect the vaginal area. Our strain sees and kills bad bacteria, but it does not affect the good bacteria, those like Lactobacillus that promote vaginal flora. It is very targeted. 

How will women have access to Brightcure’s cream?

We are using this bacterium in our cream. It will be an intimate cream sold as a cosmetic cream that women apply externally to their intimate area; our bacterium is in that cream.

The cream will be sold as a cosmetic, making it a consumer product that women can easily access. We have a newsletter on our website to get the latest updates on our product development and our product itself. We also have a list where you can sign up for pre-launch notification if you are really keen on the product. We’ll have the product ready next year (2021).

We aim to destigmatize the conversation around intimate health. The community aspect is really important for me, because there’s not enough awareness around UTIs and the stress levels around chronic infection. It has a huge impact on women’s life.

To make the claim specifically around preventing UTIs, we will be partnering with clinicians and healthcare providers for rigorous clinical studies. These will allow us to make more specific claims about efficacy in the future.

How does this cream promote a healthy intimate microbiome? 

By fighting these bad bacteria, it gives the good bacteria room to colonize the vaginal area. This is what balances and promotes the good bacteria in the intimate area.

How will Brightcure change women’s intimate health in the future?

I hope to create a huge supportive Brightcure community, who uses our products. I hope we can reduce their suffering and bring back happiness to their everyday life with less stress. I hope we raise awareness for UTI and UTI patients because it has a major impact on a woman’s life, as well as how important the vaginal flora is to boost one’s immune system.

Learn more about Brightcure and all of IndieBio New York Class 1 companies at Demo Day.

Multus Media: Enabling the Food of the Future

Multus Media is a company producing the key ingredient to allow cultivated meat to become affordable and accessible to everyone. We spoke to CEO Cai Linton about his entrepreneurial journey.

Watch and read a lightly edited version of the conversation below.

What is cultivated meat?

Conventional meat and cultivated meat actually produce the same end product. They both produce burgers, sausages, steaks, and fillets. The difference between the two is the production system. Instead of producing these meats through an animal, all we do with cultivated meat is to take a cellular sample from an animal without having to kill the animal. It’s grown in bioreactors, similar to how we brew beer, but using these cells instead of yeast. The cells are then packaged into meats to create the same product.

Cultivated meat processes solve the environmental and ethical problems associated with meat consumption, to alleviate the environmental damage and greenhouse gas production associated with livestock and conventional agriculture, as well as the heavy antibiotic use, large areas of rainforest cut down to support livestock, and microplastic contamination, among other problems. Within bioreactors, you’re only producing the meat that will actually build and eat, by feeding them the exact nutrients and supporting their growth environment with very little waste.

Why isn’t cultivated meat available at the market?

My co-founders and I wondered what challenges stood in front of producing cultivated meat at high scale. We kept seeing again and again that the biggest bottleneck that is preventing this industry from commercializing is the cost of production—specifically, the cost of the growth media.

The cost of growth media takes up more than 80% of production costs right now, and current solutions are more tailored to pharmaceutical products. There isn’t a solution that not only uses animal-free components but is able to reach the performance scale and cost requirements of the cultivated meat industry.

What is different about how Multus Media creates growth nutrients?

Most media contain serum derived from animal blood, which is used in biomedical research or biopharmaceutical production to grow mammalian cells. Serum contains a concoction of proteins and salts and other nutrients that mimic the growth environment, and in that sense, it is very good.

The downside of serum is that it is an unethical byproduct of the livestock industry. It’s not very scalable and also offers batch-to-batch variability, which isn’t good when you’re trying to produce a consistent product at scale. 

What we’re doing is taking these components that exist within animal serum and producing them without animals.

What we’re doing is taking these components that exist within animal serum and producing them without animals. We use yeast as a production system, again similar to how beer is brewed, but our yeast produce specific proteins. We then combine the proteins and other factors into formulations that make it a similar growth-promoting substance, but in a way that can be scaled and doesn’t use animal components.

Conventional serum-free media that exists is designed for a very specific use case using highly purified individual ingredients. This makes existing media both not useful for looking at a number of cell types and also very expensive.

What is your first product and what does it do?

We’re initially creating a universal serum for mammalian cells, Proliferum M. Not only will this benefit bovine, but also sheep or porcine cells as well. We can take a step further and look specifically at either individual cell lines or a group of cell lines that a cultivated meat company may be using, and so tailor our media for this specific use case.

We’re optimizing formulation today to give high performance across a number of different variants within a million cells, as well as low cost. 

Our products after that will be expanded into products that support chicken and duck as well. Then, also different types of seafood. We’re looking toward developing products for those different types and seeing what we can do to innovate novel proteins.

What is novel about the Multus Media approach?

We’re working in an area that hasn’t been researched much in the biomedical sphere: the ability to identify the key components for cultured meat and to bring these components in a way that is a real solution.

What we’re doing with our protein engineering is taking these natural proteins and changing a few amino acids within a sequence to enhance their performance characteristics. This will benefit the industry by effectively increasing the performance of the growth media, which will reduce the amount (and expense!) of growth factor components that you need. We’re excited to showcase the performance of our medium at Demo Day!

What is your hope for the future of Multus Media and the cultivated meat industry?

In 5 years, I hope that cultivated meat has really started to make an impact on the traditional meat industry and is available to mass, mass amounts of people. By starting early, we hope Multus Media is in a position where we can service the whole industry and start increasing scale. We’ll be looking at our production of products across the line, replacing for different parts of the production process. The initial stem cells may need different serum than cells differentiated into muscles or connective tissue, but all products will need to allow the whole industry to commercialize at a profitable price point. 

Learn more about Multus Media and all of IndieBio New York Class 1 companies at Demo Day.

Halomine: Making Every Surface an Antimicrobial Surface

Halomine is a company revolutionizing the way we disinfect surfaces. We asked Halomine CEO, Ted Eveleth, to tell us about the first product, Halofilm. 

Watch and read an abbreviated version of the conversation below.

What is your first product, Halofilm, and what does it do?

Halofilm is a very versatile product that allows you to turn almost any surface into an antimicrobial surface. It puts a semipermanent film down on a surface that sticks to both the surface and the chlorine. So in your normal habits of cleaning and disinfecting when you’re using a chlorinated product, the chlorine will last on a surface longer than normal.

Normally, chlorine and almost any active ingredient disappears fairly quickly. What we do is make it stick to the surface to provide continuous protection against pathogens, turning that surface into a continuous pathogen-killing machine, essentially.

How does Halofilm work?

There are 2 molecules required to make Halofilm work. One monomer sticks to the surface; it’s like an adhesive. This is a bio-inspired adhesive derived from muscles; it’s what muscles use to stick to almost anything in an aquatic environment. 

The other is an n-halamine (where we get our name), which is a molecule that interacts with chlorine. Normally, chlorine disappears from the surface. An n-halamine holds chlorine in a covalent bond until pathogens come along, and the chlorine then has a preference for the pathogen, where it kills the pathogen.

Where are major opportunities to use Halofilm?

There are a lot of application spaces: one important space is a hospital. We don’t want to cut back on disinfecting or sanitizing practices in a hospital; what we’re looking to do is to cut back hospital-acquired infections. Halofilm is something that would be used in addition to bleach-containing cleaning agents currently being used. The hope is that it could prevent either hospital-acquired infections or, more relevant these days, is reduce the COVID-19 spread.

Pretty much everything being used in the hospital right now is temporary. It seems very normal to us, but essentially it’s like mowing your lawn. You mow your lawn, it’s the right height. You let it grow for a while, you mow again. In between, the grass gets longer than you might want it. It’s the same with disinfecting: it’s a liquid that kills everything but between treatments, the disinfectant is gone. That provides pathogens the opportunity to land upon those surfaces and take hold, and to be transmitted between people that touch those surfaces. We’re essentially trying to continuously mow the lawn to keep it at the same height and turn periodic disinfection into continuous disinfection.

We’re looking at a lot of institutional uses, ranging from mass transit, cruise ships, hospitals, jails, schools, and office buildings. We originally started thinking we’d go after food processing, packaging and prep to prevent mold as well.

What types of microorganisms is Halofilm effective against?

We have an enormous amount of data on bacteria. We have a recently approved NSF grant that they turned around in record time for the NSF so that we can extend our studies to viruses.

We have done some testing to show that we can deter mold for 30 days. Essentially, once you have a film of chlorine on that surface, it will prevent anything from growing on it or taking over or creating a biofilm.

How safe are HaloFilm and chlorine-coated surfaces?

HaloFilm is extremely safe; we’re only keeping the same amount of chlorine on a surface as you would find in a pool. In fact, we can use the same dipstick to test for chlorine on a surface as you can use in a pool to measure the amount of chlorine. It doesn’t take much chlorine to be effective because it’s so potent against pathogens. It’s very hard to get the chlorine off the surface and you’d have to come into intimate contact with it. When you touch the surface, you’re not having intimate contact because the surface is rough and the finger has fingerprints, creating gaps in contact.

If you went to look microscopically at almost any surface, it would look more like a mountain range than a flat piece of glass. The polymer that makes up HaloFilm actually gets down into these crevices and holds a smaller amount of chlorine where those pathogens will go to hide, which is why it is so effective and yet safe. We’re covering the valleys in chlorine that your finger could never touch but that tiny pathogens can hide in.

Learn more about Halomine and all of IndieBio New York Class 1 companies at Demo Day.

Allied Microbiota: Using Natural Microbes to Eliminate Toxic Waste

Allied Microbiota is a company using bacteria that literally eat pollution for lunch to clean contaminated soils and turn brownfields into green fields. We spoke with CEO Lauralynn Kourtz about the discovery of the Allied Microbiota strain, ThermO+™.

Watch and read an abbreviated version of the conversation below.

What compounds are in contaminated soils and how did they get there?

Many toxic compounds are the results of industrial processes. For example, a chemical plant or electrical plant may produce residues; these compounds would be really difficult ones, such as polychlorinated biphenyls (PCBs) or petroleum-based compounds like polyaromatic hydrocarbons (PAHs). They can persist for decades, up to hundreds of years; these compounds have been designed to be really incredibly stable and persist a long time.

How does Allied Microbiota use its ThermO+™ strain to clean contaminated soils?

ThermO+™ is a pretty amazing microbe. It’s a natural microbe, yet it has the ability to break down really tough compounds like PAHs and PCBs. ThermO+™ effectively eats these compounds for lunch; it will take a compound, break the carbon-carbon bonds, and then use that compound to make a building block for cells to grow. The only byproducts are water, CO2, and that’s about it. 

ThermO+™ is a natural microbe, but it can degrade these compounds that have been made by man. It was discovered by my co-founder, Ray Sambrotto, who scoured the globe while looking for solutions to these contamination problems. He discovered ThermO+™ and developed ways that we can grow it, make larger amounts of it, so that we can then deliver it to remove these contaminants.

To decontaminate soils, we add ThermO+™, provide it with the necessary ingredients it needs to live—heat, oxygen, and nutrients—and then it breaks down the contaminants. And ThermO+™ really loves heat; as soon as you bring the temperature down to normal temperatures, it won’t grow and the natural microbes in the soil will outcompete ThermO+™.

Working with a commercial partner, we’ve shown we can treat soil on the ton scale in ex situ soil very, very rapidly.

How is contaminated soil treated?

There are 2 ways to treat contaminated soil. One is ex situ, where someone actually comes and takes the soil away back to a facility where it can be decontaminated using various processes. In situ soil treatment is directly on the site of contamination. 

These soils can be treated using various processes, one of which is thermal treatment: incinerating it to remove the contaminants. You have to heat it up to about 400 degrees Celsius; that will remove some of the contaminants and other techniques such as oxidation will oxidize the contaminants into something less harmful. Probably the most effective solution is incineration, where you burn dirt at 1800 degrees. That takes a lot of energy and requires you to dig up the soil, chuck it in an incinerator, and create significant greenhouse gas emissions. ThermO+™ is not only much more sustainable, it’s much less costly.

What opportunities exist to treat contaminated soils?

There are over 450,000 Brownfield sites in the U.S and over 1300 Superfund sites; these are EPA-designated toxic sites. Together, they contain about 100 billion tons of toxic soil—enough to cover New York, New Jersey, and Pennsylvania one-foot deep with soil that is toxic to you and me.

I previously worked across the street from a contaminated site in Boston. It was empty for decades, which is unheard of in Boston. It was considered worthless, because it was toxic. When it was cleaned up, the Genzyme Center was built, and today it’s worth over half a billion dollars and thousands of people work there. 

A lot of the Superfund sites are in urban areas, the results of industrial processes which powered the creation of these towns; many of these sites are within the hearts of cities.

What does the future look like for Allied Microbiota?

I hope Allied Microbiota and ThermO+™ become the go-to solution to clean up the soil contaminants and air and water contaminants, and that as we scale, the technology will become much more accessible to people. Right now, people and developers and companies and towns decide based on financial factors that they can’t afford to clean up a site, and it stays vacant. As the technology grows, it will become accessible so that those decisions are shifted to yes, they can clean this up and it can become a productive area of town.

Learn more about Allied Microbiota and all of IndieBio New York Class 1 companies at Demo Day.