In the mid-1900s there was no such thing as a pregnancy test you could buy from the store and administer at home. Instead, women would send a vial of urine to a clinic where a technician would, of all things, inject it into a rabbit. The test worked, but the rabbits had to be killed. It was a discomforting process that lasted until a scientist stumbled upon a better species for the test: the Xenopus frog. The frog test was far faster, easier, and cleaner, and it shifted power for family planning and post-conception birth control from doctors to women themselves.

About The Disappearing Spoon

Hosted by New York Times best-selling author Sam Kean, The Disappearing Spoon tells little-known stories from our scientific past—from the shocking way the smallpox vaccine was transported around the world to why we don’t have a birth control pill for men. These topsy-turvy science tales, some of which have never made it into history books, are surprisingly powerful and insightful.

Credits

Host: Sam Kean
Senior Producer: Mariel Carr
Producer: Rigoberto Hernandez
Associate Producer: Sarah Kaplan
Audio Engineer: Rowhome Productions

Transcript

For whatever reason, human beings associate certain animals with pregnancy. Birds. Bees. Storks. But last century, no animal was more central to family planning than Xenopus laevis, the African clawed frog.

The association between babies and frogs began with a man with the fanciful name of Lancelot Hogben, who stumbled upon a secret: that frogs could predict pregnancy. It sounds like something out of a fairy tale. But it had nothing to do with princesses kissing toads. It was straight physiology. If you expose frogs to urine, the frogs can reliably predict who was pregnant and who wasn’t.

This was the first fast, cheap, widespread pregnancy test in history, and it empowered women’s health in unprecedented ways. But the legacy of Hogben’s frog test was not wholly benign. For all the good the test did for women, it’s also been blamed for the worst pandemic that scientists have ever seen.

Doctors in ancient Egypt developed the first-known pregnancy test around 1400 B.C. In it, women urinated on a mix of barley and wheat seeds. If the baby was male, the barley supposedly sprouted. If female, the wheat sprouted. If neither sprouted, she wasn’t pregnant.

Now, this test doesn’t work as advertised—it can’t distinguish male fetuses from female ones. But in the 1960s, scientists determined that, in 70 percent of pregnancies, a woman’s urine did help seeds sprout and promote growth, perhaps due to the elevation of certain hormones during pregnancy. 

After that, the science of pregnancy prediction stalled for the next 3300 years. But starting in 1928, scientists finally developed a few reliable tests. The tests involved injecting the urine of possibly-pregnant women into either infant mice or virgin rabbits. In both cases, if a woman was pregnant, the injection would make the ovaries of the mouse or rabbit swell in size.

The mouse test was cheaper but slower, taking four days. The more expensive rabbit test took two days. Before long, the rabbit test gave rise to a new euphemism for pregnancy. If you had a “bun in the oven” or were “in the family way,” instead people might say, “the rabbit died.”

Why? Because checking the size of the rabbit’s ovaries required slicing open its gut and killing the creature. In fact, even if you weren’t pregnant, the rabbit still died. 

This left many people uncomfortable—checking for new life by slaughtering an animal. There had to be a better way.

Lancelot Hogben found that way. Fittingly, Hogben had a dramatic birth. He was born in England two months premature in 1895. His parents were evangelical Christians, and his survival was considered such a miracle that they promised God that Hogben would become a traveling medical missionary.

Hogben did end up loving medicine, and he did lead a wandering life. But to his parents’ disappointment, he preferred lab work over patient care. He also became a militant atheist and a left-wing rabble-rouser. 

At age 17, Hogben won a scholarship to Cambridge University, the first student ever from his school to win one, and it was a rare scholarship extended to a poor family at the time. He studied physiology there, especially hormones—the chemical interface between brain and body. 

Hogben found his classes fascinating, but he never fit in socially at Cambridge amid the sons of dukes and business magnates. Then, he refused to serve as a soldier during World War I, and spent three months in prison, which made him something of a pariah.

After prison, he married a woman named Enid, with whom he would have four children. Meanwhile, he resumed his science career by lecturing in zoology. He really wanted to conduct research, but unlike the aristocratic gentleman-scientists he knew from Cambridge, Hogben couldn’t use daddy’s money to fund his own lab. He needed a university position. And with each new child, he needed a bigger paycheck. 

This led to years of hopping between schools, chasing more money—in London, Edinburgh, Montreal, Aberdeen, Birmingham, even the University of Guyana in South America. But one stint in South Africa in the 1920s would make his career.

His research there involved the African clawed frog, the Xenopus. It’s a grey-green croaker two to four inches long. It has no tongue and no eyelids, so it stares at you forevermore, never blinking. It also has long, thin fingers, more human-like than amphibian. It’s native to Southern Africa.

Xenopus has one notable property: it changes color, depending on its surroundings. If raised in a dark environment, it turns black. If raised in light surroundings, it turns white. This color shift provides camouflage.

Hogben suspected that this change was controlled by the pituitary gland. It’s a hormone factory attached to the bottom of the brain. Sure enough, when he removed the pituitary glands from some frogs, they remained white their whole lives, no matter the surroundings.

But removing the pituitary had an unwelcome side effect: it caused the female frogs’ ovaries to shrivel. To counteract this, Hogben injected some pituitary extracts from an ox. To his surprise, the frogs immediately released eggs.

Normally, clawed frogs never release eggs in captivity without a male frog being present. But even a drop of ox hormone caused them to spew hundreds of eggs. The eggs looked like tiny black-eyed peas coated in slime.

Other scientists might have written this off as a useless quirk of frog physiology. But given his left-wing politics, Hogben had another idea—for a pregnancy test. 

Frankly, the idea was a stretch. It involved HCG—human chorionic gonadotrophin. HCG is a hormone pregnant women produce. It thickens the lining of the uterus to support an embryo, and halts the release of new eggs from the ovaries. 

The production of HCG spikes between the sixth and twelfth weeks of pregnancy, then it sharply declines. During the spike, pregnant women produce so much HCG that they excrete the excess in their urine. 

Hogben’s idea was this: if you inject a frog with some pituitary extract from an ox, the frog will lay eggs. Oxen and human are both mammals, so they’re vaguely related. And HCG affected the release of eggs in humans. So maybe the urine of pregnant women, which contains HCG, would also stimulate frogs to lay eggs. Maybe?

It doesn’t sound promising. But that’s genius for you—it doesn’t have to make sense beforehand, as long as it’s right. And Hogben was right. The urine of pregnant women really will make frogs ovulate and release eggs. 

This had all the makings of a brilliant pregnancy test, far superior to the mouse or rabbit tests. Frogs were cheaper to keep, in part because they’d eat anything, from minced liver to dead flies. They also release their eggs quickly, within five hours of being injected. That was far better than the 48 hours for a positive test with rabbits.

Best of all, you didn’t have to kill the frogs! They released their big, fat, slimy eggs externally, at the bottom of the tank. You could even reuse the same frogs over and over.

Hogben grew so enchanted with the African clawed frog that he named his house in South Africa the Xenopus. People would talk of swinging by the Xenopus for dinner, or stopping at Xenopus for drinks. Very chic.

Unfortunately, Hogben was less enamored with South Africa itself. The political system that would lead to apartheid was hardening into place at the time. He fought back by encouraging Black students to attend his lectures and inviting them to his house. But he could do only so much, and he quit South Africa in disgust in 1930 and went to London.

There, true to form, he began attacking the British class system and later helped find jobs for Jews persecuted in Nazi Germany. Scientifically, he imported several cages of his beloved frogs and hired a researcher to perfect the pregnancy test.

Eventually, a protocol emerged. Clinics generally kept the frogs in aquariums with a few inches of water—although a few later realized that the vegetable-crisping drawers of refrigerators worked just as well. Just toss some moss and water into the drawer, and the frogs were perfectly content.

Women wanting to take a pregnancy test would mail their urine to the clinic. Morning urine was preferred, since it was the most concentrated. Given delays with the postal system sometimes, samples often arrived smelling a bit funky. Other times, the packages arrived sodden, the vials having broken in transit.

The technicians who ran the tests were mostly female. They’d pinch their noses, treat the urine with chemicals like alcohol or vinegar, centrifuge the mix, and add some baking soda to get the pH right. Then they’d grab the frog and inject two cubic centimeters of urine into a lymph sac or its thigh. 

Afterward, they’d plop the frog in a numbered jar. Five to twelve hours later, if the woman was pregnant, a few hundred black-and-white eggs would be bobbing on the bottom of the jar. Mazel tov. 

In addition to being fast and cheap, the frog test was incredibly accurate—around 99.8 percent. Engineers sometimes talk about the tradeoffs you face in developing new technologies. As the saying goes—better, faster, cheaper. Pick two. 

But with frogs, women didn’t have to choose. This fairytale test was superior in every way.

Given its superiority, by the 1940s, the Hogben pregnancy test was in high demand. Tanks of Xenopus frogs were shipped across the globe. The biggest labs carried out 10,000 tests per year. 

The consequences were nothing less than revolutionary. As strange as it sounds, before this point, pregnancy tests weren’t really about detecting pregnancy. 

You see, certain medical disorders can mimic the symptoms of pregnancy. If you feel nauseous and have missed a period, yes, you might be pregnant. But you might also have a tumor or an endocrine imbalance. 

The rabbit and mouse pregnancy tests allowed doctors to diagnose these disorders. If you had signs of pregnancy, but the ovaries of the dead mouse or rabbit were not enlarged, then it was time to look for other causes. Pregnancy tests also helped detect ectopic pregnancies, where an embryo implants in a woman’s Fallopian tubes. If there was a lump and pain there, a pregnancy test could detect this dangerous condition.

The point is that the tests were not intended for everyday women to determine whether they were pregnant. The tests were too expensive for that, and the grisly nature of killing mice and rabbits made doctors hesitate to order too many.

Frankly, doctors also liked the control that they had. The early 1900s were a paternalistic age in medicine. Doctors alone determined what was good for women medically, including what tests they could take. They preferred making women wait until a baby bump appeared at four to five months.

In all, pregnancy tests were seen as diagnostic tools, not for family planning. Conservative doctors also feared that early pregnancy tests would lead to a rash of illegal abortions. 

The frog test changed everything. It was cheap enough for most women to afford. No animals died, either. Enterprising doctors set up testing labs, and year by year, early pregnancy testing became more common.

This allowed women to make better, more informed decisions. It removed mystery and stress. Women with high-risk conditions like heart trouble or tuberculosis could also get medical attention sooner. The test was especially helpful for single women who needed more time to rearrange their lives and secure help to care for a child. Or terminate the pregnancy if they chose.

If nothing else, some women wanted to know they were pregnant as early as possible, so they could celebrate. They were excited! And the frog test let them celebrate sooner.

But for all the good Xenopus did for women, its spread across the globe harmed its fellow amphibians. That’s because Xenopus has been indicted as a vector in what some scientists call the worst pandemic in history—a real life plague of frogs. Only this time, frogs are the victims. 

I’ve put together a bonus episode on this plague at patreon.com/disappearingspoon. It covers both the frog holocaust, and efforts to combat it—including the cutest little frog saunas you’ll ever see. As a mini-bonus, you’ll also hear how making frogs wear trousers in one experiment produced one of the most important breakthroughs in the history of biology. All that and more at patreon.com/disappearingspoon.

After establishing his pregnancy test, Lancelot Hogben didn’t rest on his laurels. He continued doing research in physiology and helped his beloved Xenopus become a common research tool in physiology labs. Even today, thousands of labs worldwide still employ this frog. It was one of the first animals ever cloned, and it even flew in a space shuttle, where it became the first vertebrate to reproduce in outer space. You can actually hear more about this in the Science History Institute’s flagship podcast, Distillations, in an episode called, “Science, Interrupted.”

Hogben also kept up his social activism. As we’ll hear next week, he became a committed foe of the dark pseudoscience of eugenics. As part of this battle, Hogben traveled to Norway in March 1940 to attack Nazi Germany’s embrace of so-called race science.

However brave, this attack on Nazi science proved to be foolhardy. Because the day after Hogben’s last lecture in Norway, the Nazis invaded the country.

Hogben and his daughter, who’d tagged along, were driving to the airport when the Nazis stormed in and took control of it. The Nazis also shut down all ports, highways, and railroads out of Norway. Then stormtroopers began marching through the streets of cities, rounding up enemies of the conquering regime. A far-left scientist who’d publicly attacked their ideology was a prime target.

Hogben and his daughter bribed a truck driver to smuggle them to a border town. They slipped into Sweden the next night with nothing but their passports. They stayed two months there while Hogben translated scientific papers for money. With that cash, they flew to Moscow, then took the trans-Siberian railroad to the Pacific Ocean. They eventually sailed to San Francisco. 

In America, Hogben and his daughter met up with his oldest son in Wisconsin, where the lad was attending college. He decided to stay and teach for a semester. While there, he reunited with his wife, who had divorced him and moved to Ottawa with their two youngest children. This would mark the last time ever the family was all together in one place.

Hogben sailed to England in February 1941, where he resumed his research. He became an early whistleblower about the overuse of antibiotics and the rise of drug-resistant microbes. He also continued hopping jobs. Along the way, he published a few popular science books. He even invented an artificial language called Interglossa, which he hoped would promote peace and cooperation among all humankind. Not quite. 

Although Hogben has slipped into obscurity today, his frog test completely reshaped our world. The test appeared at roughly the same time as the first birth-control pills, which have received far more attention. But quick, reliable pregnancy tests proved an equally vital part of the women’s health revolution, by shifting control of early pregnancy away from doctors. Hogben never became the missionary that his parents desired. But for women of the time, his work was nothing short of a godsend.