A conventionally sourced sea bass from a fishery.
Ever wonder why you've never heard of wild-caught organic fish? It's because there's no way to certify a food that has a mysterious history. Mike Selden, a 26-year-old biochemist with an animal lover's heart and an entrepreneur's mind, decided there must be better way to consume one of our planet's primary sources of animal protein. A way that would eliminate the need to kill billions of fish per year while also producing toxin-free, cheap, delicious fish meat for your dinner table. Enter Finless Foods, a young startup with a bold vision. Selden took time out of chauffeuring fish carcasses around San Francisco (no joke!) to share his journey with LeapsMag.
What is the biggest problem with the way fish is consumed today?
There are a lot of problems ranging from metals to animal welfare to human health. Technology is solving those problems at the same time. You've got extreme over fishing, which is collapsing ocean ecosystems and removing populations of fish that are traditionally used as food sources in developing nations.
In terms of animal welfare, fish are killed in massive numbers, billions a year. Even if people don't care too much about that, we want to give them another option.
In terms of health, which I think for most people is the most convincing argument, current fish have mercury and plastic in them. And if you're getting that fish from a farm, you will also have high levels of antibiotics and growth hormones if you're getting it from outside the U.S. What we're doing is producing fish that doesn't have any of those contaminants.
What gave you the idea to start a company around lab-grown fish?
I studied biochemistry and molecular biology at UMass Amherst, traditionally an agricultural school out in the woods of Massachusetts. I have always been an environmental activist and cared about animals. I thought, animal agriculture is so incredibly inefficient, what could be done to change it?
"The worst way you can possibly make a hamburger is with a cow."
Agriculture is a system of inputs and outputs, the inputs being feed and the outputs being meat – so why are we wasting all of this input on outputs we don't care about? Why are we creating these animals that waste all this energy through sitting around, moving around, having a heartbeat, blinking? All of this uses energy and that's valuable input.
The worst way you can possibly make a hamburger is with a cow. It's an awful transfer of energy: you have to feed it many times its own weight in food that could have fed other people or other things.
In February, I got funding from Indie Bio, a startup accelerator for synthetic biology, and moved out to San Francisco with my co-founder Brian Wyrwas. We started working in our lab in March. We're the newest company in the space.
Walk me through the process of creating edible fish in the lab. Do you have to catch a real live fish first and get their cells?
We have a deal with the Aquarium of the Bay, and whenever a fish dies, they call me, I get in a zip car, drive over, and bring the fish back to the lab, where Brian cultures it up into a cell culture. We do use real, high-quality fish stock. From there, we get the cells going in a bioreactor in a suspension culture, grow them into large quantities, and then bring them out to differentiate them into the cells people want to eat—the muscle and fat tissue. Then we formulate it and bring it to people's tables.
How long does the whole process take from the phone call about the fish dying to the food on the table?
There are two different processes: One is a research process, getting the initial cells and engineering them to be what we're looking for.
The other is a production process – we have a cell line ready and need to grow it out. That timing depends on how big of a facility we have. Since we're working with cell division: If you have 1 cell, in 24 hours, you'll have two cells. Let's say you have 1 ton of cells, in 24 hours you'll have two tons of cells.
"We want to give people the wholesome food they are used to in a healthier setting."
How are you looking to scale this process?
We're trying to find a middle ground between efficiency and local distribution. Organic farming is hilariously bad for the environment and horrifyingly inefficient, but on the other hand, industrial agriculture requires lots of transport, which is also bad for the environment. We're looking to create regionally distributed facilities which don't require a lot of transit, so people can have fresh fish even extremely far inland.
What kinds of fish are you "cooking"?
Our first product will be Bluefin tuna. It's a high-quality fish with high demand and it's also a conservation issue. We also currently have a culture going with Branzino, European sea bass, that we're really happy with.
There's a concept in science called a model organism – one that is extremely well studied and understood. Like the fruit fly, for example. For fish, it's the zebra fish, which is used for genetic research, but no one eats it. It's tiny, so we started by thinking: what fish do people eat that is also close evolutionarily to the zebra fish? We came up with carp, even though it's not too widely eaten.
But our process is very species agnostic. We've done work in trout, salmon, goldfish. Any fish with a dorsal fin works with our process. We tried a wolf eel but it didn't work. Eels are pretty far evolutionarily from fish, so we dropped that one.
From left to right, Ron Shigeta (IndieBio), Brian Wyrwas (Finless Foods), Amy Fleming (The Guardian), and Jihyun Kim (Finless Foods) tasting the first ever clean carp croquettes.
(Courtesy Mike Selden)
Why fish as opposed to, say, a cow?
Scientifically, there are a lot of advantages. Fish have a simpler structure than land animals. A fillet from a cow has complex marbling going on between the fat and muscle. When it's fish, like sashimi, it's in layers of muscle and fat. So it's simpler to build, plus fish are cold-blooded, so because they breathe underwater, our equipment needs less complexity. We don't need a CO2 line and we don't need to culture our cells at 37 degrees Celsius. We culture them at room temperature.
It's also easier to get to market since there's much higher value. Chicken in the last year was $3.84 per pound in America, whereas Bluefin tuna is between $100 and $1200 a pound. Because this is about dropping cost, we can get to market faster and give investors a better value proposition.
What's also cool is that something like Bluefin tuna is something many people haven't had the opportunity to eat. We can get these down in cost until there is price parity with any cheap conventional fish. We want to give people a choice between buying something like albacore tuna in a can –with mercury and plastic– or high-quality tuna without any contaminants for the same price.
Do you shape them like fish fillets to help the consumer overcome whatever discomfort they might feel about eating a bunch of lab-grown cells?
Yeah, people want to continue eating food they are eating, and that's fine. We want to give people a better option. We don't want to give them something weird and out there. We want to give them the wholesome food they are used to in a healthier setting that also solves some environmental issues.
How about the taste? Have you done any blind side-by-side tests with the real thing and your version?
Not blind taste tests. But we have been tasting it, and it is firmly fish. I even tried leaving it outside of the fridge – and man, that tasted like spoiled fish.
We want it to have the exact same properties as real fish. We don't want people to have to learn how to cook with it. We want them to just bring it into their homes and eat it exactly like they were doing before, but better.
What you're growing isn't the whole fish, right? It is not an actual organism?
Right, we're only growing muscle cells. It doesn't know where it is. There is no brain, nervous system, or pain receptors.
Are you the only people in this lab-grown food space working on fish?
We're the only ones doing fish so far. Other companies are doing chicken, duck, egg white, milk, gelatin, leather, and beef.
Are people generally weirded out by sci-fi lab food, or intrigued?
It's been very positive. When people sit down and talk to us, they realize it's not some crazed money grab or some weird Ted talk, it's real activists using real science trying to solve real problems. Sure, there will be some pushback from people who don't understand it, and that's fine.
When can I expect to see Finless Food at my local Whole Foods?
We plan on being in restaurants in two years, and grocery stores in four years.
What about people who aren't big fans of fish in the first place? Like those who don't eat sushi, because consuming something raw with an unknown history isn't very appetizing.
There are too many examples of food poisoning because fish are in a less clean environment than they should be, swimming around in their own fecal matter, and being doused in antibiotics so their diseases don't transmit. It's a bit of a mess. That's why as an industry, we're calling this clean meat. Fish is a healthy thing, or at least it should be, with Omega 3 and 6, and DHA. This is a way for people to continue getting those nutrients without any of the questions of where it came from. For people who are skeptical of fish, we invite you to dive in.
Brian Wyrwas, Co-Founder & CSO, and Mike Selden, Co-Founder & CEO
(Courtesy Mike Selden)
Recent advancements in engineering mean that the first preclinical trials for an artificial kidney could happen soon.
Still, the devices aren’t ready for testing in humans—yet. But recent advancements in engineering mean that the first preclinical trials for an artificial kidney could happen soon, according to Jonathan Himmelfarb, a nephrologist at the University of Washington.
“It would liberate people with kidney failure,” Himmelfarb says.
An engineering marvel
Compared to the heart or the brain, the kidney doesn’t get as much respect from the medical profession, but its job is far more complex. “It does hundreds of different things,” says UCLA’s Ira Kurtz.
Kurtz would know. He’s worked as a nephrologist for 37 years, devoting his career to helping those with kidney disease. While his colleagues in cardiology and endocrinology have seen major advances in the development of artificial hearts and insulin pumps, little has changed for patients on hemodialysis. The machines remain bulky and require large volumes of a liquid called dialysate to remove toxins from a patient’s blood, along with gallons of purified water. A kidney transplant is the next best thing to someone’s own, functioning organ, but with over 600,000 Americans on dialysis and only about 100,000 kidney transplants each year, most of those in kidney failure are stuck on dialysis.
Part of the lack of progress in artificial kidney design is the sheer complexity of the kidney’s job. Each of the 45 different cell types in the kidney do something different.
Part of the lack of progress in artificial kidney design is the sheer complexity of the kidney’s job. To build an artificial heart, Kurtz says, you basically need to engineer a pump. An artificial pancreas needs to balance blood sugar levels with insulin secretion. While neither of these tasks is simple, they are fairly straightforward. The kidney, on the other hand, does more than get rid of waste products like urea and other toxins. Each of the 45 different cell types in the kidney do something different, helping to regulate electrolytes like sodium, potassium, and phosphorous; maintaining blood pressure and water balance; guiding the body’s hormonal and inflammatory responses; and aiding in the formation of red blood cells.
There's been little progress for patients during Ira Kurtz's 37 years as a nephrologist. Artificial kidneys would change that.
UCLA
Dialysis primarily filters waste, and does so well enough to keep someone alive, but it isn’t a true artificial kidney because it doesn’t perform the kidney’s other jobs, according to Kurtz, such as sensing levels of toxins, wastes, and electrolytes in the blood. Due to the size and water requirements of existing dialysis machines, the equipment isn’t portable. Physicians write a prescription for a certain duration of dialysis and assess how well it’s working with semi-regular blood tests. The process of dialysis itself, however, is conducted blind. Doctors can’t tell how much dialysis a patient needs based on kidney values at the time of treatment, says Meera Harhay, a nephrologist at Drexel University in Philadelphia.
But it’s the impact of dialysis on their day-to-day lives that creates the most problems for patients. Only one-quarter of those on dialysis are able to remain employed (compared to 85% of similar-aged adults), and many report a low quality of life. Having more flexibility in life would make a major different to her patients, Harhay says.
“Almost half their week is taken up by the burden of their treatment. It really eats away at their freedom and their ability to do things that add value to their life,” she says.
Art imitates life
The challenge for artificial kidney designers was how to compress the kidney’s natural functions into a portable, wearable, or implantable device that wouldn’t need constant access to gallons of purified and sterilized water. The other universal challenge they faced was ensuring that any part of the artificial kidney that would come in contact with blood was kept germ-free to prevent infection.
As part of the 2021 KidneyX Prize, a partnership between the U.S. Department of Health and Human Services and the American Society of Nephrology, inventors were challenged to create prototypes for artificial kidneys. Himmelfarb’s team at the University of Washington’s Center for Dialysis Innovation won the prize by focusing on miniaturizing existing technologies to create a portable dialysis machine. The backpack sized AKTIV device (Ambulatory Kidney to Increase Vitality) will recycle dialysate in a closed loop system that removes urea from blood and uses light-based chemical reactions to convert the urea to nitrogen and carbon dioxide, which allows the dialysate to be recirculated.
Himmelfarb says that the AKTIV can be used when at home, work, or traveling, which will give users more flexibility and freedom. “If you had a 30-pound device that you could put in the overhead bins when traveling, you could go visit your grandkids,” he says.
Kurtz’s team at UCLA partnered with the U.S. Kidney Research Corporation and Arkansas University to develop a dialysate-free desktop device (about the size of a small printer) as the first phase of a progression that will he hopes will lead to something small and implantable. Part of the reason for the artificial kidney’s size, Kurtz says, is the number of functions his team are cramming into it. Not only will it filter urea from blood, but it will also use electricity to help regulate electrolyte levels in a process called electrodeionization. Kurtz emphasizes that these additional functions are what makes his design a true artificial kidney instead of just a small dialysis machine.
One version of an artificial kidney.
UCLA
“It doesn't have just a static function. It has a bank of sensors that measure chemicals in the blood and feeds that information back to the device,” Kurtz says.
Other startups are getting in on the game. Nephria Bio, a spinout from the South Korean-based EOFlow, is working to develop a wearable dialysis device, akin to an insulin pump, that uses miniature cartridges with nanomaterial filters to clean blood (Harhay is a scientific advisor to Nephria). Ian Welsford, Nephria’s co-founder and CTO, says that the device’s design means that it can also be used to treat acute kidney injuries in resource-limited settings. These potentials have garnered interest and investment in artificial kidneys from the U.S. Department of Defense.
For his part, Burton is most interested in an implantable device, as that would give him the most freedom. Even having a regular outpatient procedure to change batteries or filters would be a minor inconvenience to him.
“Being plugged into a machine, that’s not mimicking life,” he says.
This article was first published by Leaps.org on May 5, 2022.
New research focuses on methods that could change medicine-making worldwide. The scientists propose bursting cells open, removing their DNA and using the cellular gears inside to make therapies.
Rao and his team of collaborators, which spans multiple research institutions, believe they have a better approach that may change medicine-making worldwide. They suggest forgoing the concept of using living cells as medicine-producers. Instead, they propose breaking the cells and using the remaining cellular gears for assembling the therapeutic compounds. Instead of inserting the DNA into living cells, the team burst them open, and removed their DNA altogether. Yet, the residual molecular machinery of ribosomes, polymerases and other cogwheels still functioned the way it would in a cell. “Now if you drop your DNA drug-making instructions into that soup, this machinery starts making what you need,” Rao explains. “And because you're no longer worrying about living cells, it becomes much simpler and more efficient.” The collaborators detail their cell-free protein synthesis or CFPS method in their recent paper published in preprint BioAxiv.
While CFPS does not use living cells, it still needs the basic building blocks to assemble proteins from—such as amino acids, nucleotides and certain types of enzymes. These are regularly added into this “soup” to keep the molecular factory chugging. “We just mix everything in as a batch and we let it integrate,” says James Robert Swartz, professor of chemical engineering and bioengineering at Stanford University and co-author of the paper. “And we make sure that we provide enough oxygen.” Rao likens the process to making milk from milk powder.
For a variety of reasons—from the field’s general inertia to regulatory approval hurdles—the method hasn’t become mainstream. The pandemic rekindled interest in medicines that can be made quickly and easily, so it drew more attention to the technology.
The idea of a cell-free protein synthesis is older than one might think. Swartz first experimented with it around 1997, when he was a chemical engineer at Genentech. While working on engineering bacteria to make pharmaceuticals, he discovered that there was a limit to what E. coli cells, the workhorse darling of pharma, could do. For example, it couldn’t grow and properly fold some complex proteins. “We tried many genetic engineering approaches, many fermentation, development, and environmental control approaches,” Swartz recalls—to no avail.
“The organism had its own agenda,” he quips. “And because everything was happening within the organism, we just couldn't really change those conditions very easily. Some of them we couldn’t change at all—we didn’t have control.”
It was out of frustration with the defiant bacteria that a new idea took hold. Could the cells be opened instead, so that the protein-forming reactions could be influenced more easily? “Obviously, we’d lose the ability for them to reproduce,” Swartz says. But that also meant that they no longer needed to keep the cells alive and could focus on making the specific reactions happen. “We could take the catalysts, the enzymes, and the more complex catalysts and activate them, make them work together, much as they would in a living cell, but the way we wanted.”
In 1998, Swartz joined Stanford, and began perfecting the biochemistry of the cell-free method, identifying the reactions he wanted to foster and stopping those he didn’t want. He managed to make the idea work, but for a variety of reasons—from the field’s general inertia to regulatory approval hurdles—the method hasn’t become mainstream. The pandemic rekindled interest in medicines that can be made quickly and easily, so it drew more attention to the technology. For their BioArxiv paper, the team tested the method by growing a specific antiviral protein called griffithsin.
First identified by Barry O’Keefe at National Cancer Institute over a decade ago, griffithsin is an antiviral known to interfere with many viruses’ ability to enter cells—including HIV, SARS, SARS-CoV-2, MERS and others. Originally isolated from the red algae Griffithsia, it works differently from antibodies and antibody cocktails.
Most antiviral medicines tend to target the specific receptors that viruses use to gain entry to the cells they infect. For example, SARS-CoV-2 uses the infamous spike protein to latch onto the ACE2 receptor of mammalian cells. The antibodies or other antiviral molecules stick to the spike protein, shutting off its ability to cling onto the ACE2 receptors. Unfortunately, the spike proteins mutate very often, so the medicines lose their potency. On the contrary, griffithsin has the ability to cling to the different parts of viral shells called capsids—namely to the molecules of mannose, a type of sugar. That extra stuff, glued all around the capsid like dead weight, makes it impossible for the virus to squeeze into the cell.
“Every time we have a vaccine or an antibody against a specific SARS-CoV-2 strain, that strain then mutates and so you lose efficacy,” Rao explains. “But griffithsin molecules glom onto the viral capsid, so the capsid essentially becomes a sticky mess and can’t enter the cell.” Mannose molecules also don’t mutate as easily as viruses’ receptors, so griffithsin-based antivirals do not have to be constantly updated. And because mannose molecules are found on many viruses’ capsids, it makes griffithsin “a universal neutralizer,” Rao explains.
“When griffithsin was discovered, we recognized that it held a lot of promise as a potential antiviral agent,” O’Keefe says. In 2010, he published a paper about griffithsin efficacy in neutralizing viruses of the corona family—after the first SARS outbreak in the early 2000s, the scientific community was interested in such antivirals. Yet, griffithsin is still not available as an off-the-shelf product. So during the Covid pandemic, the team experimented with synthesizing griffithsin using the cell-free production method. They were able to generate potent griffithsin in less than 24 hours without having to grow living cells.
The antiviral protein isn't the only type of medicine that can be made cell-free. The proteins needed for vaccine production could also be made the same way. “Such portable, on-demand drug manufacturing platforms can produce antiviral proteins within hours, making them ideal for combating future pandemics,” Rao says. “We would be able to stop the pandemic before it spreads.”
Top: Describes the process used in the study. Bottom: Describes how the new medicines and vaccines could be made at the site of a future viral outbreak.
Image courtesy of Rao and team, sourced from An approach to rapid distributed manufacturing of broad spectrumanti-viral griffithsin using cell-free systems to mitigate pandemics.
Rao’s idea is to perfect the technology to the point that any hospital or pharmacy can load up the media containing molecular factories, mix up the required amino acids, nucleotides and enzymes, and harvest the meds within hours. That will allow making medicines onsite and on demand. “That would be a self-contained production unit, so that you could just ship the production wherever the pandemic is breaking out,” says Swartz.
These units and the meds they produce, will, of course, have to undergo rigorous testing. “The biggest hurdles will be validating these against conventional technology,” Rao says. The biotech industry is risk-averse and prefers the familiar methods. But if this approach works, it may go beyond emergency situations and revolutionize the medicine-making paradigm even outside hospitals and pharmacies. Rao hopes that someday the method might become so mainstream that people may be able to buy and operate such reactors at home. “You can imagine a diabetic patient making insulin that way, or some other drugs,” Rao says. It would work not unlike making baby formula from the mere white powder. Just add water—and some oxygen, too.