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Just past a “squid sign-out” sheet, on the ground floor of a stately brick building at the Marine Biological Laboratory (MBL) in Woods Hole, Massachusetts, a handful of people in lab coats shimmy between rows of microwave-sized tanks. They check water quality, administer food, jot down notes, and otherwise go about the business of transforming the landscape of marine biological research.
Led by squid wizard Bret Grasse, the workers here at MBL’s Marine Resources Center are attempting to master the science of rearing cephalopods—a group that includes squid, cuttlefish, and octopuses—in captivity. A constant gurgle of fresh Cape Cod seawater originating from an adjacent inlet trickles through a network of pipes adding to a sense of chaos in the spacious but tightly packed wet lab. As my tour continues, order emerges. What at first looks like misplaced plastic bottles inside some tanks turn out to be old Coke bottles, purposefully placed mid-tank to incubate cephalopod eggs. Air piped into each bottle keeps translucent eggs the size of raisins oscillating inside. Some cephalopod parents oxygenate their eggs until they hatch, but Grasse developed the soda bottle incubator to automate the task, freeing the parents up to produce the next batch of eggs. This is one of several low-tech innovations the team has implemented toward mass producing cephalopods as lab animals. If they succeed, they will have helped usher in the world’s newest marine model organism.
A model organism is used as a test system to reveal universal truths of biology. The model can either represent a larger group of animals, or serve as a proxy for humans or other species. Much of our knowledge of the development of living organisms, including genetics, comes from research on a handful of model organisms such as fruit flies, roundworms, zebra fish, mice, and rats. These are small animals with short generation times that are easy to keep and breed and whose genomes we can easily analyze and modify to study the interplay of genetics, biology, and disease and then try to apply the insights to humans, too.
Scientists already have access to other marine animals for their lab work, and have used them to tease out discoveries about everything from nerve transmission, to fertilization, to mechanisms behind learning and memory. But as the scientific community has embraced the study of genetics over the past three decades, its need for new, genetically tractable marine models—that is, lab animals with genes that can be readily manipulated—has become obvious. MBL wants to fill the void by producing the world’s first genetically tractable cephalopod model organism.
When it comes to what we might learn from cephalopods, the possibilities abound.
Scientists organize animals into roughly 35 phyla, but only study a few in detail, says Caroline Albertin, cephalopod biologist at MBL, which leaves gaping holes in our biological knowledge. It’s akin to wanting to understand human physiology but only ever studying men.
“There are whole swaths of the biological world that we’re not accessing,” says Albertin. In 2015, she was part of the first team to sequence an octopus genome. Cephalopods have a lot in common with vertebrates, she says—“things like big brains, camera eyes, and a closed circulatory system”—but they evolved completely independently. “They are most closely related to other mollusks, like snails and clams, that don’t have these features,” she adds.
Studying cephalopod genes and their embryology—how those genes are deployed during development—could help us improve our knowledge of evolution and organismal biology. As Albertin points out, investigating the nuances of the cephalopod’s large nervous system might yield insights into the human brain. And figuring out how cephalopods regenerate their arms, despite having large nerve cords running down them, could lead to a breakthrough in addressing human spinal cord injuries.
Other cephalopod experts, such as neuro-molecular biologist Josh Rosenthal, who oversees the cephalopod model organism development project at MBL, are excited by prospects of studying additional innovations that cephalopods evolved, such as their ability to edit their own genetic information. Cephalopods’ three hearts and ability to match the color, pattern, and shape of their surroundings also fascinate biologists hoping to uncover the underlying biological principles of those traits.
But before MBL can build momentum around cephalopod research, staff scientists first need to master the art of keeping their squirmy subjects happy and mass producing in captivity—which is much trickier with cephalopods than it is with mice.
MBL, an affiliate of the University of Chicago, prides itself on studying nature through a hands-on approach, rather than through books. A few years ago, a group of researchers connected with the nonprofit corporation started discussing the development of a new marine model species with a tractable genetic system. MBL’s proximity to a rich part of the ocean, where tropical waters brought by the Gulf Stream meet cold North Atlantic waters, has helped make it a global hub for marine research. Scores of students and scientists arrive for training and research each summer, creating a palpable vibe of excitement about unraveling nature’s mysteries. The researchers knew that any new model organism they developed here would likely be quickly embraced by visiting scientists who would take the new ideas and techniques back to their home labs.
The group eventually agreed on cephalopods, and in April 2017, MBL started the work of making a new model species a reality. One of the first calls was to Grasse.
With his laid-back style, aquarist Grasse gives off a West Coast surfer vibe as he pauses between tanks to talk about big ideas in biology and small adjustments to his aquaria. In his last job as a senior aquarist at Monterey Bay Aquarium in California, he designed and developed the world’s first large-scale cephalopod public exhibition. “For every two species that we displayed, there were probably another four behind the scenes we were tinkering around with,” he says. “I’ve got many years of hands-on, groundbreaking innovative experience troubleshooting different challenges in raising cephalopods.” Now MBL’s cephalopod project is relying on that expertise to make it a success.
MBL, which has a long, venerable history with cephalopod research, already had a collection of live cephalopods, mostly squid and cuttlefish that were wild-caught or donated from other labs. And the organization had experience breeding cephalopods at a smaller scale, which gave it a good head start. But to become a dependable source of cephalopods, MBL expects it will need to continuously produce large numbers of these animals—hundreds, thousands, or more—to support the wider scientific community with ready-to-ship model organisms.
One key to successfully rearing such notoriously difficult animals, says Grasse, is learning to read their subtle cues, like a slight change in the coloration of their skin or a minor behavioral change. “Just the way they’re breathing, swimming, siphoning, or color displaying at one another will give me clues about what they need and allow me to proactively address these.”
It also takes round-the-clock work to maintain conditions that are right for a cephalopod’s life stage—with considerations of food, habitat, company, and water quality—and to tweak for better results. Most cephalopod species at MBL have a natural longevity of six months to a year and reach sexual maturity at three months. “They have that live fast, die young lifestyle,” says Grasse. His group’s work has already increased longevity to exceed the typical life span in nature and has raised egg survivorship to 90 percent or higher for some species.
Combining Grasse’s experience with scientists’ requirements, the MBL team has honed in on several species that fit a few important criteria for potential model organisms: the animals are small, have short life spans, and maintain predictable reproduction cycles. The star performers include the Hawaiian bobtail squid, California two-spot octopus, flamboyant cuttlefish, striped pyjama squid, and dwarf cuttlefish. The pygmy zebra octopus is a more recent addition to the roster. Scientists have been trying to rear the lozenge-sized animal in captivity since the 1970s, and in late 2018, MBL became the first to culture it over multiple generations, says Grasse. The list might be further whittled down depending on how well each species continues to reproduce, or we might end up with several of these species as the new lab organisms.
It is an excellent strategy to choose a few representative cephalopods and concentrate our efforts on really understanding them, says Jennifer Mather, a cephalopod researcher at the University of Lethbridge in Alberta, who is not involved with the project. “We know far too little about these animals, including such fundamental aspects of their lives as behavior and ecology.”
The MBL cephalopod team’s ultimate goal is to have a ready supply of their chosen species at various life stages, so it can respond immediately to requests from scientists around the world. “So, depending on the scientific question, the researchers can have exactly the kind of resource they need and desire,” says Grasse. Before the cephalopod program, MBL possessed maybe 50 cuttlefish and 30 squid and now has somewhere around 4,000 cephalopods, almost all of them cultured.
While Grasse’s crew figures out the best methodologies for culturing cephalopods, Rosenthal’s team of geneticists at MBL are equally immersed in the other half of the equation: prodding deep into their test subjects’ genes. After a steady supply of cephalopods is available and they have finished sequencing and cataloging the genomes, they plan to start manipulating the DNA of some broods, to give future customers more options. Scientists may want to order cephalopods with certain genes added or deleted to study a particular issue, for example. Part of the geneticists’ work is fine-tuning a scientific technique that will enable researchers to make those alterations. Many of the insights scientists hope to gain from cephalopods will depend on their ability to manipulate genes one at a time—often during the embryo stage—and then study the impact on the animal, Rosenthal says.
Once scientists successfully alter a gene, they need to be able to keep the animal alive, growing, and breeding in order to see if the genetic change is evident in successive generations, Rosenthal adds. “Culturing them is key.” External researchers might nurture cephalopods from MBL in their own labs, if they have the skills, or work on-site at MBL for a period of time with help from the cephalopod team.
The project’s benefits to MBL are clear: there’s prestige associated with being the first and only source of one of the world’s few genetically tractable model organisms—though the researchers say prestige is not their driving motivation—and there’s potential for financial gain.
For now, the cephalopods, and the lessons Grasse and his team have learned from rearing them, are available for free to other scientists who want to conduct research at MBL. If the project succeeds, it will also make it easier for MBL to attract more scientists to do their lab work here year-round, not just during the idyllic summer months when Woods Hole becomes picture-perfect, with shacks floating on calm bay waters, gulls gliding alongside boats, and families strolling a sunny promenade.
Those who want to take cephalopods back to their home labs will need to pay. MBL has already begun selling some of their animals to external researchers to help cover costs of the project while staff scientists proceed with the development work, but isn’t making a profit yet. Cephalopod embryos may sell for US $5 each, the adults anywhere from $25 to $300. “We’re not trying to become rich; our short-term goal is to nurture science and research, and to nurture the usage of these animals,” says Grasse. “If we all kept using exactly the same models, the same fruit flies, the same zebra fish … if we keep asking the question of the same animals, we can only go so far. So it’s up to us as scientific culture to branch out a little bit.”
The cephalopod project is predicated on an understanding that the scientific community needs new lab animals. But I leave Grasse’s lab conflicted about whether MBL should be pursuing cephalopods as model organisms at all, given how seemingly intelligent and charismatic these creatures are.
Before my tour with Grasse, I met Roger Hanlon, senior scientist at MBL and a world expert in cephalopods. He explained there are early indications that some cephalopods have episodic-like memory—able to remember the what, where, and when of an event—a sign of high cognitive abilities in comparison to many vertebrates. The sheer complexity and speed of a cephalopod’s camouflage behavior is also impressive.
Because of their complex brains, cephalopods are protected by laboratory animal laws in Canada, the European Union, New Zealand, and some Australian states. Researchers in those places must get ethical approval for their studies and treat the animals humanely. But there is no such regulation in the United States. While some critics oppose any experimentation on cephalopods, most scientists I talked to, including Hanlon, say that as long as cephalopods are kept in good welfare conditions, it is ethical to continue such work.
Before I leave the Marine Resources Center, I get a moment on my own in one corner of the building housing stacks of mini-aquaria, like a sort of cuttlefish condo, and peer into one of them. A couple of cuttlefish hover mid-aquarium like an alien spaceship, staring with their huge eyes, studying me back. I wish I could read their minds and tell the story from their perspective.