Crafting Proteins with Precision Fermentation
I had a chance to briefly chat with the founder of Every at the AI * Vegan meetup (I know, everything has to be AI in SF now). They make cruelty-free products like egg proteins. As I was asking him how exactly they produce it, he mentioned that they use precision fermentation. I’ve never heard of the term, but as I asked him more questions, I figured that they are probably just using the same technology Genentech used for their insulin production. With some googling afterwards, I was convinced that it is a combination of recombinant DNA (rDNA) technology and fermentation.
It is probably not too much to say that modern biotechnology originated in 1973 with the invention of recombinant DNA, which led to medical drug development of insulin and success of biotech company behind it, Genentech.
In the early 1970s, two scientists, Herbert Boyer and Stanley Cohen, crossed paths at a scientific conference. Boyer, a biochemist at the University of California, was researching enzymes that could cut DNA precisely, while Cohen, a geneticist from Stanford, was focused on finding ways to transfer DNA between organisms. When Cohen heard Boyer speak about his research on DNA-cutting enzymes, he had a realization: these enzymes could help him solve a key problem in his own work.
After the presentation, Cohen approached Boyer with an idea: what if they combined their research to cut DNA from one organism and insert it into another, creating new, recombined DNA? This idea led to the invention of recombinant DNA technology, a method that allows scientists to combine DNA from different organisms and give them new properties. Together, the two began a collaboration that would lead to experiments showing that they could insert DNA into bacteria, which would then reproduce the foreign DNA and express it.
Their early experiments showed promise, but the real breakthrough came when they realized that this technique could be used to produce proteins like insulin. At the time, insulin, a hormone essential for managing diabetes, was extracted from animals—a slow and costly process. But with recombinant DNA technology, the human gene responsible for insulin production could be inserted into bacteria. These bacteria, in turn, could be grown in large quantities to produce insulin, making it easier to manufacture and more accessible to those who needed it.
This simple idea—using bacteria as tiny factories to produce human insulin—was revolutionary for diabetes treatment and became one of the first major commercial applications of recombinant DNA. It also laid the foundation for the biotechnology industry, allowing scientists to create medicines and therapies in ways that were previously impossible. Genentech, founded by one of the scientists Herbert Boyer and ex-venture capitalist Robert A. Swanson, commercialized insulin, and it went public in 1980, making it one of the first biotech firms to do so.
Now, alt protein companies like Every use the same technology to produce animal proteins by taking advantage of the natural fermentation process.
Fermentation has been used by humans for thousands of years to produce food and drink, and it is still used in many of the same ways today. It is a natural metabolic process where microorganisms, like yeasts or bacteria, convert sugar into other products like alcohol, acids, or gases. Beer, cheese, sake, yogurt, kimchi, and bread are all produced through fermentation.
However, in nature, fermentation cannot produce anything it wants. This is where recombinant DNA comes in. You can give microorganisms like yeasts genetic instructions so that they can produce what we desire like egg proteins through their fermentation.
I’d imagine that the simplified steps of eggs protein precision fermentation look like this:
- Gene Extraction: Scientists first extract the desired gene from the source DNA using DNA-cutting enzymes called Restriction enzymes. For example, they can take the gene responsible for egg proteins production from chicken’s DNA.
- Inserting the Gene: The gene is inserted into plasmids of a host organism, such as bacteria or yeasts cells. The plasmids are like tiny bonus instruction booklets inside the cell. Then these host organisms will act as tiny factories for producing the desired egg proteins.
- Growing the Cells: The genetically modified organisms, which carries the recombinant DNA, are grown in a controlled environment like large cultures or bioreactors. They are fed sugar or other nutrients. As they multiply, they express the egg proteins encoded by the inserted recombinant DNA.
- Harvesting: The target product (e.g., egg proteins) is collected from the cell culture and purified using techniques like centrifugation, filtration, chromatography, or precipitation before production.
Precision fermentation should be much more scalable today compared to capex-heavy solutions like cultivated meat. It may be a good mid-term solution or a viable option for some forms of animal proteins.
Beyond the Natural - Cultivated Meat and the Fallacy of Nature’s Goodness
Cultivated meat has many challenges, such as regulatory approval, high costs, scaling, and the reproduction of taste and flavor. But none of these would matter if people don’t buy it. I am optimistic that someday we can cultivate meat that people want, but branding is a challenge. The common reason why people wouldn’t want to try it is that it is not natural.
When you go shopping in San Francisco, you sooner or later notice that many products are presented as natural products. In supermarkets, you’ll find vegetables marketed as “naturally grown without pesticides,” water bottles branded as “natural,” and spices labeled as “natural without additives” or “Non-MSG.” In pharmacies, shampoo is promoted as “organic” (a synonym for natural), moisturizers are advertised as “100% natural,” and cleaning products are touted as “free from synthetic chemicals” or “Non-GMO.”
Consumers are increasingly buying organic food. It’s wonderful that they are choosing products that benefit both our planet and our health. It’s also fantastic that many companies are responding to this demand by creating such products.
Many natural products are good for you, and people who love them will probably get more benefits than those who don’t care much.
However, natural isn’t always good, just as something unnatural isn’t always bad. Nature is filled with products that, while entirely natural, can be highly toxic, like poisonous mushrooms and castor beans. Many “unnatural” foods and medicines offer real health benefits, from synthetic vitamins that address nutrient gaps, to mRNA vaccines for COVID-19 and insulin for type 1 diabetes.
At first, I thought this pervasive disbelief in unnatural products stemmed from corporate propaganda mainly by food and cosmetic household products companies, but this may have been just a reaction to public needs.
Industrialization brought artificial products that had enormous negative externalities on human health and environmental pollution. Our parents may still remember DDT, a pesticide once hailed for its effectiveness but later banned due to its detrimental environmental and health impacts. Asbestos, a once-popular material praised for its heat resistance and durability in construction, was banned or restricted worldwide after it was found to cause serious respiratory diseases, including lung cancer and mesothelioma. Lead-based paints, once valued for their vibrant colors and durability, were eventually banned due to their neurotoxic effects, which are especially harmful to children.
It’s understandable that people began to equate artificial with bad and view its opposite, natural, as good. The term natural has become so prevalent in marketing campaigns probably in response to this fear.
However, overvaluing natural or organic foods is misguided, just as overvaluing appearance in people is. This leads to judging others based on their looks and foods based solely on their naturalness, despite the existence of beneficial unnatural foods.
This trend is challenging for alt-protein companies that are trying to bring meat alternatives to the market. That said, when the benefits outweigh their skepticism of trying something unnatural, people are willing to try unnatural products such as insulin and botox.
Thus, cultivated meat companies and alt-protein companies in general, need to make 10x better products to overcome skepticism against unnatural foods.
Sperm Donation in Social Networks
In Japan, men are using social networks like X to offer sperm donations for free under hashtags such as #精子提供. Some donors have become prolific, with one reportedly donating around 100 times a year, leading to the birth of over 50 children. But why would women turn to strangers for sperm donations? Japan’s public broadcaster, NHK, has documented the stories of women conceiving children through these informal sperm donations.
I learned that Japanese law only allows sperm donation in hospitals for married couples where the husband is diagnosed with aspermia. These strict regulations have inadvertently created an underground market where single women by choice and sexual minorities seek sperm from strangers.
The growing number of single mothers by choice (a number that has tripled since 2000) and sexual minority couples reflects a wider gap between the traditional legal assumptions and the reality of Japan’s evolving family structures. With no legal recourse, some women are left to navigate risky, unregulated channels.
After obtaining sperm, most women perform at-home inseminations using intrauterine insemination (IUI). This typically involves a needle-free syringe to inject sperm directly into the cervix or uterus, bypassing intercourse.
While some donors, including sexual minorities, genuinely want to help women conceive, there have also been troubling reports of donors engaging in sexual harassment. Additionally, without proper medical oversight, women are exposed to potential health risks, including sexually transmitted infections, hepatitis, HIV, and other viral diseases. Some individuals do conduct their own testing, but it is far from the rigor of clinical screening.
International sperm banks could provide a safer alternative if Japanese women are willing to accept sperm from other races. However, many women choose informal networks due to financial constraints. Overseas sperm banks involve costs for the sperm, shipping, and sometimes expensive travel and hospital treatments. In contrast, social network donations are usually free, with only minimal expenses for transportation and testing.
As new reproductive technologies emerge, policymakers will be faced with more challenges where they need to account for sexual diversity and new family forms to protect people against unsafe environments such as this underground sperm market.
Embryo Selection
When you are in San Francisco, you get to meet a lot of interesting people with interesting ideas. Among all the interesting ideas I’ve heard this year, the wildest one was embryo selection for cosmetic purposes. I cannot give you too many details for their privacy, but they have already raised millions of dollars from investors and have been providing their embryo selection service privately. The team seems legit, with founders from MIT.
Their embryo selection service is built on in vitro fertilization (IVF), which helps fertilize an egg outside a body. IVF is already so common that more than 5 million babies have been born through this technology. The company focuses on the software side of things by analyzing different embryos provided by their customers through IVF.
You may be thinking that their service is nothing noble because it has been common to choose embryos based on gender or for therapeutic reasons. For example, you can deterministically figure out if a baby has genetic diseases like Down syndrome and sickle cell disease, and parents can already choose not to grow these embryos.
Here is their catch. They help you choose the best embryo for cosmetic reasons. They analyze relationships between gene sequences and some traits like intelligence, attractiveness, creativity, and other factors using a genome database from a biobank like The UK Biobank. The founder told me that although these traits can be determined only probabilistically, the best embryo’s standard deviation is +12%, which means it is 12% better than the average. This is significant when you compare the most intelligent embryo with the least intelligent one which you might choose randomly without their analysis.
It sounded like it was not their initial plan to focus on cosmetic selection, but they started gaining traction when they introduced it.
I bet that with the democratization of techniques like In vitro fertilization (IVF) and in vitro gametogenesis (IVG), we will have an abundance of embryos in the future. With that, embryo selection will be much more common. Our normal way of fertilization will be a lot less common and sex will be done only for pleasure.
What was once limited to choosing an embryo free of genetic disorders could evolve into a world where parents can shape the very essence of their child’s future based on genetic data in the not-too-distant future. Perhaps, in our lifetime, we might find ourselves discussing, over ramen in the city, which embryo we should choose with our partner.
From Skin Cells to Sperm
I went to San Mateo this Friday to see my new friend, who was a bioscientist at Stanford. We were talking about a variety of topics over ramen (definitely try Taishoken Ramen if you are in the Bay Area!), and at some point, we started discussing gender inequality and how artificial wombs (aka, ectogenesis) can reduce the high burden of pregnancy. Then he introduced me to a technique called in vitro gametogenesis (IVG). It turns somatic cells, which are basically regular cells such as skin or muscle cells that make up most of your body, into gametes like sperm and eggs.
This is interesting because people with fertility problems can have their genetic children without getting gametes from donors. Also, sexual minority couples of both sexes could have genetic children that are genetically related to both of them, although male couples would need a surrogate mother.
In short, you create induced pluripotent stem cells (iPSCs) from somatic cells and guide them through various stages of development into functional gametes.
iPSCs are undifferentiated cells that can change into anything, including sperm or eggs, similar to a fertilized egg. The beauty of iPSCs is that you can create these undifferentiated cells by reprogramming somatic cells.
Once you get an egg or sperms, you can fertilize them through In vitro fertilization (IVF) to create an embryo.
This process still faces many challenges in humans, even though it works in other animals. Additionally, producing eggs is more difficult than producing sperm.
If you enjoy dystopian sci-fi, you may have envisioned intriguing concepts like unibaby, where one person produces both sperm and an egg to conceive a child. Additionally, since it’s easy to steal a somatic cell—such as after someone drinks a cup of coffee—genome theft could become more prevalent for acquiring the genetic material of celebrities.
Illegal Sheep Cloning and Breeding
Arthur “Jack” Schubarth, an 81-year-old breeder in Montana has been jailed for six months for cloning the world’s largest sheep from Kyrgyzstan(Marco Polo argali sheep) and selling its offspring at high prices for trophy hunting.
It is reported that the semen from the cloned sheep was used to artificially breed more ewes, all to breed a more valuable sheep species. One of those offspring sold for $10,000.
But how was the sheep cloned? Typically, reproduction requires an egg from a female and sperm from a male. However, this method does not result in an identical offspring.
The breeder sent the genetic material to a lab to create cloned embryos. In the lab, they probably used somatic cell nuclear transfer (SCNT). This technique can produce embryos that are genetically identical to the donor animal without fertilization. Dolly the sheep was born this way.
In SCNT, the nucleus of a somatic cell from an adult organism is inserted into an egg cell that had its own nucleus removed. You can take a somatic cell from almost any part of the body, as long as the cell contains a complete set of DNA. The important part is that the cell used contains a healthy, intact nucleus with the complete DNA sequence of the organism you wish to clone.
From Wikipedia.
Once you have the egg with the nucleus of the donor, you stimulate the egg to begin development. Then the resulting embryo is implanted into a surrogate mother, leading to the birth of a genetically identical clone of the original organism like Dolly.
The breeder paid only $4,200 to the lab. It’s astonishing that a breeder can clone a rare sheep for profit with such a small amount. I believe this story marks the beginning of illegal genetic engineering practices. As gene engineering becomes more accessible, we can expect to see more illegal activities like this in the future.