Forget Farm-to-Table: Lab-to-Table Fresh Fish Is Making Waves
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
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)
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
Jamie Rettinger was still in his thirties when he first noticed a tiny streak of brown running through the thumbnail of his right hand. It slowly grew wider and the skin underneath began to deteriorate before he went to a local dermatologist in 2013. The doctor thought it was a wart and tried scooping it out, treating the affected area for three years before finally removing the nail bed and sending it off to a pathology lab for analysis.
"I have some bad news for you; what we removed was a five-millimeter melanoma, a cancerous tumor that often spreads," Jamie recalls being told on his return visit. "I'd never heard of cancer coming through a thumbnail," he says. None of his doctors had ever mentioned it either. "I just thought I was being treated for a wart." But nothing was healing and it continued to bleed.
A few months later a surgeon amputated the top half of his thumb. Lymph node biopsy tested negative for spread of the cancer and when the bandages finally came off, Jamie thought his medical issues were resolved.
Melanoma is the deadliest form of skin cancer. About 85,000 people are diagnosed with it each year in the U.S. and more than 8,000 die of the cancer when it spreads to other parts of the body, according to the Centers for Disease Control and Prevention (CDC).
There are two peaks in diagnosis of melanoma; one is in younger women ages 30-40 and often is tied to past use of tanning beds; the second is older men 60+ and is related to outdoor activity from farming to sports. Light-skinned people have a twenty-times greater risk of melanoma than do people with dark skin.
"When I graduated from medical school, in 2005, melanoma was a death sentence" --Diwakar Davar.
Jamie had a follow up PET scan about six months after his surgery. A suspicious spot on his lung led to a biopsy that came back positive for melanoma. The cancer had spread. Treatment with a monoclonal antibody (nivolumab/Opdivo®) didn't prove effective and he was referred to the UPMC Hillman Cancer Center in Pittsburgh, a four-hour drive from his home in western Ohio.
An alternative monoclonal antibody treatment brought on such bad side effects, diarrhea as often as 15 times a day, that it took more than a week of hospitalization to stabilize his condition. The only options left were experimental approaches in clinical trials.
Early research
"When I graduated from medical school, in 2005, melanoma was a death sentence" with a cure rate in the single digits, says Diwakar Davar, 39, an oncologist at UPMC Hillman Cancer Center who specializes in skin cancer. That began to change in 2010 with introduction of the first immunotherapies, monoclonal antibodies, to treat cancer. The antibodies attach to PD-1, a receptor on the surface of T cells of the immune system and on cancer cells. Antibody treatment boosted the melanoma cure rate to about 30 percent. The search was on to understand why some people responded to these drugs and others did not.
At the same time, there was a growing understanding of the role that bacteria in the gut, the gut microbiome, plays in helping to train and maintain the function of the body's various immune cells. Perhaps the bacteria also plays a role in shaping the immune response to cancer therapy.
One clue came from genetically identical mice. Animals ordered from different suppliers sometimes responded differently to the experiments being performed. That difference was traced to different compositions of their gut microbiome; transferring the microbiome from one animal to another in a process known as fecal transplant (FMT) could change their responses to disease or treatment.
When researchers looked at humans, they found that the patients who responded well to immunotherapies had a gut microbiome that looked like healthy normal folks, but patients who didn't respond had missing or reduced strains of bacteria.
Davar and his team knew that FMT had a very successful cure rate in treating the gut dysbiosis of Clostridioides difficile, a persistant intestinal infection, and they wondered if a fecal transplant from a patient who had responded well to cancer immunotherapy treatment might improve the cure rate of patients who did not originally respond to immunotherapies for melanoma.
The ABCDE of melanoma detection
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Clinical trial
"It was pretty weird, I was totally blasted away. Who had thought of this?" Jamie first thought when the hypothesis was explained to him. But Davar's explanation that the procedure might restore some of the beneficial bacterial his gut was lacking, convinced him to try. He quickly signed on in October 2018 to be the first person in the clinical trial.
Fecal donations go through the same safety procedures of screening for and inactivating diseases that are used in processing blood donations to make them safe for transfusion. The procedure itself uses a standard hollow colonoscope designed to screen for colon cancer and remove polyps. The transplant is inserted through the center of the flexible tube.
Most patients are sedated for procedures that use a colonoscope but Jamie doesn't respond to those drugs: "You can't knock me out. I was watching them on the TV going up my own butt. It was kind of unreal at that point," he says. "There were about twelve people in there watching because no one had seen this done before."
A test two weeks after the procedure showed that the FMT had engrafted and the once-missing bacteria were thriving in his gut. More importantly, his body was responding to another monoclonal antibody (pembrolizumab/Keytruda®) and signs of melanoma began to shrink. Every three months he made the four-hour drive from home to Pittsburgh for six rounds of treatment with the antibody drug.
"We were very, very lucky that the first patient had a great response," says Davar. "It allowed us to believe that even though we failed with the next six, we were on the right track. We just needed to tweak the [fecal] cocktail a little better" and enroll patients in the study who had less aggressive tumor growth and were likely to live long enough to complete the extensive rounds of therapy. Six of 15 patients responded positively in the pilot clinical trial that was published in the journal Science.
Davar believes they are beginning to understand the biological mechanisms of why some patients initially do not respond to immunotherapy but later can with a FMT. It is tied to the background level of inflammation produced by the interaction between the microbiome and the immune system. That paper is not yet published.
Surviving cancer
It has been almost a year since the last in his series of cancer treatments and Jamie has no measurable disease. He is cautiously optimistic that his cancer is not simply in remission but is gone for good. "I'm still scared every time I get my scans, because you don't know whether it is going to come back or not. And to realize that it is something that is totally out of my control."
"It was hard for me to regain trust" after being misdiagnosed and mistreated by several doctors he says. But his experience at Hillman helped to restore that trust "because they were interested in me, not just fixing the problem."
He is grateful for the support provided by family and friends over the last eight years. After a pause and a sigh, the ruggedly built 47-year-old says, "If everyone else was dead in my family, I probably wouldn't have been able to do it."
"I never hesitated to ask a question and I never hesitated to get a second opinion." But Jamie acknowledges the experience has made him more aware of the need for regular preventive medical care and a primary care physician. That person might have caught his melanoma at an earlier stage when it was easier to treat.
Davar continues to work on clinical studies to optimize this treatment approach. Perhaps down the road, screening the microbiome will be standard for melanoma and other cancers prior to using immunotherapies, and the FMT will be as simple as swallowing a handful of freeze-dried capsules off the shelf rather than through a colonoscopy. Earlier this year, the Food and Drug Administration approved the first oral fecal microbiota product for C. difficile, hopefully paving the way for more.
An older version of this hit article was first published on May 18, 2021
All organisms have the capacity to repair or regenerate tissue damage. None can do it better than salamanders or newts, which can regenerate an entire severed limb.
That feat has amazed and delighted man from the dawn of time and led to endless attempts to understand how it happens – and whether we can control it for our own purposes. An exciting new clue toward that understanding has come from a surprising source: research on the decline of cells, called cellular senescence.
Senescence is the last stage in the life of a cell. Whereas some cells simply break up or wither and die off, others transition into a zombie-like state where they can no longer divide. In this liminal phase, the cell still pumps out many different molecules that can affect its neighbors and cause low grade inflammation. Senescence is associated with many of the declining biological functions that characterize aging, such as inflammation and genomic instability.
Oddly enough, newts are one of the few species that do not accumulate senescent cells as they age, according to research over several years by Maximina Yun. A research group leader at the Center for Regenerative Therapies Dresden and the Max Planck Institute of Molecular and Cell Biology and Genetics, in Dresden, Germany, Yun discovered that senescent cells were induced at some stages of regeneration of the salamander limb, “and then, as the regeneration progresses, they disappeared, they were eliminated by the immune system,” she says. “They were present at particular times and then they disappeared.”
Senescent cells added to the edges of the wound helped the healthy muscle cells to “dedifferentiate,” essentially turning back the developmental clock of those cells into more primitive states.
Previous research on senescence in aging had suggested, logically enough, that applying those cells to the stump of a newly severed salamander limb would slow or even stop its regeneration. But Yun stood that idea on its head. She theorized that senescent cells might also play a role in newt limb regeneration, and she tested it by both adding and removing senescent cells from her animals. It turned out she was right, as the newt limbs grew back faster than normal when more senescent cells were included.
Senescent cells added to the edges of the wound helped the healthy muscle cells to “dedifferentiate,” essentially turning back the developmental clock of those cells into more primitive states, which could then be turned into progenitors, a cell type in between stem cells and specialized cells, needed to regrow the muscle tissue of the missing limb. “We think that this ability to dedifferentiate is intrinsically a big part of why salamanders can regenerate all these very complex structures, which other organisms cannot,” she explains.
Yun sees regeneration as a two part problem. First, the cells must be able to sense that their neighbors from the lost limb are not there anymore. Second, they need to be able to produce the intermediary progenitors for regeneration, , to form what is missing. “Molecularly, that must be encoded like a 3D map,” she says, otherwise the new tissue might grow back as a blob, or liver, or fin instead of a limb.
Wound healing
Another recent study, this time at the Mayo Clinic, provides evidence supporting the role of senescent cells in regeneration. Looking closely at molecules that send information between cells in the wound of a mouse, the researchers found that senescent cells appeared near the start of the healing process and then disappeared as healing progressed. In contrast, persistent senescent cells were the hallmark of a chronic wound that did not heal properly. The function and significance of senescence cells depended on both the timing and the context of their environment.
The paper suggests that senescent cells are not all the same. That has become clearer as researchers have been able to identify protein markers on the surface of some senescent cells. The patterns of these proteins differ for some senescent cells compared to others. In biology, such physical differences suggest functional differences, so it is becoming increasingly likely there are subsets of senescent cells with differing functions that have not yet been identified.
There are disagreements within the research community as to whether newts have acquired their regenerative capacity through a unique evolutionary change, or if other animals, including humans, retain this capacity buried somewhere in their genes.
Scientists initially thought that senescent cells couldn’t play a role in regeneration because they could no longer reproduce, says Anthony Atala, a practicing surgeon and bioengineer who leads the Wake Forest Institute for Regenerative Medicine in North Carolina. But Yun’s study points in the other direction. “What this paper shows clearly is that these cells have the potential to be involved in tissue regeneration [in newts]. The question becomes, will these cells be able to do the same in humans.”
As our knowledge of senescent cells increases, Atala thinks we need to embrace a new analogy to help understand them: humans in retirement. They “have acquired a lot of wisdom throughout their whole life and they can help younger people and mentor them to grow to their full potential. We're seeing the same thing with these cells,” he says. They are no longer putting energy into their own reproduction, but the signaling molecules they secrete “can help other cells around them to regenerate.”
There are disagreements within the research community as to whether newts have acquired their regenerative capacity through a unique evolutionary change, or if other animals, including humans, retain this capacity buried somewhere in their genes. If so, it seems that our genes are unable to express this ability, perhaps as part of a tradeoff in acquiring other traits. It is a fertile area of research.
Dedifferentiation is likely to become an important process in the field of regenerative medicine. One extreme example: a lab has been able to turn back the clock and reprogram adult male skin cells into female eggs, a potential milestone in reproductive health. It will be more difficult to control just how far back one wishes to go in the cell's dedifferentiation – part way or all the way back into a stem cell – and then direct it down a different developmental pathway. Yun is optimistic we can learn these tricks from newts.
Senolytics
A growing field of research is using drugs called senolytics to remove senescent cells and slow or even reverse disease of aging.
“Senolytics are great, but senolytics target different types of senescence,” Yun says. “If senescent cells have positive effects in the context of regeneration, of wound healing, then maybe at the beginning of the regeneration process, you may not want to take them out for a little while.”
“If you look at pretty much all biological systems, too little or too much of something can be bad, you have to be in that central zone” and at the proper time, says Atala. “That's true for proteins, sugars, and the drugs that you take. I think the same thing is true for these cells. Why would they be different?”
Our growing understanding that senescence is not a single thing but a variety of things likely means that effective senolytic drugs will not resemble a single sledge hammer but more a carefully manipulated scalpel where some types of senescent cells are removed while others are added. Combinations and timing could be crucial, meaning the difference between regenerating healthy tissue, a scar, or worse.