How one cell turns back time

None of us was made from scratch. Every human develops from the fusion of two cells, an egg and a sperm, that are the descendants of other cells. The lineage of cells that joins one generation to the next - called the germline - is, in a sense, immortal. Biologists have puzzled over the resilience of the germline for 130 years, but the phenomenon is still deeply mysterious.

Over time, a cell's proteins become deformed and clump together. When cells divide, they pass that damage to their descendants. Over millions of years, the germline ought to become too devastated to produce healthy new life. "You take humans - they age two, three or four decades, and then they have a baby that's brand-new," said K Adam Bohnert, a postdoctoral researcher at Calico Life Sciences in San Francisco, California, USA. "There's some interesting biology there we just don't understand."

Recently in the journal Nature, Adam and Cynthia Kenyon, vice president for ageing research at Calico, reported the discovery of one way in which the germline stays young. Right before an egg is fertilised, it is swept clean of deformed proteins in a dramatic burst of housecleaning.

The researchers discovered this process by studying a tiny worm called Caenorhabditis elegans (C. elegans). The worm has been a favourite of biologists for 50 years because its inner workings are much the same as our own. C. elegans relies on many of the same genes that we do to control the division of cells, for example, and to programme faulty cells to commit suicide.

The germline's secrets

In 1993, Cynthia discovered that a gene called daf-2 greatly influenced the lifespan of these worms. Shutting down the gene more than doubled the worm's lifetime from 18 days to 42 days. That finding, which Cynthia made while a professor at the University of California, San Francisco, USA, led to the discovery of an entire network of genes involved in repairing cells, allowing animals to live longer.

Humans depend on similar genes to repair cells, too. "Cynthia really pioneered the field of ageing and rejuvenation using C. elegans," said Irina M Conboy, a biologist at the University of California, Berkeley, USA. The longest-lived mutant worms savoured only an extra few weeks of life, but their germlines kept rolling along from one generation to the next.

Cynthia's curiosity about the germline's secrets was sharpened in 2010 by a study by Jérôme Goudeau and Hugo Aguilaniu, two biologists then at the University of Lyon in France. They took a close look at the proteins in the worm's egg-like cells, called oocytes. Most C. elegans are hermaphrodites, producing both eggs and sperm. As the eggs mature, they travel down a tube, at the end of which they encounter sperm.

Jérôme and Hugo discovered that a worm's eggs carry a surprisingly heavy burden of damaged proteins, even more than in the surrounding cells. But in eggs that were nearing the worm's sperm, the researchers found far less damage. Jérôme and Hugo then ran the same experiment with a twist.

They mutated a gene in the worms, leaving them unable to make sperm. The eggs in these entirely 'female' worms were filled with damaged proteins and did not get repaired. These experiments raised the possibility that the sperm were sending out a signal that somehow prompted the eggs to rid themselves of damaged proteins.

In 2013, Cynthia and Adam set out to test that possibility. (They moved the research to Calico in 2015.) Clumping proteins are involved in many diseases of old age, such as Alzheimer's disease. Cynthia and Adam set up an experiment using a special strain of worms in which clumping proteins glowed. In hermaphrodite worms, they discovered, immature eggs were loaded with protein clumps, while the ones close to the sperm had none. The researchers then created mutant "female" worms and observed that their eggs all became littered with protein clumps. When Adam let them mate with males, however, the clumps disappeared from the eggs. "In thirty minutes you typically see them cleared out," he said.

Adam and Cynthia then carried out additional studies, such as looking for other mutant worms that could not clear out protein clumps even though they could make sperm. Combining these findings, the researchers worked out the chain of events by which the eggs rejuvenate themselves. It begins with a chemical signal released
by the sperm, which triggers drastic changes in the egg. The protein clumps within the egg "start to dance around," Adam said.

The clumps come into contact with little bubbles called lysosomes, which extend fingerlike projections that pull the clumps inside. The sperm signal causes the lysosomes to become acidic. That change switches on the enzymes inside the lysosomes, allowing them to swiftly shred the clumps. "It's a huge, coordinated shift," Adam said. Adam and Cynthia hypothesise that the worms normally keep their eggs in a dormant state. The eggs accumulate a lot of damage, but make little effort to repair it.

Only in the last minutes before fertilisation do they destroy protein clumps and damaged proteins, so that their offspring won't inherit that burden. The detritus might even be recycled, Cynthia speculated, into building blocks needed to make the new proteins that are required to develop an embryo. "Once the oocyte hears the knocks on the door, then it can just clean it all out and even use it as food, maybe," she said.

In human reproduction

If her previous research is any guide, then we very likely could use the same strategy in human reproduction. "The hypothesis is that it's not just a worm thing," Cynthia said. That remains to be seen. In their new paper, Cynthia and Adam reported that they had tested this hypothesis on frogs, which are much more closely related to humans than is C. elegans.

The scientists exposed frog eggs to a hormone that signals them to mature. The lysosomes in the frog eggs became acidic, just as happens in worms. "I think it's a way to guarantee that you clean the slate for the next generation," Adam said.

The germline might not be the only place where cells restore themselves in this way. Throughout our lives, we maintain a supply of stem cells that can rejuvenate our skin, guts and brains. It could be that stem cells also use lysosomes to eradicate damaged proteins.

"That would have huge implications," Irina said. It might be possible, for example, to treat diseases by giving ageing tissues a signal to clean house. But Cynthia doesn't see new medicine emerging from this research anytime soon. "We didn't patent anything from it," she said. "I would think you'd need to know a lot more before you know exactly what to do. This is still the very early stage."