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Process & Nature of Science

The Vaulted Secrets of Cells

Some things that scientists seek to understand are very, very far away. Other things occurred long, long ago. It's not too surprising to learn that both kinds of things are hard for scientists to understand (take, for example, the origin of life, the topic of last week's post). But some mysteries are sitting in plain view--enigmas made all the more enigmatic by being so familiar. One of my favorite familiar enigmas can be found in your cells--by the thousands.

In the mid-1980s, Leonard Rome and his colleagues at UCLA were studying how proteins are shuttled around cells to perform their particular tasks. Some proteins are chauffered to their destinations in little bubble-like structures called coated vesicles. Nancy Kedersha, a researcher who was working with Rome at the time, opened cells and collected their coated vesicles. But when she looked at them under a powerful electron microscope she discovered something strange: along with the ordinary, ball-shaped coated vesicles, she also saw tiny structures that had elegantly geometrical shapes. They reminded the scientists of the vaulted ceilings of cathedrals.

There were thousands of these odd shells in a single cell, and yet Kedersha and Rome had never seen them before. No scientists had, in the 350 years that they've been looking at cells. In the mid-1600s, the newly invented microscope allowed researchers to peer at tissues from plants. They noticed that the plants were actually made up of tiny building blocks. Later, it turned out that animals had similar building blocks, which came to be known as cells. In the 1700s, researchers began to notice tubes and spheres and other structures inside the cells. Experiments eventually revealed the roles of some of those parts. The nucleus, for example, housed DNA. The ribosome used information encoded in genes to assemble proteins. Mitochondria created fuel by storing energy in molecules. Yet for all the research on cells, nobody realized that there were thousands of peculiar little shells hiding in them as well. Rome and Kedersha had to give them a name so that other people would know what they were talking about. They dubbed them vaults.

Once Rome and Kedersha had discovered vaults, they did not automatically know what vaults were for. Electrons and mountains and other things in the natural world do not speak to scientists, explaining themselves. Scientists must observe things, make hypotheses, and test those hypotheses against new observations. Did vaults carry out some basic function for living things? It turned out that vaults exist in the cells of a huge range of species, from mice to slime molds. These species must have inherited those vaults from their ancestors, suggesting that they have been floating around in cells for hundreds of millions, or even billions, of years. Their longevity suggests they're doing something important.

One common way biologists figure out how something works is to break it. A fly with broken wings can walk but can't fly--which suggests that wings are important for flight. Scientists can also shut down genes so that they can't make proteins. Without certain essential proteins, organisms may suffer various diseases or--if the gene is especially important--they may even die. Yet mice that could not make vaults grew up seemingly normal.

Yet other experiments suggest that vaults do something. Scientists have noticed that cancer cells have many more vaults than normal ones. And the more vaults they find in cancer cells, the more likely those cells will resist cancer-killing drugs.

In 2007, Gerald Pier of Harvard and his colleagues found another clue to the nature of vaults essentially by accident. They wanted to understand how our lungs remain healthy even as we breathe in air laced with bacteria. When bacteria make contact with the cells on the inner surface of the lungs, the cells respond. Rafts of molecules grow on the surface of the cells, and they appear to trigger a series of reactions inside the cells that ultimately leads to the cells devouring the bacteria and destroying them. Pier and his colleagues teased apart 150 different kinds of proteins in these rafts. One of them was the main protein in vaults.

This result suggested that vaults floated up the membranes of lung cells when they encountered bacteria and joined the rafts. So Pier and his colleagues engineered their own vault-free mice, and did something previous scientists hadn't: they sprayed bacteria into the noses of mice with and without vaults. The mice without vaults were three times more likely to die. Autopsies on the mice showed that without vaults the cells lining their lungs did a bad job of absorbing and kill the bacteria.

ZimmerBlog3.jpg
Acta Crystallogr D Biol Crystallogr.
2008 May 1; 64(Pt 5): 525-531.
Published online 2008 April 19. doi:
10.1107/S0907444908004277.

Better understanding the shape of vaults has also allowed scientists to test some hypotheses for what vaults do. The first pictures of vaults were fuzzy images captured through microscopes. In recent years, several teams of scientists have created more detailed ones by creating vault crystals. They stack vaults together in neat piles and then blast X-rays at them. The X-rays bounce off the repeating patterns of the vaults, and by tracking their path, scientists can figure out how the molecules that make up the vaults fit together. This week Tomitake Tsukihara of Osaka University and his colleagues published the most detailed picture of vaults ever made.

A vault is, of course, tiny. If you enlarged a vault 10 million times, it would be the size of a football. If you enlarged a football 10 million times, it would be the size of the Earth. It is made of two cups that fit together, a bit like the two halves of a Russian Matryoska doll. The ends of the caps are shaped much like parts of proteins that are known to attached to rafts on the membranes of cells. The walls of the vault are exquisitely thin, and the interior is hollow. Tsukihara and his colleagues say that their new work confirms earlier suggestions that the vaults can open up at their waists, the two half-cups folding open like the petals of a flower.

That's a beautiful image, but it also raises a nagging question: do they open up for any good reason? It's possible that vaults swallow certain molecules and deliver them to another part of the cell--perhaps to the membranes, where they attach to rafts. But no one can say exactly what the vaults are carrying. Still, this hypothesis may explain the cancer connection: perhaps in cancer cells, the vaults trap chemotherapy drugs and deliver them to places where they can't damage a cancer cell. By making exta vaults, the cancer cell protects itself from death.

It's also possible, however, that vaults are more than ferries. Scientists have observed that the proteins that make up the vault can interact with proteins that carry signals around the cell. Some researchers have suggested that the surface of vaults are like cafes for signalling molecules to meet and exchange information.

At the moment, scientists will not accept any of these hypotheses. For now, these beautiful pieces of cellular sculpture remain beyond firm explanation. Yet they also remain in plain sight--a reminder of how much scientists have yet to learn about the world.

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