Humans still raise flocks of sacred chickens, just as the Romans did. Priests no longer tend them, nor do we use them to divine the future. Instead, we rear them in undisclosed locations protected by bodyguards. The number of chickens the US government keeps and what it pays for them are unknown; these numbers are a national security secret but are probably very large. In 2017, the US Department of Health and Human Services paid a single egg provider $42 million for a three-year contract. CNN estimated that the United States might require 140 million eggs each year to fight the flu alone. A nation with a healthy workforce—a vaccinated workforce—thrives, and we owe many of our modern vaccines to the egg.1
Humans used to die of contagious diseases in droves; we were desperate to stop the waves of death and disfigurement. Smallpox, for example, once killed about one in three patients. Possibly as early as 1000 CE in China, doctors began blowing powdered smallpox scabs up patients’ noses, while later, in Europe, people rubbed smallpox pus into wounds on healthy people’s arms to help confer immunity. Only 2 to 3 percent of patients thus treated—variolated—with live disease died from the treatment, a vast improvement over the numbers who died from the disease. Unfortunately, the variolated sometimes kicked off epidemics.2
In 1798, British doctor Edward Jenner made a leap forward for smallpox prevention when he figured out that the dairy workers’ tales were true: people who caught cowpox, a disease present in livestock, gained immunity to smallpox. No one knew conclusively that smallpox and cowpox viruses were related and that a virus that evolved to attack cows could leave humans unscathed. Jenner had received childhood smallpox variolation, so was unable to experiment on himself. He took material from milkmaid Sarah Nelmes’s cowpox sore and injected it into eight-year-old James Phipps. After the boy recovered from feeling a bit unwell, he tried variolating the boy with live smallpox. The vaccine worked. Further tests showed that those inoculated with cowpox, or sometimes horsepox, didn’t spread smallpox and were much less likely to die from the treatment. And the vaccine could be transferred from arm to arm, as those inoculated with cowpox developed sores at the injection site. Jenner had made a breakthrough—the creation of a nonlethal, effective live inoculation that used an animal virus similar to a human disease. Jenner’s friend, physician Richard Dunning, suggested the new treatment be named vaccine, from vacca, the Latin for cow.3
Of course, there were still a few kinks to work out, including access to the virus. Unlike bacteria, which lives happily on nutrient broth in petri dishes, many viruses require living tissue to survive over long periods. Doctors in Europe once dried smallpox lymph fluid (pus from sores) on fabric, then reconstituted it in the next town down the road for vaccinations. But the dried lymph didn’t survive long sea voyages. Spain turned to orphan boys to transport the jab overseas, infecting them in pairs for backup across the long sea voyage. In return, the boys received education and adoptive families. In 1803, the Royal Philanthropic Vaccine Expedition set sail to Caracas with twenty-two orphans ages three to nine aboard. The first orphans received their injections, and when the sore that formed at the injection site became ripe, physicians onboard transferred cowpox into the arms of the next pair, and so on, until the boat landed in Venezuela and the single ripe pustule remaining went into the arms of the local population. Over the next few years, the mission managed to vaccinate people in Colombia, Ecuador, Peru, Bolivia, and Mexico, then set sail to the Philippines, and from there to China, vaccinating more than 320,000 people in under a decade. Arm-to-arm transmission, which was also used in places like England, had major drawbacks beyond the exploitation of children. It lacked convenience and could spread blood-borne diseases like hepatitis or syphilis along with immunity.4
Living animals were a standard method for cultivating viruses for vaccines. By 1836, English physician Edward Ballard had noticed that over time, arm-to-arm transmission methods became less effective, almost as if the virus was petering out. Building on earlier research, he began recommending mixing vaccine strains with fresh cowpox, with the results injected into cows and then back into people, and so on. Eventually, relying on animals to create vaccine supplies helped tamp down some of the problems with arm-to-arm transmission among humans.5
Pathologist Dr. Ernest Goodpasture wanted to find a better way. His viral research came in the wake of the 1918 flu pandemic that ravaged the globe. About a third of the global population contracted the virus, and 10 percent of those—50 million people in total—died. While most lethal for young and elderly people, the flu also targeted otherwise healthy folks of any age. In the years that followed, viral research became a hot and well-funded area. Goodpasture believed that fighting lethal viruses depended on finding cheap and easy ways to cultivate pure strains for use in vaccines. In 1925, he became the professor and department head of pathology at Vanderbilt University. Two years later, he tasked his new assistant, Alice Woodruff, a Mount Holyoke graduate with a PhD in physiology from Yale, to grow fowl pox in something besides a live chicken. He suggested a fertilized egg. At Vanderbilt, she began as an assistant in the physiology department but moved to the Department of Pathology the following year. She’d spend her next three years there working alongside Goodpasture and her husband, Eugene Woodruff, who was a Yale medical school graduate.6
Alice’s cleverness changed vaccine production for the next century. After candling the eggs, she placed them in egg cups, marking the location of the embryo and air sac in pencil. Using a tiny pair of scissors, she cut a small window in the eggs. Later, others would use dentist’s drills for this. She could then pass a needle through the egg membrane and inject the developing chick with fowl pox virus. Afterward, she sealed up this self-contained laboratory with a sliver of glass, held in place by Vaseline, and returned the egg to the incubator.7
Although she maintained a sterile environment throughout the process, frustratingly, her embryos kept going moldy before they became infected. She called in her husband, who worked in a lab down the hall, to consult on this issue. Together they realized that the problem lay in the viral culture itself; they discovered that mold had contaminated it. Eugene traced the mold contamination to the skin of the chicks they’d used to harvest the virus, so he shaved and sterilized their heads as well as the knife he used to collect samples. Then he cultured part of a sample in broth to see if any yeast formed. If it didn’t, he knew it wasn’t contaminated. He also used tiny needles and pipettes and contrived a way to pick out small grains of pure virus. Both methods worked. One day Alice returned to the incubator to find an embryo—still alive!—with a puffy foot. As she told Greer Williams for his 1959 book Virus Hunters, “I can’t forget the thrill of that moment when Dr. Goodpasture came into my lab, and we stood by the hood where the incubator was installed and I showed him this swollen claw from the inoculated embryo. . . . One might say it represented the Achilles’ heel of virus resistance.” The following year she and colleague Gerrit Buddingh also grew cowpox and herpesvirus in eggs.8
History has not remembered Alice Woodruff. Only credited in about a third of the sources I read, the historical glory goes to Goodpasture. But he did give credit where it was due: Alice received first authorship on their 1931 paper describing the new technique. She felt Goodpasture had been “over-generous” with the credit as “the work started as a result of his suggestion and continued under his expert guidance.” As Williams puts it in Virus Hunters, after three years on the job and six months after publishing that landmark paper, “she resigned to become a mother.” She and Eugene moved to Michigan for his work on tuberculosis. Though she offered vague hopes to Williams of returning to research after her three children finished school, there is no indication that happened. For Alice, as for many professional women of the 1930s, motherhood meant she left research and that her work on vaccines went mostly unremembered. Forget Shakespeare’s imaginary sister—I want to know what Alice Woodruff, Ernest Goodpasture’s brilliant assistant, might have accomplished if her era’s idea of motherhood hadn’t confined her.9
Goodpasture’s work continued. He figured that a single chicken egg could produce about a thousand doses of smallpox vaccine and ran studies proving these vaccines safe and effective. He made discoveries about the etiology of viruses and explored the egg as a medium for growing bacteria, fungi, and protozoa. He also published papers of scientific utility but ones that for laymen like me, at least, also serve up mad scientist vibes. He grew human and chicken skin in eggs to help study skin infections and put fetal membranes (from placentas) in eggs to explore viral infections in the uterus. One of his papers is titled “Infection of Newborn Syrian Hamsters with the Virus of Mare Abortion”—wild stuff. But none of his later discoveries had a wider reach than his research with Alice Woodruff. Their discovery came in 1931; five years later, Max Theiler had used the egg technique to produce a vaccine for yellow fever. After human trials, it became the universal standard. Egg-based vaccines for other diseases, including chickenpox and the flu, followed. Drs. Thomas Francis Jr. and Jonas Salk used the technique to develop a flu vaccine in the 1940s, an effort that the military funded after nearly forty-five thousand soldiers fell ill and died of flu during World War I (by comparison, fifty-three thousand died in combat). The egg-based flu vaccine still accounted for most flu vaccines administered worldwide in 2021. All the manufacturing is based on the procedure Alice Woodruff pioneered.10
Eggs can multiply viruses because they can multiply cells. Alive enough to sustain life, eggs are not as cumbersome to care for as, say, a live chicken. Plus each egg is its own little laboratory, conveniently packaged with nature’s defenses against contamination. However, the hen eggs’ use in vaccines may soon be obsolete.
I learned about this change from my friend Dr. Ane Marie Anderson, a Norwegian medical doctor pursuing a PhD in immunology. I always picture her in a shaggy, full-body sheep suit, the one she wore at the last gala for experience designers I attended, part of a complex joke. She has a bone-dry sense of humor, and I have missed her in the years since my childbirth and the pandemic made travel impossible. When we chatted, she had recently stepped down from a medical position at one of the largest hospitals in Norway. She worked in its vaccine and testing clinic. Her duties included thinking through COVID prevention measures—she was a member of their Quarantine Council—and providing data to the people making the high-pressure decisions during that time. For example, the hospital had about a week and a half to decide which 10 percent of their twenty-five thousand employees would receive the first vaccine shots. When we talked, eighteen months into the pandemic, with Norway on the brink of reopening, she seemed exhausted. Or perhaps it was simply the first day of her new job, returning to work in immunology and transfusion medicine. A colleague of hers said it was a good job for women since it allowed work-life balance for starting a family. Yes, Ane shot back, it’s a good job for me since I am finishing my PhD.
Ane explained that although growing vaccines in eggs proved a major development in its day, the technique is still inefficient, particularly since the flu, like COVID, mutates quickly. The flu virus doesn’t have an internal control checking to see if it replicates correctly. “So it makes these sloppy mistakes that are evolutionarily brilliant,” Ane said. This means that creating a vaccine against the flu is a continually moving target. Winter is flu season, and researchers have plenty of theories why: perhaps it’s that the weather drives people indoors where their germs marinate; maybe the short, cold days wear down our immune systems; maybe it’s that cold air holds less water, which means virus droplets float around for longer; maybe it’s a combination of all these factors. Since flu is a winter thing, the Northern and Southern Hemispheres have opposite flu seasons. The World Health Organization (WHO) watches each hemisphere during its flu season and uses the observations to guess what will circulate in the other hemisphere. The trouble, Ane said, is the chicken eggs. Growing enough vaccine components to make, for example, 160 million doses of the vaccine—the approximate amount required for the US 2019 flu season—requires a six-month lead time. WHO’s work monitoring the flu is ongoing. A board of directors reviews data and makes its best guesses about which flu strains will circulate twice a year—in February for the Northern Hemisphere’s vaccine and in September for the Southern Hemisphere’s vaccine. Governmental medical bodies—such as the Centers for Disease Control and Prevention in the United States and its analogs elsewhere—watch WHO and make localized recommendations to manufacturers who then get to work. In a good year, the flu doesn’t mutate much between the time WHO offers its recommendations and when vaccination starts six months later. In a bad year, fast-evolving viral strains mutate quite a bit. This explains the middling efficacy of the flu vaccine—about 30 to 40 percent effective on average. In a bad year, that number might drop below 20 percent, while in a good year it might be higher than 50 percent. Although those numbers might seem low, getting a flu vaccine is still wise, Ane reminds me. The CDC agrees: flu vaccines reduce the chance of hospitalization and death from the flu significantly.11
Egg-based vaccination may have a few other problems. “There are mysteries,” Ane said. Chickens and humans have some biological differences, to put it mildly. A virus that adapts to thrive in a hen could evolve so that it is unable to bind to human cells or cause human disease. As Ane told me, “That’s a really cool and useful general principle,” since that adaptation attenuates the virus for humans. But when outside of human cells for too long, certain strains of flu can develop mutations that cause them to adapt to the egg environment so much that they become less effective as vaccines in humans. Case in point: a 2019 paper in the Journal of Virology passed a bronchitis virus through eggs a hundred times (and repeated this experiment four times) and compared viral RNA at the end of the process. Its results “highlight the unpredictable nature of attenuation by serial egg passage and the need to develop mechanisms . . . for the next generation of effective vaccines.” In the world of vaccinations, the age of egg as bioreactor may be ending, possibly good news for those with egg allergies, although vaccines manufactured via cell culture or recombinant technology have long been available.12
A new method for making vaccines is gaining traction, though. In recent years, the cost of synthesizing DNA and RNA has dropped thanks to dramatic technological advancements. To understand how DNA- and RNA-based vaccines work, let’s return briefly to the workings of traditional vaccines. Basically, a vaccine alarms the body’s immune system in a nondangerous way, which causes the immune system to start preparing its defenses against a particular invader. Traditionally, vaccines injected a body with a live, weakened, or chopped-up viral protein known as an antigen, which triggers an immune response. If the flu is an army of Lex Luthors, then the flu vaccine sends in weakened Lex Luthors—say, his nicer brother Tex Luthor, dead or cryopreserved Lex Luthors, or maybe just Lex’s head or a couple of arms. The body uses these weakened versions to set up an antibody training camp that will produce an army of Supermen ready to crush the threat. Gene-based vaccines, on the other hand, use a different form of delivery. Instead of sending in a bunch of Lex’s heads, a gene-based vaccine hands out recipes for making Lex’s head, in the form of bits of DNA or RNA. And that is what the new tech allows scientists to do: custom-build sequences of DNA and RNA in a lab with a high degree of precision and without as much lead time. In 2021, vaccination campaigns for the worldwide COVID pandemic provided a massive proof of concept for the speed, economy, safety, and effectiveness of this method.13
While vaccine production may move away from the egg, as a single-serving, self-enclosed, naturally sterile laboratory, the egg still has uses at the cutting edge of medicine. Consider the chicken as a little machine that turns food into easily accessible proteins and fats, molecules that are useful in the pharmaceutical industry. Designer proteins are the trend for future medicines because they perform a variety of important duties within cells, especially messaging functions. These functions can be useful levers for new medicines to work on, as my computational biologist husband tells me, but the designer proteins that do the work are expensive and hard to create in labs. What if instead we could program the chickens to produce eggs containing drugs?
It sounds like science fiction, but it’s already happening. Researchers are using eggs to produce human monoclonal antibodies. A monoclonal antibody is an antibody derived from a single specialized cell. To understand how they work, you have to understand a bit about how the body produces antibodies. Ane calls this process “magical and amazing.”
You have up to ten billion B-cells in your body. Each of these white blood cells contains a random receptor on its surface. Picture B-cells as an enormous crowd of master chefs, and antigens, threats from outside the body, as picky customers with highly specific tastes. Each master chef specializes in exactly one egg dish and offers about one hundred thousand servings of it. Inside the lymphatic system, master chefs meet a sampling of customers; the sheer number of chefs practically guarantees that one of them will be holding the correct, precisely calibrated breakfast. When the antigen grabs the bait, the B-cell undergoes an amazing transformation. It rapidly begins to clone itself, creating an army of short-order cooks who rapidly churn out the egg dish (antibody) in question, flooding the body’s system with them. (Some of the clones become memory cells, culinary professors who stick around the body for years, in case the antigen pops up again.) Produced en masse, the antibodies bond to specific sites on specific viruses. Viruses are hungry customers: while the average human has but one mouth to fill with egg, viruses are covered with receptors. This means the antibodies can bond to multiple sites at once. I envision the resulting antibody-encrusted viruses like a diner patron coated in egg—both obvious to everyone else at the restaurant and too slippery to do anything useful. Such viruses struggle to bond to host cells, and all the antibodies make them obvious to the sanitation workers of the immune system—macrophages, which engulf and neutralize them. A polyclonal antibody response—the most common type of immune response—is produced by several B-cells at once. Monoclonal antibodies, in contrast, derive from one particular B-cell and are usually made in a lab. Scientists select that particular B-cell for the precise ability of the particular egg dish it cooks.14
Monoclonal antibody therapy briefly bolsters a person’s immunity to a particular disease and gives a person passive immunity. Whereas vaccines prompt an active immune response, encouraging the body to make its own antibodies, monoclonal antibody therapy injects a person with the needed antibodies directly. It’s the equivalent of giving a person some fish instead of teaching them to fish. Since the body hasn’t learned to make the antibodies on its own, the effect is temporary. A fetus receives nature’s version of antibody therapy. If you jab mom with a flu virus, she will produce antibodies that can cross the placenta to protect her fetus from infection. Likewise, babies receive antibodies from breast milk. Monoclonal antibody therapy is helpful to people who have weak immune systems that can’t recognize viruses or a vaccine’s antigens. Cancer patients may have immune systems damaged by their treatment; the elderly have aging bodily equipment and likely some comorbidities; and babies and children aren’t yet fully developed.15
Monoclonal antibodies are useful, but they’re also expensive to make because the process involves cloning white blood cells in a lab. This is where eggs come in, leveraging the power of the hen’s immune system. A vaccinated chicken passes antibodies into her egg yolk to protect her developing chick. Researchers can then purify the antibodies from the egg yolk and put them to a variety of uses like fighting gum disease, norovirus, the flu, hepatitis, rotavirus, Zika virus, Ebola, and even COVID-19.16
But that is only the yolk. The egg white has even more mind-blowing possibilities. Egg whites are old medicine. The ancient Greeks used them to help seal wounds. According to a paper in PLoS One, in Asian countries, the membrane under the shell “has been used as an alternative natural bandage on burned and cut skin injuries for more than four hundred years.” Recent studies bear out these beneficial qualities. Researchers are studying egg membrane as a salve for burn victims, a material to promote corneal wound healing, a joint health supplement, an antiaging substance, and more. But the most astonishing medical development by far is the use of transgenic chickens to produce drugs. It sounds nuts, yes, but genetically altering a chicken might cause it to create eggs full of pharmaceuticals.17
The story begins with researchers Jennifer Doudna and Emmanuelle Charpentier who together won the 2020 Nobel Prize in Chemistry for their 2012 work discovering what is known as CRISPR-Cas9 gene-editing technology. Broadly speaking, viruses have a superpower: they can splice new lines of code into cellular DNA, which leads host cells to generate more viruses. Doudna and Charpentier figured out how to leverage that power. What if, instead of splicing in its own DNA, the virus inserted code chosen by researchers? Doudna and Charpentier’s technology opens a vista of possibilities. Cancer arises due to errors in genetic code at the cellular level. Could CRISPR be used to correct that code, leading to remissions? The applications of the field are moving fast. As I wrote this chapter, for example, news broke that scientists had used CRISPR to restore partial sight in a small number of people with Leber congenital amaurosis, whose limited vision arose from DNA errors in the retina.18
CRISPR is making sci-fi dreams possible, including that of designer chickens with curative egg whites. In 2015, the Food and Drug Administration approved the first transgenic chicken and eggs for medical use for lysosomal acid lipase deficiency, a rare inherited disorder that causes fat to pile up in various internal organs and the vascular system. Infants with the disease die quickly, while the form that affects adults causes a range of maladies, from liver problems to cardiovascular disease. Scientists used CRISPR to insert a sequence into chicken DNA that codes for a protein, in this case an enzyme that breaks down fat within cells. The chickens then lay eggs with whites full of the enzyme, which is refined and purified, then marketed as the drug Kanuma, and delivered intravenously to patients.19
More treatments are on the horizon, waiting for translation to clinical practice. In 2018, a team of Japanese and Korean scientists created transgenic chickens that laid egg whites with anticancer antibodies. The following year, Scotland’s Roslin Institute—most famous for cloning Dolly the sheep—produced a transgenic chicken line that laid eggs full of immune-stimulating proteins with antiviral, anticancer, and tissue repair properties. Scientists estimated that the method is economical, with three eggs producing a clinical dose. Meanwhile, Japanese researchers also ran a proof-of-principle study in 2020. They produced eggs containing anti-HER2 monoclonal antibodies, a key ingredient in existing drugs that fight a common but aggressive form of breast cancer. The press has given the whole field, which encompasses other designer animal–based therapeutics, a groaner of a name: farmaceuticals.20
The egg’s utility has its own dark side, though. Many more female animals will spend their lives never raising a single offspring, the magic of their bodies stolen for another species’ gain. On an industrial scale, the production and use of eggs represent the theft of the female body’s labor. I find this existentially sad, even while I continue to eat eggs and the idea of next-gen cancer treatments fills me with hope.