A rendering of a 3D-printed burger.
Imagine it's 2050. You wake up and make breakfast: fluffy scrambled eggs that didn't come from a chicken, but that taste identical to the ones you remember eating as a kid. You would never know that the egg protein on your plate, ovalbumin, was developed in an industrial bioreactor using fungi.
"We have this freedom to operate, freedom to engineer way beyond what we have now with livestock or plants."
For lunch, you head to your kitchen's 3D printer and pop in a cartridge, select your preferred texture and flavor, then stand back while your meal is chemically assembled. Afterward, for dessert, you snack on some chocolate that tastes more delicious than the truffles of the past. That's because these cocoa beans were gene-edited to improve their flavor.
2050 is not a random year –it's when the United Nations estimates that the world population will have ballooned to nearly 10 billion people. That's a staggering number of mouths to feed. So, scientists are already working on ways to make new food products that are unlike anything we consume today, but that could offer new, potentially improved nutritional choices and sustainable options for the masses. To whet your appetite, here are three futuristic types of food that are currently in development around the world:
1) Cellular Agriculture
Researchers at VTT Technical Research Centre of Finland, a leading R&D organization in Europe, are on the cutting-edge of developing a whole new ecosystem of food with novel ingredients and novel functionality.
In the high-tech world of cellular agriculture, single-cell organisms can be used in contained environments to produce food ingredients that are identical to traditionally sourced ingredients. For example, whey protein can be developed inside a bioreactor that is functionally the same as the kind in cow's milk.
Ditto for eggs without a chicken – so the world will finally know which came first.
The steel tank bioreactors in VTT´s piloting facility are used to grow larger amounts of plant cells or to brew dairy and egg proteins with microbes.
(VTT)
"We take the gene from a chicken genome, and place that in a microbe, and then the microbe can, with those instructions, make exactly the same protein," explains Lauri Reuter, a Senior Specialist at VTT who holds a doctorate in biotechnology. "It will swim in this bioreactor and kick out the protein, and we get this liquid that can be purified. Then you would cook or bake with it, and the food you would eat tastes and looks like food you would eat right now."
But why settle for what chickens can do? With this technology, it's possible, for example, to modify the ovalbumin protein to decrease its allergenicity.
"This is the power of what we can do with modern tools of genetic engineering," says Christopher Landowski,a Research Team Leader of the Protein Production Team. And the innovative potential doesn't stop there.
"We have this freedom to operate, freedom to engineer way beyond what we have now with livestock or plants," Reuter says. Future foods sourced from cells could include meat analogues, sugar substitutes, dairy substitutes, nutritious veggies that don't taste bitter, personalized nutrition – ingredients designed for individual needs; the list goes on. It could even be used one day to produce food on Mars.
The researchers emphasize the advantages of this method: their living cell factories are efficient – no care of complex animals is required; they can scale up or down in reaction to demand; their environments are contained and don't require antibiotics; and they provide an alternative to using animals.
But the researchers also readily admit that the biggest obstacle is consumer acceptance, which is why they seek to engage with people along the way to alleviate any concerns and to educate them about the technology. Novel foods of this sort have already been eaten in research settings, but it may take another three to five years before the egg and milk proteins hit the market, probably first in the United States before Europe.
Eventually, the researchers anticipate widespread adoption.
Emilia Nordlund, who directs the Food Solutions team, predicts, "Cellular agriculture will revolutionize the food industry as dramatically as the Internet revolutionized many other industries."
Jams made of culture cells of various plants: strawberry, scurvy grass, arctic bramble, tobacco, cloudberry and lingonberry.
(VTT/Lauri Reuter)
2) 3D-printed foods
In South Korea, researchers are developing 3D-printed foods to help solve a problem caused by aging. Elderly people often rely on soft foods which are easier to chew, but aren't always healthy, like Jello and pudding.
With 3D printing, foods of softer textures can be created with the same nutritional value as firmer food, via a processing method that breaks down the food into tiny nutrients by grinding it at a very low temperature with liquid nitrogen.
"The goal is that someone at home can print out food with whatever flavor and texture they want."
The micro-sized food materials are then reconstructed in layers to form what looks like a Lego block. "The cartridges are all textures, some soft and some stiff," explains Jin-Kyu Rhee, associate professor at Ewha Womans University, whose project has been funded for the last three years by the South Korean government. "We are developing a library of food textures, so that people can combine them to simulate a real type of food."
Users could then add powdered versions of various ingredients to create customized food. Flavor, of course, is of prime importance too, so the cartridges have flavors like barbecue to help simulate the experience of eating "real" food.
"The goal is that someone at home can print out food with whatever flavor and texture they want," Rhee says. "They can order their own cartridge and digital recipes to generate their own food, ready to cook with a microwave oven." It could also be used for space travel.
Rhee expects the prototype of the printer to be completed by the end of this year and will then seek out a commercial partner. If all goes well, you might be able to set up your 3D printer next to your coffee pot by 2025.
3) CRISPR-edited foods
You may not know that the cocoa plant is having a tough time out there in nature. It's plagued by fungal disease; on farms, about 30 to 40 percent of the potential cocoa beans are lost every year. For all the chocolate lovers of the world, this means less to go around.
Conventional plant breeding is very slow for trees, so researchers like Mark Guiltinan at Penn State University are devising ways to increase the plants' chances for survival – without moving any genes between species, as in genetically modified organisms (GMOs).
"Because society hasn't really embraced [GMOs] very much, we're trying to develop ways that don't use transgenic plants and speed up breeding," Guiltinan says.
He and his colleagues are using CRISPR-cas9, the precise method of editing DNA, to imbue cocoa plants with immunity to fungal disease.
How does it work? Similar to humans, the plants have an immune system. Part of it functions like brakes, repressing the whole system so it's only working when it needs to.
"Like when you get a fever, your immune system is working full blast, but your body shuts it down when it doesn't need it," he explains. "Plants do exactly the same thing. One idea is if we can reduce or eliminate that brake on the immune system, we could make plants that have a very high immunity."
A CRISPR-edited npr3 mutant cacao plantlet, not too much to see yet, but soon it will become a happy plant in the greenhouse.
(Photo credit: Mark Guiltinan)
The CRISPR-cas9 system allows "a really amazing little protein" to go into the cocoa plant cell, find a specific gene, and shut it off to put the whole immune system into overdrive. This confers the necessary immunity, and though the plant burns through a lot of energy, as if it has a fever all the time, this method would allow for more plants to fend off the fungal attacks every year. Which means more chocolate. It could also greatly reduce the need for pesticides.
"Replacing chemicals with genetics is one part of our goal," Guiltinan says. "And it's totally safe." Another goal of his project is to improve the cocoa beans' quality and flavor profile through gene editing.
Yum. Is your mouth watering yet?
Probiotic bacteria can be engineered to fight antibiotic-resistant superbugs by releasing chemicals that kill them.
In recent years, researchers have been exploring a promising avenue: the use of synthetic biology to engineer new bacteria that may work better than antibiotics. The need continues to grow, as a Lancetstudy linked antibiotic resistance to over 1.27 million deaths worldwide in 2019, surpassing HIV/AIDS and malaria. The western sub-Saharan Africa region had the highest death rate (27.3 people per 100,000).
Researchers warn that if nothing changes, by 2050, antibiotic resistance could kill 10 million people annually.
To make it worse, our remedy pipelines are drying up. Out of the 18 biggest pharmaceutical companies, 15 abandoned antibiotic development by 2013. According to the AMR Action Fund, venture capital has remained indifferent towards biotech start-ups developing new antibiotics. In 2019, at least two antibiotic start-ups filed for bankruptcy. As of December 2020, there were 43 new antibiotics in clinical development. But because they are based on previously known molecules, scientists say they are inadequate for treating multidrug-resistant bacteria. Researchers warn that if nothing changes, by 2050, antibiotic resistance could kill 10 million people annually.
The rise of synthetic biology
To circumvent this dire future, scientists have been working on alternative solutions using synthetic biology tools, meaning genetically modifying good bacteria to fight the bad ones.
From the time life evolved on earth around 3.8 billion years ago, bacteria have engaged in biological warfare. They constantly strategize new methods to combat each other by synthesizing toxic proteins that kill competition.
For example, Escherichia coli produces bacteriocins or toxins to kill other strains of E.coli that attempt to colonize the same habitat. Microbes like E.coli (which are not all pathogenic) are also naturally present in the human microbiome. The human microbiome harbors up to 100 trillion symbiotic microbial cells. The majority of them are beneficial organisms residing in the gut at different compositions.
The chemicals that these “good bacteria” produce do not pose any health risks to us, but can be toxic to other bacteria, particularly to human pathogens. For the last three decades, scientists have been manipulating bacteria’s biological warfare tactics to our collective advantage.
In the late 1990s, researchers drew inspiration from electrical and computing engineering principles that involve constructing digital circuits to control devices. In certain ways, every cell in living organisms works like a tiny computer. The cell receives messages in the form of biochemical molecules that cling on to its surface. Those messages get processed within the cells through a series of complex molecular interactions.
Synthetic biologists can harness these living cells’ information processing skills and use them to construct genetic circuits that perform specific instructions—for example, secrete a toxin that kills pathogenic bacteria. “Any synthetic genetic circuit is merely a piece of information that hangs around in the bacteria’s cytoplasm,” explains José Rubén Morones-Ramírez, a professor at the Autonomous University of Nuevo León, Mexico. Then the ribosome, which synthesizes proteins in the cell, processes that new information, making the compounds scientists want bacteria to make. “The genetic circuit remains separated from the living cell’s DNA,” Morones-Ramírez explains. When the engineered bacteria replicates, the genetic circuit doesn’t become part of its genome.
Highly intelligent by bacterial standards, some multidrug resistant V. cholerae strains can also “collaborate” with other intestinal bacterial species to gain advantage and take hold of the gut.
In 2000, Boston-based researchers constructed an E.coli with a genetic switch that toggled between turning genes on and off two. Later, they built some safety checks into their bacteria. “To prevent unintentional or deleterious consequences, in 2009, we built a safety switch in the engineered bacteria’s genetic circuit that gets triggered after it gets exposed to a pathogen," says James Collins, a professor of biological engineering at MIT and faculty member at Harvard University’s Wyss Institute. “After getting rid of the pathogen, the engineered bacteria is designed to switch off and leave the patient's body.”
Overuse and misuse of antibiotics causes resistant strains to evolve
Adobe Stock
Seek and destroy
As the field of synthetic biology developed, scientists began using engineered bacteria to tackle superbugs. They first focused on Vibrio cholerae, whichin the 19th and 20th century caused cholera pandemics in India, China, the Middle East, Europe, and Americas. Like many other bacteria, V. cholerae communicate with each other via quorum sensing, a process in which the microorganisms release different signaling molecules, to convey messages to its brethren. Highly intelligent by bacterial standards, some multidrug resistant V. choleraestrains can also “collaborate” with other intestinal bacterial species to gain advantage and take hold of the gut. When untreated, cholera has a mortality rate of 25 to 50 percent and outbreaks frequently occur in developing countries, especially during floods and droughts.
Sometimes, however, V. cholerae makes mistakes. In 2008, researchers at Cornell University observed that when quorum sensing V. cholerae accidentally released high concentrations of a signaling molecule called CAI-1, it had a counterproductive effect—the pathogen couldn’t colonize the gut.
So the group, led byJohn March, professor of biological and environmental engineering, developed a novel strategy to combat V. cholerae. They genetically engineered E.coli toeavesdrop on V. cholerae communication networks and equipped it with the ability to release the CAI-1 molecules. That interfered with V. cholerae progress.Two years later, the Cornell team showed that V. cholerae-infected mice treated with engineered E.coli had a 92 percent survival rate.
These findings inspired researchers to sic the good bacteria present in foods like yogurt and kimchi onto the drug-resistant ones.
Three years later in 2011, Singapore-based scientists engineered E.coli to detect and destroy Pseudomonas aeruginosa, an oftendrug-resistant pathogen that causes pneumonia, urinary tract infections, and sepsis. Once the genetically engineered E.coli found its target through its quorum sensing molecules, it then released a peptide, that could eradicate 99 percent of P. aeruginosa cells in a test-tube experiment. The team outlined their work in a Molecular Systems Biology study.
“At the time, we knew that we were entering new, uncharted territory,” says lead author Matthew Chang, an associate professor and synthetic biologist at the National University of Singapore and lead author of the study. “To date, we are still in the process of trying to understand how long these microbes stay in our bodies and how they might continue to evolve.”
More teams followed the same path. In a 2013 study, MIT researchers also genetically engineered E.coli to detect P. aeruginosa via the pathogen’s quorum-sensing molecules. It then destroyed the pathogen by secreting a lab-made toxin.
Probiotics that fight
A year later in 2014, a Nature study found that the abundance of Ruminococcus obeum, a probiotic bacteria naturally occurring in the human microbiome, interrupts and reduces V.cholerae’s colonization—by detecting the pathogen’s quorum sensing molecules. The natural accumulation of R. obeumin Bangladeshi adults helped them recover from cholera despite living in an area with frequent outbreaks.
Engineered bacteria can be trained to target pathogens when they are at their most vulnerable metabolic stage in the human gut. --José Rubén Morones-Ramírez.
These findings inspired researchers to sic the good bacteria present in foods like yogurt and kimchi onto the drug-resistant ones. So far, researchers have engineered various probiotic organisms to fight pathogenic bacteria like Staphylococcus aureus (leading cause of skin, tissue, bone, joint and blood infections) and Clostridium perfringens (which causes watery diarrhea) in test-tube and animal experiments. In 2020, Russian scientists engineered a probiotic called Pichia pastoris to produce an enzyme called lysostaphin that eradicated S. aureus in vitro. Another 2020 study from China used an engineered probiotic bacteria Lactobacilli casei as a vaccine to prevent C. perfringens infection in rabbits.
In a study last year, Ramírez’s group at the Autonomous University of Nuevo León, engineered E. coli to detect quorum-sensing molecules from Methicillin-resistant Staphylococcus aureus or MRSA, a notorious superbug. The E. coli then releases a bacteriocin that kills MRSA. “An antibiotic is just a molecule that is not intelligent,” says Ramírez. “On the other hand, engineered bacteria can be trained to target pathogens when they are at their most vulnerable metabolic stage in the human gut.”
Collins and Timothy Lu, an associate professor of biological engineering at MIT, found that engineered E. coli can help treat other conditions—such as phenylketonuria, a rare metabolic disorder, that causes the build-up of an amino acid phenylalanine. Their start-up Synlogic aims to commercialize the technology, and has completed a phase 2 clinical trial.
Circumventing the challenges
The bacteria-engineering technique is not without pitfalls. One major challenge is that beneficial gut bacteria produce their own quorum-sensing molecules that can be similar to those that pathogens secrete. If an engineered bacteria’s biosensor is not specific enough, it will be ineffective.
Another concern is whether engineered bacteria might mutate after entering the gut. “As with any technology, there are risks where bad actors could have the capability to engineer a microbe to act quite nastily,” says Collins of MIT. But Collins and Ramírez both insist that the chances of the engineered bacteria mutating on its own are virtually non-existent. “It is extremely unlikely for the engineered bacteria to mutate,” Ramírez says. “Coaxing a living cell to do anything on command is immensely challenging. Usually, the greater risk is that the engineered bacteria entirely lose its functionality.”
However, the biggest challenge is bringing the curative bacteria to consumers. Pharmaceutical companies aren’t interested in antibiotics or their alternatives because it’s less profitable than developing new medicines for non-infectious diseases. Unlike the more chronic conditions like diabetes or cancer that require long-term medications, infectious diseases are usually treated much quicker. Running clinical trials are expensive and antibiotic-alternatives aren’t lucrative enough.
“Unfortunately, new medications for antibiotic resistant infections have been pushed to the bottom of the field,” says Lu of MIT. “It's not because the technology does not work. This is more of a market issue. Because clinical trials cost hundreds of millions of dollars, the only solution is that governments will need to fund them.” Lu stresses that societies must lobby to change how the modern healthcare industry works. “The whole world needs better treatments for antibiotic resistance.”
Today's podcast guest, Dr. Renee Wegrzyn, directs ARPA-H, a new agency formed last year to spearhead health innovations. Time will tell if ARPA-H will produce advances on the level of its fellow agency, DARPA.
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How will the agency figure out which projects to take on, especially with so many patient advocates for different diseases demanding moonshot funding for rapid progress?
I talked with Dr. Wegrzyn about the opportunities and challenges, what lessons ARPA-H is borrowing from Operation Warp Speed, how she decided on the first ARPA-H project that was announced recently, why a separate agency was needed instead of reforming HHS and the National Institutes of Health to be better at innovation, and how ARPA-H will make progress on disease prevention in addition to treatments for cancer, Alzheimer’s and diabetes, among many other health priorities.
Dr. Wegrzyn’s resume leaves no doubt of her suitability for this role. She was a program manager at DARPA where she focused on applying gene editing and synthetic biology to the goal of improving biosecurity. For her work there, she received the Superior Public Service Medal and, in case that wasn’t enough ARPA experience, she also worked at another ARPA that leads advanced projects in intelligence, called I-ARPA. Before that, she ran technical teams in the private sector working on gene therapies and disease diagnostics, among other areas. She has been a vice president of business development at Gingko Bioworks and headed innovation at Concentric by Gingko. Her training and education includes a PhD and undergraduate degree in applied biology from the Georgia Institute of Technology and she did her postdoc as an Alexander von Humboldt Fellow in Heidelberg, Germany.
Dr. Wegrzyn told me that she’s “in the hot seat.” The pressure is on for ARPA-H especially after the need and potential for health innovation was spot lit by the pandemic and the unprecedented speed of vaccine development. We'll soon find out if ARPA-H can produce gamechangers in health that are equivalent to DARPA’s creation of the internet.
Show links:
ARPA-H - https://arpa-h.gov/
Dr. Wegrzyn profile - https://arpa-h.gov/people/renee-wegrzyn/
Dr. Wegrzyn Twitter - https://twitter.com/rwegrzyn?lang=en
President Biden Announces Dr. Wegrzyn's appointment - https://www.whitehouse.gov/briefing-room/statement...
Leaps.org coverage of ARPA-H - https://leaps.org/arpa/
ARPA-H program for joints to heal themselves - https://arpa-h.gov/news/nitro/ -
ARPA-H virtual talent search - https://arpa-h.gov/news/aco-talent-search/
Dr. Renee Wegrzyn was appointed director of ARPA-H last October.