Untold numbers of animals have contributed to science, in ways big and small. Studying cows and cowpox helped English doctor Edward Jenner create a smallpox vaccine; Ivan Pavlov's experiments on dogs' reactions to external stimuli heavily influenced modern behavioral psychology.
We have these five animals to thank for some of our most important scientific advancements, from space travel to better organ replacement options.
Scientists still work with rats, rabbits, and other mammals to test cosmetics and pharmaceuticals and to conduct infectious disease research. Most of these animals remain nameless and unknown to the public, but over the years, certain individuals have had an outsize effect. We have these five animals to thank for some of our most important scientific advancements, from space travel to better organ replacement options.
1) LAIKA THE DOG
Laika was the first living creature ever to orbit the Earth. In October 1957, the Soviet Sputnik I ship had made history as the first man-made object sent into Earth's orbit; Premier Nikita Khrushchev was keen to gain another Space Race victory by sending up a canine cosmonaut.
Laika ("barker" in Russian), was a stray dog, reportedly a husky-spitz mix, recruited among several other female strays for the trip. Although the scientists put extensive work into preparing Laika and the other canine finalists—evaluating their reactions to air-pressure variations, training them to adapt to pelvic sanitation devices meant to contain waste, and eventually having them live in pressurized capsules for weeks—there was no expectation that the dog would return to Earth, and only one meal's worth of food was sent up with her.
Laika the dog, with a mockup of her space capsule.
Sputnik II, six times heavier than its predecessor, launched on November 3, 1957. Soviet broadcasts reported that Laika, fitted out with surgically implanted devices to monitor her heart rate, blood pressure, and breathing rates, survived until November 12; the spacecraft stayed in orbit for five more months, burning up when it re-entered the atmosphere.
At the time, the Sputnik II team reassured the world that Laika had died painlessly of oxygen deprivation. It was only decades later, in the 1990s, that Oleg Gazenko—one of the scientists and dog trainers assigned to the mission—revealed that Laika had died 5 to 7 hours after launch from a combination of heat and stress. The capsule had overheated, probably as a result of the rushed preparation; after the fourth orbit, the temperature inside Sputnik was over 90 degrees, and it's doubtful she could have survived much past that. "The more time passes, the more I'm sorry about it. We shouldn't have done it," Gazenko said. "We did not learn enough from the mission to justify the death of the dog."
Yet even the four or five orbits that Laika did complete were enough to spur scientists to press on in the effort to send a human into space.
2) HAM THE CHIMP
Four years after Laika's ill-fated flight, a chimpanzee named Ham entered suborbital flight in the American Project Mercury MR-2 mission on January 31, 1961, becoming the first hominid in space—and unlike Laika, he returned to Earth, alive, after a 16-minute flight.
Even though Ham's flight was not destined for orbit, the spacecraft and booster used on his trip were the same combination intended for the first (human) American's trip later that year. If he came back unharmed, NASA's medical team would be prepared to okay astronaut Alan Shepard's flight.
Ham receives his well-deserved apple.
For approximately 18 months before liftoff, Ham was trained to perform simple tasks, like pushing levers, in response to visual and auditory cues. (If he failed, he received an electric shock; correct performance earned him a treat. Pavlov would have been pleased.)
At 37 pounds, Ham was also the heaviest animal to ever make it to space. His vital signs and movements were monitored from Earth, and after a light electric shock from the ground team reminded him of his tasks, he performed his lever-pushing just a bit slower than he had on Earth, verifying that motion would not be seriously impaired in space.
Less than three months after Ham returned to Earth, on April 12, 1961, Soviet cosmonaut Yuri Gagarin became the first human to complete an orbital flight; Shepard was close behind, successfully crewing the MR-3 mission on May 5. For his part, Ham "retired" to the National Zoo in Washington D.C. for 17 years, before being transferred to the North Carolina Zoological Park; he died of liver failure in 1983 at age 26. His grave is at the International Space Hall of Fame in New Mexico.
3) KOKO THE GORILLA
A western lowland gorilla born at the San Francisco Zoo, Hanabi-ko, or "Koko," became famous in the 1970s for her cognitive and communicative abilities. Psychologist Francine "Penny" Patterson, then a doctoral student at Stanford, chose Koko to work on a language research project, teaching her American Sign Language; by age four, Koko demonstrated the ability both to make up new words and to combine known words to express herself creatively, as opposed to simply mimicking her trainer.
Koko and Penny compare notes.
Koko's work with Patterson reflected levels of cognition that were higher than non-human primates had previously been thought to have; by the end of her life, her language skills were roughly equivalent to a young child's, with a vocabulary of around 1,000 signs and the ability to understand 2,000 words of spoken English.
An especially impactful study in 2012 showed that Koko had learned to play the recorder, revealing an ability for voluntary breath control that scientists had previously thought was linked closely to speech and could only be developed by humans. Barbara J. King, a biological anthropologist, suggested that Koko's immersion in a human environment may have helped her develop such a skill, and that it might be misleading to consider similar abilities "innate" or lacking in either humans or non-human primates.
Koko's displays of emotions also fascinated the public, especially those that seemed to closely mirror humans': she cared for pet kittens; appeared on Mr. Rogers' Neighborhood and untied the host's shoes for him; acted playfully with Robin Williams during a visit from him, and later expressed grief when told about the comedian's death. Koko died in her sleep in June 2018, at age 46. Patterson continues to run The Gorilla Foundation, which is dedicated to using inter-species communication to motivate conservation efforts.
4) DOLLY THE SHEEP
Dolly—named after country singer Dolly Parton—was the first mammal ever to be cloned from an adult somatic cell, using the process of nuclear transfer. She was born in 1996 as part of research by scientists Keith Campbell and Ian Wilmut of the University of Edinburgh.
Dolly the cloned sheep.
By taking a donor cell from an adult sheep's mammary gland, using it to replace the cell nucleus of an unfertilized, developing egg cell, and then bringing the resultant embryo to term, Campbell and Wilmut proved that even a mature cell (one that had developed to perform mammary gland functions) could revert to an embryonic state and go on to develop into any and all parts of a mammal.
Although cloned livestock are legal in the U.S.—the FDA approved the practice in 2008, after determining that there was no difference between the meat and milk of cattle, pigs, and goats—Dolly has had an even bigger impact on stem cell research. The successful test of nuclear transfer proved that it was possible to change a cell's gene expression by changing its nucleus.
Japanese stem cell biologist Shinya Yamanaka, inspired by the birth of Dolly, won the Nobel Prize in 2012 for his adaptation of the technique. He developed induced pluripotent stem cells (iPS cells) by chemically reverting mature cells back to an embryonic-like blank state that is highly desirable for disease research and treatment. This technique allows researchers to work with such stem cells without the ethically charged complication of having to destroy a human embryo in the process.
5) LAIKA THE PIG
Named in honor of the dog who made it to space, the second science-famous Laika was a genetically engineered pig born in China in 2015 as a result of gene editing carried out by Cambridge, MA startup eGenesis and collaborators.* eGenesis aims to create pigs whose organs—hearts, kidneys, lungs, and more—are safe to transplant into people.
Laika the gene-edited pig.
Using animal organs in humans (xenotransplantation) is tricky: the immune system is very good at recognizing interlopers, and the human body can start to reject an organ from another species in as little as five minutes. But pigs are otherwise exceptionally good potential donors for humans: their organs' sizes and functions are very similar, and their quick gestation and maturation make them attractive from an efficiency standpoint, given that twenty Americans die every day waiting for organ donors.
Perhaps unsurprisingly, Dolly the sheep helped move xenotransplantation forward. In the 1990s, immunologist David Sachs was able to use a similar cloning method to eliminate alpha-gal, an enzyme that is produced by most animals with immune systems, including pigs—but not humans. Since our immune systems don't recognize alpha-gal, attacks on that enzyme are a major cause of organ rejection. Sachs' experiments increased the survival time of pig organs in primates to weeks: a huge improvement, but not nearly enough for someone in need of a liver or heart.
The advent of CRISPR technology, and the ability to edit genes, has allowed another leap. In 2015, researchers at eGenesis used targeted gene-editing to eliminate the genes for porcine endogenous retroviruses from pig kidney cells. These viral elements are part of all pigs' genomes and pose a potentially high risk of infecting human cells. (After the HIV/AIDS crisis especially, there was a lot of anxiety about potentially introducing a new virus into the human population.)
The eGenesis lab used nuclear transfer to embed the edited nuclei into egg cells taken from a normal pig; and Laika was born months later—without the dangerous viral genes. eGenesis is now working to make the organs even more humanlike, with the goal of one day providing organs to every human patient in need.
*[Disclosure: In 2019, eGenesis received a series B investment from Leaps By Bayer, the funding sponsor of leapsmag. However, leapsmag is editorially independent of Bayer and is under no obligation to cover companies they invest in.]
[Correction, March 3, 2020: Laika the gene-edited pig was born in China, not Cambridge, and eGenesis is pursuing xenotransplant programs that include heart, kidney, and lung, but not skin, as originally written.]
In early 2020, Moderna Inc. was a barely-known biotechnology company with an unproven approach. It wanted to produce messenger RNA molecules to carry instructions into the body, teaching it to ward off disease. Experts doubted the Boston-based company would meet success.
Today, Moderna is a pharmaceutical power thanks to its success developing an effective Covid-19 vaccine. The company is worth $124 billion, more than giants including GlaxoSmithKline and Sanofi, and evidence has emerged that Moderna's shots are more protective than those produced by Pfizer-BioNTech and other vaccine makers. Pressure is building on the company to deliver more of its doses to people around the world, especially in poorer countries, and Moderna is working on vaccines against other pathogens, including Zika, influenza and cytomegalovirus.
But Moderna encountered such difficulties over the course of its eleven-year history that some executives worried it wouldn't survive. Two unlikely scientists helped save the company. Their breakthroughs paved the way for Moderna's Covid-19 shots but their work has never been publicized nor have their contributions been properly appreciated.
Derrick Rossi, a scientist at MIT, and Noubar Afeyan, a Cambridge-based investor, launched Moderna in September 2010. Their idea was to create mRNA molecules capable of delivering instructions to the body's cells, directing them to make proteins to heal ailments and cure disease. Need a statin, immunosuppressive, or other drug or vaccine? Just use mRNA to send a message to the body's cells to produce it. Rossi and Afeyan were convinced injecting mRNA into the body could turn it into its own laboratory, generating specific medications or vaccines as needed.
At the time, the notion that one might be able to teach the body to make proteins bordered on heresy. Everyone knew mRNA was unstable and set off the body's immune system on its way into cells. But in the late 2000's, two scientists at the University of Pennsylvania, Katalin Karikó and Drew Weissman, had figured out how to modify mRNA's chemical building blocks so the molecule could escape the notice of the immune system and enter the cell. Rossi and Afeyan couldn't convince the University of Pennsylvania to license Karikó and Weissman's patent, however, stymying Moderna's early ambitions. At the same time, the Penn scientists' technique seemed more applicable to an academic lab than a biotech company that needed to produce drugs or shots consistently and in bulk. Rossi and Afeyan's new company needed their own solution to help mRNA evade the body's defenses.
Some of Moderna's founders doubted Schrum could find success and they worried if their venture was doomed from the start.
The Scientist Who Modified mRNA: Jason Schrum
In 2010, Afeyan's firm subleased laboratory space in the basement of another Cambridge biotech company to begin scientific work. Afeyan chose a young scientist on his staff, Jason Schrum, to be Moderna's first employee, charging him with getting mRNA into cells without relying on Karikó and Weissman's solutions.
Schrum seemed well suited for the task. Months earlier, he had received a PhD in biological chemistry at Harvard University, where he had focused on nucleotide chemistry. Schrum even had the look of someone who might do big things. The baby-faced twenty-eight-year-old favored a relaxed, start-up look: khakis, button-downs, and Converse All-Stars.
Schrum felt immediate strain, however. He hadn't told anyone, but he was dealing with intense pain in his hands and joints, a condition that later would be diagnosed as degenerative arthritis. Soon Schrum couldn't bend two fingers on his left hand, making lab work difficult. He joined a drug trial, but the medicine proved useless. Schrum tried corticosteroid injections and anti-inflammatory drugs, but his left hand ached, restricting his experiments.
"It just wasn't useful," Schrum says, referring to his tender hand.
He persisted, nonetheless. Each day in the fall of 2010, Schrum walked through double air-locked doors into a sterile "clean room" before entering a basement laboratory, in the bowels of an office in Cambridge's Kendall Square neighborhood, where he worked deep into the night. Schrum searched for potential modifications of mRNA nucleosides, hoping they might enable the molecule to produce proteins. Like all such rooms, there were no windows, so Schrum had to check a clock to know if it was day or night. A colleague came to visit once in a while, but most of the time, Schrum was alone.
Some of Moderna's founders doubted Schrum could find success and they worried if their venture was doomed from the start. An established MIT scientist turned down a job with the start-up to join pharmaceutical giant Novartis, dubious of Moderna's approach. Colleagues wondered if mRNA could produce proteins, at least on a consistent basis.
As Schrum began testing the modifications in January 2011, he made an unexpected discovery. Karikó and Weissman saw that by turned one of the building blocks for mRNA, a ribonucleoside called uridine, into a slightly different form called pseudouridine, the cell's immune system ignored the mRNA and the molecule avoided an immune response. After a series of experiments in the basement lab, Schrum discovered that a variant of pseudouridine called N1- methyl-pseudouridine did an even better job reducing the cell's innate immune response. Schrum's nucleoside switch enabled even higher protein production than Karikó and Weissman had generated, and Schrum's mRNAs lasted longer than either unmodified molecules or the modified mRNA the Penn academics had used, startling the young researcher. Working alone in a dreary basement and through intense pain, he had actually improved on the Penn professors' work.
Years later, Karikó and Weissman who would win acclaim. In September 2021, the scientists were awarded the Lasker-DeBakey Clinical Medical Research Award. Some predict they eventually will win a Nobel prize. But it would be Schrum's innovation that would form the backbone of both Moderna and Pfizer-BioNTech's Covid-19 vaccine, not the chemical modifications that Karikó and Weissman developed. For Schrum, necessity had truly been the mother of invention.
The Scientist Who Solved Delivery: Kerry Benenato
For several years, Moderna would make slow progress developing drugs to treat various diseases. Eventually, the company decided that mRNA was likely better suited for vaccines. By 2017, Moderna and the National Institutes of Health were discussing working together to develop mRNA–based vaccines, a partnership that buoyed Moderna's executives. There remained a huge obstacle in Moderna's way, however. It was up to Kerry Benenato to find a solution.
Benenato received an early hint of the hurdle in front of her three years earlier, when the organic chemist was first hired. When a colleague gave her a company tour, she was introduced to Moderna's chief scientific officer, Joseph Bolen, who seemed unusually excited to meet her.
"Oh, great!" Bolen said with a smile. "She's the one who's gonna solve delivery."
Bolen gave a hearty laugh and walked away, but Benenato detected seriousness in his quip.
It was a lot to expect from a 37-year-old scientist already dealing with insecurities and self-doubt. Benenato was an accomplished researcher who most recently had worked at AstraZeneca after completing post-doctoral studies at Harvard University. Despite her impressive credentials, Benenato battled a lack of confidence that sometimes got in her way. Performance reviews from past employers had been positive, but they usually produced similar critiques: Be more vocal. Do a better job advocating for your ideas. Give us more, Kerry.
Benenato was petite and soft-spoken. She sometimes stuttered or relied on "ums" and "ahs" when she became nervous, especially in front of groups, part of why she sometimes didn't feel comfortable speaking up.
"I'm an introvert," she says. "Self-confidence is something that's always been an issue."
To Benenato, Moderna's vaccine approach seemed promising—the team was packaging mRNAs in microscopic fatty-acid compounds called lipid nanoparticles, or LNPs, that protected the molecules on their way into cells. Moderna's shots should have been producing ample and long-lasting proteins. But the company's scientists were alarmed—they were injecting shots deep into the muscle of mice, but their immune systems were mounting spirited responses to the foreign components of the LNPs, which had been developed by a Canadian company.
This toxicity was a huge issue: A vaccine or drug that caused sharp pain and awful fevers wasn't going to prove very popular. The Moderna team was in a bind: Its mRNA had to be wrapped in the fatty nanoparticles to have a chance at producing plentiful proteins, but the body wasn't tolerating the microscopic encasements, especially upon repeated dosing.
The company's scientists had done everything they could to try to make the molecule's swathing material disappear soon after entering the cells, in order to avoid the unfortunate side effects, such as chills and headaches, but they weren't making headway. Frustration mounted. Somehow, the researchers had to find a way to get the encasements—made of little balls of fat, cholesterol, and other substances—to deliver their payload mRNA and then quickly vanish, like a parent dropping a teenager off at a party, to avoid setting off the immune system in unpleasant ways, even as the RNA and the proteins the molecule created stuck around.
Benenato wasn't entirely shocked by the challenges Moderna was facing. One of the reasons she had joined the upstart company was to help develop its delivery technology. She just didn't realize how pressing the issue was, or how stymied the researchers had become. Benenato also didn't know that Moderna board members were among those most discouraged by the delivery issue. In meetings, some of them pointed out that pharmaceutical giants like Roche Holding and Novartis had worked on similar issues and hadn't managed to develop lipid nanoparticles that were both effective and well tolerated by the body. Why would Moderna have any more luck?
Stephen Hoge insisted the company could yet find a solution.
"There's no way the only innovations in LNP are going to come from some academics and a small Canadian company," insisted Hoge, who had convinced the executives that hiring Benenato might help deliver an answer.
Benenato realized that while Moderna might have been a hot Boston-area start- up, it wasn't set up to do the chemistry necessary to solve their LNP problem. Much of its equipment was old or secondhand, and it was the kind used to tinker with mRNAs, not lipids.
"It was scary," she says.
When Benenato saw the company had a nuclear magnetic resonance spectrometer, which allows chemists to see the molecular structure of material, she let out a sigh of relief. Then Benenato inspected the machine and realized it was a jalopy. The hulking, aging instrument had been decommissioned and left behind by a previous tenant, too old and banged up to bring with them.
Benenato began experimenting with different chemical changes for Moderna's LNPs, but without a working spectrometer she and her colleagues had to have samples ready by noon each day, so they could be picked up by an outside company that would perform the necessary analysis. After a few weeks, her superiors received an enormous bill for the outsourced work and decided to pay to get the old spectrometer running again.
After months of futility, Benenato became impatient. An overachiever who could be hard on herself, she was eager to impress her new bosses. Benenato felt pressure outside the office, as well. She was married with a preschool-age daughter and an eighteen-month-old son. In her last job, Benenato's commute had been a twenty-minute trip to Astra-Zeneca's office in Waltham, outside Boston; now she was traveling an hour to Moderna's Cambridge offices. She became anxious—how was she going to devote the long hours she realized were necessary to solve their LNP quandary while providing her children proper care? Joining Moderna was beginning to feel like a possible mistake.
She turned to her husband and father for help. They reminded her of the hard work she had devoted to establishing her career and said it would be a shame if she couldn't take on the new challenge. Benenato's husband said he was happy to stay home with the kids, alleviating some of her concerns.
Back in the office, she got to work. She wanted to make lipids that were easier for the body to chop into smaller pieces, so they could be eliminated by the body's enzymes. Until then, Moderna, like most others, relied on all kinds of complicated chemicals to hold its LNP packaging together. They weren't natural, though, so the body was having a hard time breaking them down, causing the toxicity.
Benenato began experimenting with simpler chemicals. She inserted "ester bonds"—compounds referred to in chemical circles as "handles" because the body easily grabs them and breaks them apart. Ester bonds had two things going for them: They were strong enough to help ensure the LNP remained stable, acting much like a drop of oil in water, but they also gave the body's enzymes something to target and break down as soon as the LNP entered the cell, a way to quickly rid the body of the potentially toxic LNP components. Benenato thought the inclusion of these chemicals might speed the elimination of the LNP delivery material.
This idea, Benenato realized, was nothing more than traditional, medicinal chemistry. Most people didn't use ester bonds because they were pretty unsophisticated. But, hey, the tricky stuff wasn't working, so Benenato thought she'd see if the simple stuff worked.
Benenato also wanted to try to replace a group of unnatural chemicals in the LNP that was contributing to the spirited and unwelcome response from the immune system. Benenato set out to build a new and improved chemical combination. She began with ethanolamine, a colorless, natural chemical, an obvious start for any chemist hoping to build a more complex chemical combination. No one relied on ethanolamine on its own.
Benenato was curious, though. What would happen if she used just these two simple modifications to the LNP: ethanolamine with the ester bonds? Right away, Benenato noticed her new, super-simple compound helped mRNA create some protein in animals. It wasn't much, but it was a surprising and positive sign. Benenato spent over a year refining her solution, testing more than one hundred variations, all using ethanolamine and ester bonds, showing improvements with each new version of LNP. After finishing her 102nd version of the lipid molecule, which she named SM102, Benenato was confident enough in her work to show it to Hoge and others.
They immediately got excited. The team kept tweaking the composition of the lipid encasement. In 2017, they wrapped it around mRNA molecules and injected the new combination in mice and then monkeys. They saw plentiful, potent proteins were being produced and the lipids were quickly being eliminated, just as Benenato and her colleagues had hoped. Moderna had its special sauce.
That year, Benenato was asked to deliver a presentation to Stephane Bancel, Moderna's chief executive, Afeyan, and Moderna's executive committee to explain why it made sense to use the new, simpler LNP formulation for all its mRNA vaccines. She still needed approval from the executives to make the change. Ahead of the meeting, she was apprehensive, as some of her earlier anxieties returned. But an unusual calm came over her as she began speaking to the group. Benenato explained how experimenting with basic, overlooked chemicals had led to her discovery.
She said she had merely stumbled onto the company's solution, though her bosses understood the efforts that had been necessary for the breakthrough. The board complimented her work and agreed with the idea of switching to the new LNP. Benenato beamed with pride.
"As a scientist, serendipity has been my best friend," she told the executives.
Over the next few years, Benenato and her colleagues would improve on their methods and develop even more tolerable and potent LNP encasement for mRNA molecules. Their work enabled Moderna to include higher doses of vaccine in its shots. In early 2020, Moderna developed Covid-19 shots that included 100 micrograms of vaccine, compared with 30 micrograms in the Pfizer-BioNTech vaccine. That difference appears to help the Moderna vaccine generate higher titers and provide more protection.
"You set out in a career in drug discovery to want to make a difference," Benenato says. "Seeing it come to reality has been surreal and emotional."
Editor's Note: This essay is excerpted from A SHOT TO SAVE THE WORLD: The Inside Story of the Life-or-Death Race for a COVID-19 Vaccine by Gregory Zuckerman, now on sale from Portfolio/Penguin.
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Kira Peikoff is the editor-in-chief of Leaps.org. 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.