🧫 What if we could grow anything?

The promise of cellular agriculture and synthetic biology

Look at your surroundings: your table, your clothes, your food, yourself, and other living creatures. What if we didn’t exploit natural resources to obtain them? What if that was profitable too? What if we could grow anything?

Inspired by Ginkgo Bioworks, I would say that this is one of the promises of synbio. The how is the second promise: biology is technology. Synthetic biology as a discipline is multidisciplinary, and aims to standardize biology so we can become biohackers; organism engineers and developers.

In a simplified manner, cellular agriculture involves differentiating and multiplying cells in the lab through various biotechnologies, including synthetic biology.

More clearly, synbio meets growth in a type of cell ag called acellular agriculture, which grows compounds that aren’t cells, inside of cells. In other words, acellular agriculture is about manufacturing a variety of compounds using synthetic biology.

If you look around you again, one of the first things that you’ll notice is that electronic device in which you’re reading this article. This is digital technology assembled from hundreds of different components (the hardware) and running code (the software).

Biological technology is similar. Despite recent research, we generally use the analogy of DNA being software and cells being hardware. One difference is provided by Neri Oxman: computers are assembled, while nature grows.

That was (probably) it for the romantic and inspirational part of this article. Next, we will dive deep into different types of BioApps — as I like to call biotech products. — The questions to answer are what we are growing and how.

Is this an accurate way to think about synbio? 🤔

Acell ag science

Perhaps the most important point to understand as an outsider to the deep science of all cell ag is this: these products are the real thing. The how changes, not the what.

Engineers like Elon Musk apply first principles thinking to reinvent things. Bioengineering and cell ag are similar: we reverse engineering nature; ask “what makes [insert organic thing here] itself?”, and then use biotech tools to produce it in a viably, efficiently, and sustainably.

Beyond a technology, I see cell ag as a principle. That means that lab-grown milk uses the same science as lab-grown palm oil. Synbio is what makes the difference.

These are the 3 main steps to acellular agriculture which will be further discussed in this section:

1. Synbio: inserting genetic code into the cells, which will make them produce the proteins for the products we want to grow
2. Cell ag: this mainly involves the use of a culture medium and fermentation
3. Other bio-technologies: purify the proteins and turn them into a product

1) I ❤️ GMO

Bacteria and yeast cells are the most commonly used biofactories in biotechnology. We know enough about their molecular biology to be able to engineer them, they may not be as picky as mammalian cells when it comes to nutrients, and they reproduce fast.

*Synthetic biology is quite a broad, new, and fascinating field which for sure deserves its own article. To put the fundamentals in place, we can elaborate on the initial romantic explanation and explain the synbio dogma: design, build, test, and learn.

In practical terms, the first phase can take the shape of a plasmid in Benchling. A plasmid is a short, circular piece of DNA found in organisms like bacteria. Benchling is a pretty awesome, cloud-based design tool for bioengineers.

Every plasmid has 3 main components:

1. Origin of replication (ORI): to reproduce, cells create copies of the genetic info they have. The ORI indicates the starting place to do this
2. Selection marker: the selection marker is normally an antibiotic resistance gene. If the cells grow in a plate with an antibiotic, it means that the plasmid made it inside them
3. Something to express (promoter + coding gene): this is the key element. The gene for an egg protein will be different to that of a honey protein. The promoter kickstarts the production of that protein

Image credits to Khan Academy

*People debate about calling this field synthetic biology or bioengineering. I use both interchangably for this article 🤷🏻‍♀️
*Using this as an example. The principles are the same for anything we want to grow 🙌
+One more shoutout to Ginkgo for their #ILoveGMO culture. Being strict on the term, a lot of the times acell ag deals with transgenic organisms too

2) Cheese and cheers

Both in nature and in biotech, fermentation is a marvelous gift! Many people know that it allows our bodies to produce more energy and to create that drink that so many love (you know I’m talking about beer ;)).

Now, if we enter the world of acellular agriculture, we will know that fermentation is a technique used to manufacture stuff. The simple explanation is: microorganisms like bacteria and fungi are biofactories. They need energy to work, and they obtain it (primarily) through fermentation.

When there is oxygen, cells can go through cellular respiration, comprising glycolisis, the krebs cycle, and the electron transport chain. At the end, there should be an electron acceptor, which most of the time is oxygen’s job. Thus, it makes sense why fermentation is literally a life-saver.

Although it doesn’t produce ATP on its own, fermentation does allow for its synthesis by reducing NADH. Since the cell still receives glucose, it can still produce NADH and pyruvate, just that instead of taking them to the next steps, it takes them to fermentation.

1. 2 NADH molecules help convert that pyruvate into lactic acid or alcohol and CO2, which are sort of byproducts
2. As the NADH is used, it is converted back into NAD+
3. 2 molecules of NAD+ are recycled back to glycolysis, which allows glycolysis to continue

Image credits to TEKS

Acell ag companies

Why re-invent the wheel when you can reverse engineer life?

I’d love to give a huge shoutout to the founders and leaders who shared these disruptive companies in my previous LinkedIn post about the future of food, summing to what I now call the #RealXWithoutY movement.

The industry is growing so fast that it’s hard to showcase every single startup here. I encourage you to join the movement by commenting on this LinkedIn post or this Twitter thread with: +real [product] without [traditional source], by @[tag company]. I’ll be really happy to write about them :)

Real 🍯 without 🐝 by MeliBio

Founded in 2020 by entrepreneur Darko Mandic and scientist Aaron Schaller, MeliBio is indeed a Berkely-based company reinventing honey.

The great environmental concern they’re addressing is a 90% decline in the number of bee colonies per hectare since 1962. The economic incentives are also clear: the global honey market projected to reach 14B by 2025.

They recently filled out a provisional patent for the science behind this invention, which includes plant science, synthetic biology, and precision fermentation.

The future looks sweet for MeliBio with a $850,000 in pre-seed funding, and a soft launch coming up by the end of 2021.

Real 🥛 without 🐄 by Perfect Day

Winner of Fast Company’s 2021 World Changing Ideas Awards, Perfect Day is reducing greenhouse gas emissions between 85% and 97% compared to traditional dairy industry, which is responsible for 3% of total green house emissions worldwide.

After asking what makes milk milk, the founders, Isha Datar, Ryan Pandya, and Perumal Gandhi found that the answer was casein and whey. They now produce these proteins in microflora to ultimately bring a variety of dairy products into the market… speaking of which, Graeter’s already started selling ice cream powered by Perfect Day in November of 2020.

The company has attracted people like Bob Iger (chairman @Disney!), who joined the management board in October 2020, and Leonardo DiCaprio, who is participating in the company’s sustainability council.

Real 🥚 without 🐔 by Clara Foods

Best known for their cultured egg whites, Arturo Elizondo and Dave Anchel are the co-founders of Clara Foods, where other animal-free proteins, like pepsin (used for medications) are also grown.

After 5 years, and having been part of the inaugural cohort of IndieBio (the world’s largest biotech startup accelerator), Clara Foods released its first product: a digestive supplement.

With Clara Foods, the chicken egg problem doesn’t even exist ;)

Real 🧀 without 🐄 by Change Foods

ChangeFoods was co-founded in Australia by David Bucca and Junior Te’o. After leveraging synbio and fermentation to produce the primary ingredients, they use traditional cheesemaking techniques to turn them into “the cheese that tastes, stretches, and melts just as you’d expect”.

Although their current focus lies on cheddar and mozzarella cheese, they have the long-term vision of a “modular approach to dairy” that could be producing many other types of lab-grown dairy.

On the business side, they’re main differentiator is being a B2C company. On the science realm, Change Foods can tailor their products to remove components like lactose and cholesterol, surpassing nature in that sense.

Real 🧴 without 🌴 by c16bio

Lipstick, pizza dough, instant Noodles, shampoo, detergent, and chocolate are only some examples of products containing palm oil. This $61 billion industry emits over 1 billion tons of CO2 each year and is causing the massive deforestation of tropical areas in countries like Costa Rica and Indonesia.

The little info available about C16Bio is definitely worth recognizing: it founded in 2017 by Shara Ticku, David Heller, and Harry McNamara, who were part of the Y-Combinator S18 batch + Bill Gates is an investor :0

Real 🎨 without 🐞 by Michroma

Food coloring is a $5 billion market inside a larger $70 billion market for dyes. The vast majority of these are synthetic chemicals derived from petroleum, which have been linked to allergies, hyperactivity, and even cancer.

Even though food dyes derived from fungi have been long used in Asia, the problem is that they often use a type of fungi that could contain very dangerous toxins. Michroma doesn’t.

Michroma is a food dye company, founded in Argentina by Ricky Cassini and Mauricio Braia, who participated in GridX (a latam biotech startup accelerator), after which they entered Indiebio.

They expect to enter the US market in 2022 and continue making the whole world a more colorful place from Argentina.

Real 🍼 without 🤱 by BiomilQ

Michelle Egger is the CEO and cofounder of the company creating the world’s first lab-grown breast milk. While other infant formulas are already available in the market, they lack the essential components that real breast milk (like BiomilQ) have: antibodies.

The startup’s Series A funding came from the Breakthrough Energy Ventures, primarily founded by Bill Gates, in a coalition with Jeff Bezos, Mark Zuckerberg, Richard Branson, and other top investors to solve climate change.

Real 👢without 🐊 by Bucha Bio

Sounds familiar? Bucha Bio is an Indiebio startup growing leather in the lab and currently testing their product with automobile and shoe companies, with an expect production cost lower than the status quo as well as a quicker production timeline.

The secret? Bacteria! Kombucha is actually a popular drink, where a symbiosis between yeast and bacteria can give rise to cellulose, the most abundant biopolymer on Earth, and what this company’s leather is made of.

Sustainable 📦 by Polybion

Last, but definitely not least: the company on a mission to replace 25% of styrofoam production and be the leader biomaterials company in Mexico in 10 years from now.

Polybion is different to the previous companies in many different ways. First, they’re operating in the biomaterials industry, rather than in the food one. Second, they’re not replacing, but creating the natural alternative to a very unsustainable compound that was the result of the chemical revolution.

Finally, they’re coming with an innovative approach: using agroindustrial food waste as part of the culture medium for their biofactories. Then they use the synbio-fermentation process we know to create Celium® and Fungicel®, which take just 30 days to degrade.

Chosen as part of 100 companies with most growth potential in Latam by Inc in 2017, they’ve indeed been growing a lot and are in talks with world-class companies to bring their products to market very soon.

Cell ag science

It’s important to highlight: the how changes, not the what. Current meat production pollutes even more than transportation, meaning that one can’t be completely eco-friendly by consuming meat often. In numbers, livestock make up between 14.5 and 18% of total global greenhouse gas emissions.

If that wasn’t enough, another concern of current practices is the health aspect. Lots of antibiotics and growth hormones are currently given to animals in order to sustain the economic pillar of the world.

Saving the planet comes with economic incentives in the long term: cultured meat is a cellular agriculture product that uses 76% lower GHG emissions, 94% less water, 80% less land, and 45% less energy.

The 3 simplified steps to growing real 🥩 without 🐂 are:

1. Get the cells: this first occurs through a painless biopsy. From that sample, scientists then need to select a type of cells called stem cells, which can replicate many times and turn into any time of cell
2. Grow it: first replicate the environment of the animal by using a special mix of nutrients and then using a scaffold to give the cells a shape
3. Cook it: a lot of the flavor in meat is provided by fat. Since the initial sample doesn’t have that, companies are working on adding flavor compounds or even enhancing the nutritional properties of meat

1) Biopsy

There are 2 possible methods:

• Incision: obtain more product, it’s more precise, but a worse experience for the animal
• Needle: completely the opposite

Some factors to consider are that cells from different parts have different potential for differentiation. The age and sex of the animal will also play an important role.

2) Isolation and preservation of stem cells

Not everything in the initial sample will be useful, only stem cells from the skeletal muscle tissue (aka myosatellite cells). Stem cells can self-renew and give rise to the muscle cells that we ultimately eat. The process is:

1. Physical dissociation
2. Enzymatic dissociation: use specific enzymes to get rid of the fiber, tissue debris, connective tissues, and muscle stem cells
3. Use filtration and centrifugation methods to remove the debris
4. Isolate the stem cells from that: using methods involving fluorescence (FACS) or antigens (MACS)

Further into stem cells, the diagram on the left shows the journey of differentiation from stem cells into muscle fibers. The different proteins expressed on the surface of these cells allows to purify the cells needed through a fluorescent- or magnetic- activated cell sorting protocol (FACS or MACS).

One more promise of meat cell ag is having an unlimited fountain of meat. To do that, cells need can be preserved at low temperatures or immortalized, which helps cells divide more times, overcoming what is known as the Hayflick limit.

3) Growth and processing

Media is like food for cells. It’s a solution of nutrients that helps them maintain a certain pH, proliferate and differentiate. It consists of 2 parts:

• Basal media: glucose, amino acids, salts, vitamins, and water
• Serum: the only controversial part of clean meat. It’s a blood component

After the petri dish, upscaled growth is how companies can get the industrial quantities needed to feed billions of people. It happens inside a bioreactor, which is controls environmental conditions like pH and oxygen for cells to grow. The use of scaffolds is also needed to give cells a geometric guidance.

As said before, taste normally comes from fatty acids. By adding compounds like haem iron, creatine, or carnitin glutamate, our mouths barely notice the difference between the dirty and the sustainable option.

A cellshot

The world’s first in vitro burger was by Mark Post with USD $330,000 in 2013. In 2018, Aleph Farms was able to produce a steak for USD $50. Indeed, the cost is still one of the big challenges for cell ag to go mainstream.

FBS is one of the main drivers, being an essential but ethical-concerning and highly expensive substrate for the medium. It costs approximately USD $1,000 per liter and contains many growth factors necessary for cell survival. Some companies are working on replacing it, although not many details are known.

Since the overall scaling process is considered the moonshot of cell ag and synthetic biology, I find it interesting how some companies are taking the ‘Tesla approach’ and culturing expensive steaks like wagyu and kobe. The process to culture those is similar, and they’re already sold for much more.

Having talked with a Mexican cell ag researcher, other challenges for the industry include obtaining an unlimited fountain of cells (without using GMOs, preferably), the consumer’s perception, and improving the taste and texture.

Cell ag companies

Growing with and for nature

One more shoutout to those comments in my LinkedIn post that helped me identify more companies in the space. Having talked with people in the space, I find the IP aspect to be very interesting here. It’s like nobody has the ‘the whole burger’ figured out yet.

Real 🥩 without 🐂 by Aleph Farms

The Israeli startup was co-founded in 2017 by Dr. Didier Toubia and Professor Shulamit Levenberg, the great differentiator of Aleph Farms is their technology to grow different cell types together, which will likely lead to a much better quality when they launch.

As of now, they have over $200M in investment to drop that production cost of over $3000 USD per kilogram.

Real 🥩 without 🐂 by Mosa Meat

Mosa Meat qualifies too as one of the top companies in the field, as it was co-founded by Mark Post, who many people consider the father of cultured meat, and Peter Verstrate.

In fact, they brought the very first lab-grown burger into the world in 2013, with 3 lab technicians, in three months, and with a cost of €250,000, which was funded by Google co-founder Sergey Brin.

A truly unlimited fountain of meat is the ideal scenario. Even when GMOs are the easiest route to get there, it may not be the best option for the European company. Yes, they’re going for the non-GMO label.

Real 🥩 without 🐂 by Upside Foods

Previously Memphis Meats, this startup is going for the big market: they’re growing meat, poultry, and seafood in the Bay Area. The co-founders are Will Clem, Uma Valeti, and Nicholas Genovese.

They have more than $180M dollars in funding, which include contributions from investors like Bill Gates and Richard Branson. Those must have helped since the company has plans of reaching the market this year (2021).

Real 🍗 without 🐥 by Eat JUST

Just is a company with a wide variety of products, ranging from animal-free egg to cultured chicken. Their uniqueness lies in the discovery platform they developed to obtain compounds from plants, which they use to grow the food of the future.

Through GOOD Meat, they have been the first company to commercialize their cultured chicken. You can already get a taste of the future by ordering through an app (currently available in Singapour only).

Real 👕 without 🌱 by Galy

Global production of cotton requires between 8000 and 10000 liters of water per kilogram. The team co-founded by Luciano Bueno and Paula Elbl, are skipping the plant and just growing cotton fibers in the lab 10x faster, and using 80% less water and land.

Despite being a young company, Galy recently won the annual Global Change Award from the H&M Foundation (called the Nobel Prize of fashion), which gave them $330,000 USD to continue scaling their product.

The plan is to produce yarn to sell to clothing brands, a business model that together with synthetic biology and cellular agriculture, works with and for nature.

It’s time to grow!

This article is the result of a rather inspirational and breadth-oriented cell ag exploration I did. It’s clear that the science behind these innovations is easier said than done (or grown? 👀). Any feedback is highly appreciated.

If you’re more curious about my journey, I’ve been exploring different biotech topics for 2 years now and doing some projects in the space. My mission for this year is to build/grow a more tangible project.

So far, I’ve gotten basic lab experience with biohacking kits and I’m currently looking for opportunities at a biotech startup or research lab to do more serious work or learn more about the bio-entrepreneurial world.

I’ve said this before: the future of biotech looks bright, and it’s exciting to see more people joining the bioeconomy to solve the world’s biggest problems. Thanks for reading :)

Hey! I’m S🧠FIA, an ambitious teenager researching and building innovative projects with 🧬Synthetic Biology and (occasionally) AI.
Just for growth, I also innovate at TKS🦄, create content, play the piano, read, and 🌎 connect with new people on a weekly basis (hit me up!).