We Are Viral From the Beginning

We all started out as a fertilized egg: a solitary cell about as wide as a shaft of hair. That primordial sphere produced the ten trillion cells that make up each of our bodies. We are not merely sacs of identical cells, of course. A couple hundred types of cells arise as we develop. We’re encased in skin, inside of which bone cells form a skeleton; inside the skull are neurons woven into a brain.

What made this alchemy possible? The answer, in part, is viruses.

Viruses are constantly swarming into our bodies. Sometimes they make us sick; sometimes our immune systems vanquish them; and sometimes they become a part of ourselves. A type of virus called a retrovirus makes copies of itself by inserting its genes into the DNA of a cell. The cell then uses those instructions to make the parts for new viruses. HIV makes a living this way, as do a number of viruses that can trigger cancer.

On rare occasion, a retrovirus may infect an egg. Now something odd may happen. If the egg becomes fertilized and gives rise to a whole adult individual, all the cells in its body will carry that virus. And if that individual has offspring, the virus gets carried down to the next generation.

At first, these so-called endogenous retroviruses lead a double life. They can still break free of their host and infect new ones. Koalas are suffering from one such epidemic. But over thousands of years, the viruses become imprisoned. Their DNA mutates, robbing them of the ability to infect new hosts. Instead, they can only make copies of their genes that are then inserted back into their host cell. Copy after copy build up the genome. To limit the disruption these viruses can cause, mammals produce proteins that can keep most of them locked down. Eventually, most endogenous retroviruses mutate so much they are reduced to genetic baggage, unable to do anything at all. Yet they still bear all the hallmarks of viruses, and are thus recognizable to scientists who sequence genomes. It turns out that the human genome contains about 100,000 fragments of endogenous retroviruses, making up about eight percent of all our DNA.

Evolution is an endlessly creative process, and it can turn what seems utterly useless into something valuable. All the viral debris scattered in our genomes turns out to be just so much raw material for new adaptations. From time to time, our ancestors harnessed virus DNA and used it for our own purposes. In a new paper in the journal Nature, a scientist named Samuel Pfaff and a group of fellow scientists report that one of those purposes to help transform eggs into adults.

In their study, Pfaff and his colleagues at the Salk Institute for Biological Sciences examined fertilized mouse eggs. As an egg starts to divide, it produces new cells that are capable of becoming any part of the embryo–or even the membrane that surrounds the embryo or the placenta that pipes in nutrients from the animal’s mother. In fact, at this early stage, you can pluck a single cell from the clump and use it to grow an entire organism. These earliest cells are called totipoent.

After a few days, the clump becomes a hollowed out ball. The cells that make the ball up are still quite versatile. Depending on the signals a cell gets at this point, it can become any cell type in the body. But once the embryo reaches this stage, its cells have lost the ability to give rise to an entirely new organism on their own, because they can’t produce all the extra tissue required to keep an embryo alive. Now the cells are called pluripotent. The descendants of pluripotent cells gradually lose their versatility and get locked into being certain types of cells. Some become hematopoetic cells, which can turn into lots of different kinds of blood cells but can no longer become, say, skin cells.

Pfaff and his colleagues examined mouse embryos just after they had divided into two cells, in the prime of their totipotency. They catalogued the genes that were active at that time–genes which give the cells their vastly plastic potential. They found over 100 genes that were active at the two-cell stage, and which then shut down later on, by the time the embryo had become a hollow ball.

One way cells can switch genes on and off is producing proteins that latch onto nearby stretches of DNA called promoters. The match between the protein and the promoter has to be precise; otherwise, genes will be flipping on at all the wrong times, and failing to make proteins when they’re needed. Pfaff and his colleagues found that all the two-cell genes had identical promoters–which would explain how they all managed so become active at the same time.

What was really remarkable about their discover was the origin of those promoters. They came from viruses.

During the earliest stage of the embryo’s development, these virus-controlled genes are active. Then the cells clamp down on them, just as they would clamp down on viruses. Once those genes are silenced, the totipotent cells become pluripotent.

Pfaff and his colleagues also discovered something suprising when they looked at the pluripotent ball of cells. From time to time, the pluripotent cells let the virus-controlled genes switch on again, and then shut them back down. All of the cells, it turns out, cycle in and out of what the scientists call a “magic state,” in which they become temporarily totipotent again. (The pink cells in this photo are temporarily in that magic state.)

Cells in the magic state can give rise to any part of the embryo, as well as the placenta and other tissue outside the embryo. Once the virus-controlled genes get shut down again, they lose that power. This discovery demonstrated that these virus-controlled genes really are crucial for making cells totipotent.

Pfaff and his colleagues propose that the domestication of these virus promoters was a key step in the evolution of mammals with placentas. The idea that viruses made us who were are today may sound bizarre, except that Pfaff is hardly the first person to find evidence for it. Last year, for example, I wrote about how placental mammals stole a virus protein to build the placenta.

A discovery this strange inevitably raises questions that its discoverers cannot answer. What are the virus-controlled genes doing in those first two cells? Nobody knows. How did the domestication of this viral DNA help give rise to placental mammals 100 million years ago? Who knows? Why are viruses so intimately involved in so many parts of pregnancy? Awesome question. A very, very good question. Um, do we have any other questions?

We don’t have to wait to get all the answers to those questions before scientists can start to investigate one very practical application of these viruses. In recent years, scientists have been reprogramming cells taken either from adults or embryos, trying to goose them back into an early state. By inducing cells to become stem cells, the researchers hope to develop new treatments for Parkinson’s disease and other disorders where defective cells need to be replaced. Pfaff suggests that we should switch on these virus-controlled genes to help push cells back to a magic state.

If Pfaff’s hunch turns out to be right, it would be a delicious triumph for us over viruses. What started out as an epidemic 100 million years ago could become our newest tool in regenerative medicine.

(For more on these inner passengers, see my book A Planet of Viruses.)

[Image: Courtesy Salk Institute.]