Fertile Cell Clusters Redefine Conception

Conception is an unbalanced equation: One egg plus one sperm equals a sum far more valuable than its parts. For years, University of Bath molecular embryologist Tony Perry has been trying to decode the mysterious mathematics of where life begins. In 2016, he and his team did something totally unexpected: They changed the formula itself.

Perry and his colleagues have demonstrated that a viable mouse embryo doesn’t require a sperm cell and an egg. To the contrary, they’ve found that it’s possible to hack the process of creation using a sperm cell and a one-cell “embryo” known as a parthenogenote, which forms when egg cells are chemically tricked into thinking it’s time to form an embryo, leading them to divide at will without a sperm’s input.

There’s no way the parthenogenote can survive on its own for long, let alone give rise to a new life: It’s only got one set of DNA — it takes mom and dad to make a baby, after all. Indeed, scientists have long written off parthenogenote, which don’t occur naturally in mammals as nonviable entities (they’ve been observed among invertebrates like fish but until now, hadn’t been seen as more than a necessary precursor to embryonic development among vertebrates). This makes the Perry discovery doubly important: Not only can a mammal produce a viable, standalone parthenogenote, but injecting a 13-hour-old parthenogenote with sperm can create life.

“Naturally, development starts when the sperm arrives and delivers a signal to the egg, and says, ‘Hey, I’m here! Time to party!’” Perry tells Inverse, explaining that scientists have long assumed that there’s something about the normal, intact egg environment that “reprograms” the newly arrived sperm’s DNA so that they can get life going together. Whatever that life-enabling something is, Perry has proven it’s not specific to the egg and thus changed the fundamental definition of sexual reproduction.

Hypothesis

Perry’s post-doctoral researcher, Toru Suzuki, originally had the idea of challenging the established view of natural fertilization. The notion was elegant in its simplicity: An egg, defined as a sex cell with half the DNA it needs to make a baby, has long been assumed to be the only cell that can be fertilized with sperm to make an embryo. But is this assumption correct?

“As you know, one way that you try and find out how things work is by pulling them to pieces and reconstructing them in different ways,” Perry says. So he and Suzuki ripped apart everything science believed about fertilization: They took that egg, used chemicals to turn it into something very different from an egg then managed to fertilize it anyway.

Data Collection

Challenging assumptions requires fiddling with the fundamentals. Perry and Suzuki took mouse eggs and washed them with a chemical called strontium chloride, causing them to divide and proliferate into parthenogenote. Eggs, Perry explains, are unique because they’re usually stuck halfway through meiosis, the process cells go through to cut their number of chromosomes in half. “They’re stuck there until the sperm delivers the signal to stop being stuck,” he says. Strontium chloride gives them a push.

As an egg splits into two cells, then four, and so on, it becomes a parthenogenote (an alternate term, used most often by American researchers, is “parthenote”). “That development goes for a few days in the mouse — not bad! — but it stops,” Perry says, adding that “developmental catastrophe” is inevitable without paternal chromosomes because an embryo can’t develop when its cells contain only half the genetic information required to form a new being.

Suzuki waited for a window to inject them with sperm before catastrophe could strike. Other scientists, Perry notes, have attempted to do this in the past: Some tried just minutes after the parthenogenote started dividing, while others waited a couple of hours. Every attempt ended in failure. Suzuki’s breakthrough idea was to wait a bit longer, injecting sperm after seven hours, or ten, or even thirteen. This was a gamble because there seemed to be only a tiny window during which an egg opens itself up to sperm. There was no clear reason to believe it would close and then reopen hours later — but that’s precisely what happened.

Results

As the fertilized parthenogenote grew, they looked identical to normal mouse embryos at the same stage. And why wouldn’t they? They were mouse embryos. They grew big enough to transplant into regular mouse wombs, where they incubated until they were ready to be born. Of the 259 mouse embryos that had been fertilized at the thirteen-hour stage, 8.1 percent lived to breathe air into their tiny mouse lungs. Those injected at seven hours, or ten hours, didn’t have nearly as much luck: only 1 percent and 1.8 percent of them lived, respectively.

The thirteen-hour generation was the first of its kind, and they were healthy and fertile, to boot.

Conclusions

The key to Perry’s experiment is understanding the difference between an egg and a one-cell embryo. A helpful analogy Perry uses is to think of an egg cell as a lump of dough, and an embryo as a loaf of bread. “If you want to put jam on your lump of dough and jam on a slice of bread and tell me that eating them is the same experience, then, well, good luck with that,” he says. To use push his analogy further, Perry’s research team reinvented the bread baking process.

“After 13 hours, this is an embryo. It’s no longer an egg,” Perry says. This is the eureka moment at the heart of his paper — one that he realizes is probably more exciting to biologists than to the average human. “People get very confused by this. They say, ‘You still need an egg to get the embryo, so what’s the point?’”

The point is that an egg and an egg-derived mass of cells are fundamentally different. While an egg is considered a meiotic cell, meaning it has half its chromosomes because its parent cell divided twice without copying its contents, the parthenogenote is mitotic — much like the rest of the cells in our bodies. Mitotic cells — like any other cell swabbed from the skin, or the liver, or the heart — make a copy of their DNA before splitting into daughters. In this sense, Perry explains, the one-cell embryo is much more like the rest of the body’s cells than the sex cells. If this mitotic cell can be fertilized, perhaps others can be nudged into doing so as well.

What’s Next?

Perry hesitates to say he toys with the origin of life, preferring to specify the more biological — and less philosophical — embryonic life instead. Despite his modesty, the implications of his work are profound for fertility treatment, genomic editing, and understanding cancer.

Still, scientific progress requires collaboration, and Perry is quick to point out that his research will be hard to apply until other experts have their own breakthroughs. His team, for example, isn’t in the business of figuring out whether regular, mitotic cells can be turned into cells that can be fertilized. But in March, a team of Chinese scientists did so, announcing that they had figured out how to create sperm from an embryonic stem cell — one that’s plucked from an embryo and has the potential to become any cell in the body. If they can do the same with an induced pluripotent stem cell one derived from any old cell in the adult human — the applications of his work become bountiful.

Very far into the future, scientists who have built on Perry’s work will fully understand how his mitotic, one-cell embryo became fertilizable. He imagines infertile women having their skin cells turned into egg cells; he also pictures multiple eggs in a dish being genetically edited with custom DNA before parthenogenesis begins. He’s excited about what his discoveries of the origins of embryonic life teach us about the beginnings of a cancerous death. The rapid expansion of a malignant tumor, it seems, eerily mirrors the raucous proliferation of a newly fertilized egg.

These scenarios, he insists, remain science fiction for now. But he’s encouraged by the confusion his work creates. “What’s going on?” Perry asks rhetorically. “We just really are, today, just in the tall grass. We don’t know.”