She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (72 page)

Not even gene editing with CRISPR changes this series of events. Once scientists began using CRISPR on ground-cherries and mice, their descendants still inherited DNA. The only difference was that some of the variants they inherited were put in place by people, rather than through spontaneous mutations. It's as if scientists were rerouting a river: Even in its new configuration, the river still flows.

But some recent advances in research may alter heredity itself in a far
more profound, puzzling way. In one of them, scientists accidentally broke through Weismann's barrier.

In 1999, a Japanese biologist named
Shinya Yamanaka opened a new lab at the Nara Institute of Science and Technology, hoping to find a way to make a mark for himself in a crowded field. Before coming to Nara, Yamanaka had discovered some genes that were active in the early embryos of mice. Many other scientists were also studying mouse embryos, figuring out how embryonic cells take on different identities. They pinpointed proteins that could push a lineage of stem cells to become muscles or neurons or other types of tissue. In the 1990s, research on embryonic cells raised hopes for a new way to treat diseases. Scientists could pluck a single cell from an embryo made in a fertility clinic and use it to make a colony of embryonic cells in a laboratory dish. With the right chemical signals, the embryonic cells could keep dividing into new embryonic cells for six months. A number of scientists began predicting that this method would make it possible to grow tissue on demand. People with Parkinson's disease could get transplants of healthy neurons. After a heart attack, doctors could repair a patient's damaged cardiac muscle with new cells.

Yamanaka thought that if he joined the chase, he'd get trampled into obscurity. So he decided to turn around and head in the opposite direction. Instead of figuring out how to turn embryonic cells into adult cells, Yamanaka would try to turn adult cells back into embryonic cells.

No one else was trying to pull off this trick, and with good reason. Turning back developmental time seemed impossible. If you trace a branch of the human body's pedigree from the fertilized egg to any cell in the adult body, you travel a long, twisted route. There may be hundreds or thousands of branching points along the way where one cell divided in two. And within each generation of cells, there was a flurry of biochemistry that made it possible for a different flurry to take over in daughter cells. To turn an adult skin cell back into an embryonic cell would seem to require traveling through all that history to the beginning, running all that biochemistry backward.

But Yamanaka suspected that our inner heredity might not be so hard to override after all. A few experiments carried out over the years gave him some hope. In 1960, for example, a British biologist named James Gurdon destroyed the nucleus in a frog's egg and replaced it with the nucleus from the animal's intestines. The egg began dividing, and eventually it grew into another frog. With this experiment, Gurdon had cloned the first animal. And in the process, he also showed that the genes in an adult cell could be reprogrammed to build an embryo all over again. In 1996, the Scottish biologist Ian Wilmut and his colleagues achieved much the same thing, this time in a sheep, creating a clone they dubbed Dolly.

Yamanaka wondered if there might be a simpler way to reprogram an adult cell to make it embryonic. To understand what makes embryonic cells embryonic, he looked for genes that were active only early in life and became silent in adulthood. Yamanka discovered some genes for proteins that acted like master switches, grabbing onto many genes in the cells and either shutting them down or turning them on. Yamanaka contemplated the idea of flooding adult somatic cells with proteins like these. They might seize control, forcing the cells back to an embryonic state once more.

It was, Yamanaka knew, a long shot. While he was aware of a few proteins that were active in embryonic cells, he had no idea how many others he would have to manipulate. There might be dozens, even hundreds. “
We thought at that time that the project would take 10, 20, 30 years or even longer to complete,” Yamanaka said.

Yamanaka organized his lab to start hunting for the proteins in mouse embryos. Five years of searching brought them two dozen. The scientists then tested each of the genes to see if it could reprogram an adult cell. They would add extra copies of a given gene to a skin cell from an adult mouse. The extra genes would flood the cell with extra copies of their protein. But the adult cell always stubbornly remained adult.

As the disappointments piled up, a graduate student named Kazutoshi Takahashi suggested that they stop testing the proteins one at a time. Instead, they should flood cells with all twenty-four of their proteins at once. Perhaps the combination of all the proteins might be able to deliver a little
nudge to the cells. Even such a tiny sign of hope would tell them their work wasn't in vain.

Yamanaka gave his blessing to the experiment, although he was sure Takahashi would fail. Takahashi inserted all twenty-four genes into the skin cells and waited to see what happened. Four weeks later, Takahashi came to Yamanaka with news. The adult skin cells had turned themselves into what looked like full-blown embryonic cells.

“I thought this might be some kind of mistake,” Yamanaka said. He had Takahashi rerun the experiment many times over. Time and again, the cells turned embryonic.

It was impressive enough that the cells looked like embryonic cells and made the key embryonic cell proteins. But Yamanaka wondered if they could behave like embryonic cells, too. His team injected a few of the reprogrammed cells into early mouse embryos to find out. The embryos developed into healthy adults, and the scientists found that the reprogrammed cells had given rise to normal adult cells scattered throughout the body.

This success led Yamanaka to wonder if flooding cells with all twenty-four proteins was overkill. He launched a new experiment, creating cocktails containing only some of the proteins and leaving others out. His lab found they needed only four proteins. Working with James Thomson at the University of Wisconsin–Madison, Yamanaka demonstrated that human cells became embryonic with the same simple recipe.

In his reports on the experiments, Yamanaka referred to his reprogrammed cells as induced pluripotent stem cells. Other scientists began testing out these cells, hoping they would prove even better than embryonic cells for medical treatments. It was easy to imagine doctors taking skin cells from patients, reprogramming them, and then coaxing the induced pluripotent stem cells into any type of adult cell they needed. Because the cells belonged to patients themselves, there wouldn't be any worry about rejection of foreign tissue.

In 2012, Yamanaka won the Nobel Prize. The prize not only recognized the practical promise of induced pluripotent stem cells; it also honored his discovery of a new way to think about time. August Weismann had
pictured the body as a branching tree of cells, the branches splitting through time. We could split our development into milestones: day 1, fertilization; day 2, two totipotent cells; and so on through the calendar of life. Each milestone had to come after the previous ones, because it depended on them. The heart could not appear before the three germ layers, because the heart had to form from one of those layers. Time gradually stiffened our inner heredity, committing each lineage to a single fate till death.

Yamanaka showed that time is not actually essential to the difference between an embryonic cell and a cell in the gall bladder or a hair cell in the ear. Our ancestors evolved a way to develop over time, to build one biochemical reaction on another in lineages of cells. But we can just push cells from one state to another.

Yamanaka didn't just undermine the power of time with his research; he also undermined some long-held beliefs about the germ line. The germ line has come to be seen as an all-important thread of heredity that is the sole link from one generation to the next. But this is a convenient fiction. When sperm and egg combine, they produce an embryo that has no distinct germ cells at all. Any cell in the embryo can, at that stage, give rise to new germ cells (or any other kind of cell). The germ line breaks, in other words, and only later in an embryo's life is it rebuilt. By turning somatic cells into germ cells, Yamanaka could sneak around Weismann's barrier.

Induced pluripotent stem cells behave much like the earliest cells in the embryo before the germ line reappears. With the right signals, they can develop into germ cells, just as they can become other types of tissue. In 2007, Yamanaka and his colleagues injected induced pluripotent stem cells into male mouse embryos, and found that some of the injected cells developed into sperm. The chimeric mice could even father mouse pups of their own with these sperm, which had come from a different mouse.

In order for the induced pluripotent stem cells to become sperm, a mouse's body sent it a particular series of chemical signals, guiding their development. Yamanaka's experiment led other researchers to wonder if they could deliver the same signals to cells sitting in a dish rather than in a mouse. In 2012, the Japanese biologist
Katsuhiko Hayashi managed to coax
induced pluripotent stem cells to develop into the progenitors of eggs. If he implanted them in the ovaries of female mice, they could finish maturing. Over the next few years, Hayashi perfected the procedure,
transforming mouse skin cells into eggs entirely in a dish. When he fertilized the eggs, some of them developed into healthy mouse pups. Other researchers have figured out how to make sperm from skin cells taken from adult mice.

Translating those results into experiments on human cells has proven hard. Some researchers have managed to turn a man's skin cells into a precursor of sperm called spermatids. But these transformed cells don't easily undergo meiosis, shuffling their DNA and pulling it into two sets.

Nevertheless, the success that Yamanaka and other researchers have had with animals is grounds for optimism—or worry, depending on what you think about how we might make use of this technology. It's entirely possible that, before long, scientists will learn how to swab the inside of people's cheeks and transform their cells into sperm or eggs, ready for in vitro fertilization.

If scientists can perfect this process—called
in vitro gametogenesis—it will probably be snapped up by fertility doctors. Harvesting mature eggs from women remains a difficult, painful undertaking. It would be far easier for women to reprogram one of their skin cells into an egg. It would also mean that both women and men who can't make any sex cells at all wouldn't need a donor to have a child. A man left infertile by chemotherapy, for example, could use a skin cell to make sperm instead.

Some researchers think that in vitro gametogenesis will trigger an explosion in the test-tube-baby business. Henry Greely, a bioethicist at Stanford University Law School, explored this possibility in his 2016 book
The End of Sex and the Future of Human Reproduction.
Greely speculated about a future world “where
most pregnancies, among people with good health coverage, will be started not in bed but in vitro and where most children have been selected by their parents from several embryonic possibilities.”

Today, parents who use in vitro fertilization can choose from about half a dozen embryos. In vitro gametogenesis might offer them a hundred or more. Shuffling combinations of genes together so many times could produce a much bigger range of possibilities.

Even after ruling out the embryos with disease-causing mutations, parents would still have many embryos left to choose from. They might pick embryos with variants that could affect the color of their children's eyes. Or they might follow Stephen Hsu's call, and pick out embryos that have a combination of variants that have been linked to higher intelligence scores.

But the implications of in vitro gametogenesis go far beyond these familiar scenarios—to ones that Hermann Muller never would have thought of. Induced pluripotent stem cells have depths of possibilities that scientists have just started to investigate. Men, for instance, might be able to produce eggs. A homosexual couple might someday be able to combine gametes, producing children who inherited DNA from both of them. One man might produce both eggs and sperm, combining them to produce a family—not a family of clones, but one in which each child draws a different combination of alleles. It would give the term
single-parent family
a whole new meaning.

The possibilities go on. Instead of three-parent babies, one can envision a four-parent child. It might be possible someday for four people to swab their cheeks and have induced pluripotent stem cells produced. Scientists could then turn the cells into sperm or eggs, which could then be used to make embryos. Two people would produce one set of embryos, and the other two would produce a second.

At the earliest stages of development, when the embryos were just balls of cells, scientists could remove cells from each one and coax them to develop in a dish into more eggs and sperm. And those could be used to produce a new embryo. If that embryo was then implanted in a surrogate mother and allowed to develop, the child would inherit a quarter of its DNA from each of the donors.

We haven't reached the age of multiplex parenting just yet. But it's close enough that philosophers have been thinking seriously about what it would signify. It would make mitochondrial replacement therapy look like ethical child's play. It would also leave children struggling to make sense of their own heredity. With some help from humans, any somatic cell can now gain the germ line's immortality and give rise to a new organism.

Hayashi's experiments push our language of kinship to the breaking
point. The mouse pups he produced have a mother of sorts, although they descended from her skin rather than from one of her original eggs. The same might be said of a human child born through in vitro gametogenesis. But once scientists start carrying out rounds of fertilization in their labs, it will be hard to say exactly what their pedigree is. Can your parents be eight-cell embryos? Since those original embryos won't be implanted, they will never become human beings. Robert Sparrow has argued that the embryos produced this way would be
orphaned at conception.