We Are Viral From the Beginning

By Carl Zimmer | June 14, 2012 1:42 pm

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.]

Comments (17)

  1. Typo: totipoent.

    I think that from the organismal lineage’s perspective, a virus is just another kind of mutation. Despite the somatic hypermutation hypothesis, I have a hard time thinking that the frequency of beneficial ERV genes will be all that great relative to other kinds of mutation.

  2. John–The questions of the frequency and the importance of these viruses compared to, say, a point mutation are two different questions. ERVs don’t just alter the genome the first time they get into it. They then make many copies of themselves after that. And while ERVs make up 8 percent of the human genome, something like another 50 percent (I’d have to look up the numbers) is made up of other mobile elements, many of which may also turn out to be vestiges of viruses. The reinsertion of new copies of all mobile elements is the biggest source of new mutations in the genome.

    Then there’s the question of the importance of these changes. Viral DNA shows up ready to party. It has promoters and protein-encoding genes, etc. These elements can be rapidly co-opted.

    On both counts, I think that ERVs and related mobile elements are both important to evolution and very interesting (philosophically among other ways).

  3. Colin

    I’m really curious how they know that we got the gene’s from virus’s rather than the other way around. How can they tell that virus’s aren’t just something that split off of us early on when they decided we weren’t moving fast enough for their taste.

    [CZ: Colin–You can look at the genealogy of viruses and viral DNA in human genomes to reconstruct their history. You can trace the mutations that arose in endogenous retroviruses as they spent more time in their host genomes–mutations that regular viruses lack.]

  4. Really enjoyed “A Planet of Viruses”, and the fact that viruses probably made us (and all vertebrates, probably, but definitely mammals) what we are today.

    The fact is, as I like telling anyone who will listen, and many who just have to, is that this is a viral planet: the greatest diversity of organisms on it are viruses; the greatest number of individual genomes on it are viral, and it is quite possible viruses contributed to the origin of the eukaryotic nucleus, let alone a major portion of it.

    Great blog; I look forward to the next edition!

  5. Janine

    I can’t read Carl Zimmer without wanting to scream The Auto-immune code has been cracked wide open see: the Marshal Protocol. Chloroplast and dysregulation of the vitamin D nuclear receptor.

    Changed the way I look at ‘managed’ medical research and institutions like Salk.

  6. David B. Benson

    Astounding. Better than F&SF.

  7. Jess Tauber

    There are many parallels between genome and language structures and presumably functions as well, from an abstract perspective. Some linguistic morphemes form messages, while others regulate them, or the listeners to the messages, etc. Viruses tend to be ‘executive’ heavy, that is, they control hierarchically lower-level functions to their own benefit.

    When one looks at archaeal communities, viruses are often permanently linked to them from without, yet don’t destroy their erstwhile hosts. They are probably helping to transfer genes that convey the ability to get along in their resource-poor environments, both to locals as well as to newcomers. Bacterial viruses tend to be much more selfish and destructive, but then bacteria tend to be as well, all other things being equal (being opportunists of rich pickings that archaea apparently are not- there are few hints they cause disease (and if some do its unusual)).

    In eukaryotes it may be the case (as some theorize) that nucleated cells come from a fusion of archaeal and eubacterial parents (along with their viruses one has to guess)- is there some continual give and take with external agents as well? The archaeal viruses, if benign and regulatory, would have formed the basis for much of the more cooperative executive machinery of the cell, while more opportunistic types would keep scaling the walls looking for entry. Some can be tamed. Can some of the ancient domesticated control genes mutate into fresh opportunists? My guess would be yes. Genetic dialectic. Lysenko would be proud- no, wait, he would have rejected all of this. Just as Marr would have rejected modern linguistics. God I miss the good old gulag days.

  8. I’m struck by the parallels with The Viruses That Make Us: A Role For Endogenous Retrovirus In The Evolution Of Placental Species by Luis P. Villarreal, which was brought to my attention by Greg Bear. Among his other excellent works, Bear wrote two science fiction novels that incorporated ERV-driven adaptive evolution, and pheromonal communication, which is as essential to communication in a new species of humans as it is in microbes.

    Pheromones, as we now know, are the chemicals that control nutrient chemical-dependent reproduction in all species. It seems likely that ERVs, including human ERVs (HERVs) cause the changes in intracellular signaling and stochastic gene expression that allow us to use olfaction and odor receptors in the clear evolutionary trail that can be followed from unicellular organisms to insects to humans.

    The HERVs, for example, need only alter a cell’s ability to metabolize nutrient chemicals (food) to cause downstream effects on every cell of any organism. The metabolism of the nutrient chemicals to pheromones does the rest in the context of adaptive evolution.

  9. Daniel J. Andrews

    You’re probably tired of hearing this, but you have to update and expand A Planet of Viruses. This is fantastically interesting material and deserves to be put into one big book for a general audience.

  10. Paul Burnett

    According to the “personhood” folks, the red and pink and gray blobs in the photo at the top of the article are pre-born humans with full Constitutional rights to vote, drive, bear arms and such. Did you get a model release from each one of them before the picture was taken?

  11. Bert

    “At first, these so-called endogenous retroviruses lead a double life. They can still break free of their host and infect new ones.”.

    I don’t think that the retrovirus that gets incorporated into the DNA of its host is necessarily active and capable of generating RNA copies. The translation process generates mutations and irrespective of that the packaging of the RNA, infection of a host and (after reverse transcriptase) integration into the host DNA can take place. So, the thing that gets integrated may be dead or barely alive on arrival. And that could well be the case for a majority of the cases because of selection pressure. Killing the host cell (egg) would not result in offspring.

  12. I totally agree with you Daniel J. Andrews. They should definitely update and expand on A Planet of Viruses! I think that this is very important material that should be open for people to be more aware of for sure.

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The Loom

A blog about life, past and future. Written by DISCOVER contributing editor and columnist Carl Zimmer.

About Carl Zimmer

Carl Zimmer writes about science regularly for The New York Times and magazines such as DISCOVER, which also hosts his blog, The LoomHe is the author of 12 books, the most recent of which is Science Ink: Tattoos of the Science Obsessed.

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