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Explaining 1999's Nobel Prize in Medicine

Dr. Guenter Blobel of the Rockefeller University in New York won the Nobel Prize for medicine this Monday for research that few nonscientists have ever heard about. In research carried out over 20 years, he solved one of the most fundamental riddles of cell biology.

To understand what he did, we must first consider for a moment what a cell is like. Every high school biology student learns that human cells have a complicated architecture. Each cell is subdivided into compartments, like the rooms of a building. Each compartment, called an organelle, carries out a particular function. The nucleus, for example, is responsible for heredity, while the mitochondrion carries out energy metabolism. Each cell organelle is encased by a membrane, like a skin surrounds an orange.

Here is the riddle. The cell makes all of its proteins in the matrix between organelles, called the cytoplasm. How do the large proteins busy at work within an organelle ever get in through its skin, in the first place? The membrane around an organelle provides a very tight seal, and nothing much larger than a tiny water molecule can slip through without help.

And here is an even deeper question. How does an individual protein manufactured in the cytoplasm know where it is supposed to go? How does a protein destined to be secreted from the cell know to go into the cell's transport highway (an organelle called the endoplasmic reticulum), and not into the nucleus, or into a mitochondrion?

It is these questions, among the most basic in cell biology, that Blobel answered.

In 1971, Dr. Blobel carried out a key experiment that led to a bold hypothesis. Blobel worked with what biologists call a "cell free system" -- a test tube containing all the elements of a cell's cytoplasm necessary to manufacture proteins. All that is required to make a protein is that you provide the test tube with specifications, a gene copy called messenger RNA. To his cell-free system Blobel added the messenger RNA specifying a secretory protein, one that in a normal cell is destined to enter the endoplasmic reticulum and eventually be exported from the cell. As expected, the cell free system proceeded to manufacture the secretory protein.

Now Blobel repeated the experiment, but this time he also added to the test-tube something extra, tiny artificial spheres of endoplasmic reticulum called microsomes. The secretory proteins were again manufactured, but these were slightly smaller!

Analyzing the two proteins, Blobel found there was a bit of extra protein on the tip of the larger version. Blobel called this added bit a signal peptide (a peptide is a small portion of a protein), and formed the then-radical hypothesis that organelle proteins contain signal sequences that direct them to their proper destination.

The secretory protein's signal peptide is the first part of the protein that is made. It binds to a special receptor found on endoplasmic reticulum (and nowhere else), loosely called a "docking protein." The secretory protein is then threaded through the membrane and into the endoplasmic reticulum as it is made. After the newly-made protein is completely across, its signal sequence is clipped off. That is why, in Blodel's experiment, the microsome versions were smaller.

Later studies prove Blobel's signal hypothesis right. When Blobel's clipped-off signal peptides are added to the ends of proteins that normally do not have them, the resulting signal-tagged proteins are directed to the endoplasmic reticulum, just as Blobel's signal hypothesis predicts.

Over the next 20 years, Blobel found that each kind of cell organelle has its own characteristic signal sequence, sort of a cellular "zip code" that directs it to its proper address within the cell. He worked out the molecular details of how each signal is processed, and showed that the processes are universal, operating similarly in animal, plant, and yeast cells.

Blobel had indeed found the key to understanding how cells organize themselves.

"A number of human hereditary diseases are caused by errors in these signals," the Nobel Assembly pointed out in announcing the prize. For example, cystic fibrosis is caused by a signal defect that prevents a protein called a chloride channel from reaching its proper destination. Another example is the hereditary disease primary hyperoxaluria, which causes kidney stones at a very early age. Inherited very high levels of cholesterol, the most common hereditary defect in America, is due, in some forms, to deficient transport signals.

Blobel's research provides an excellent example of the benefits of basic research to all of us. His dogged pursuit of a rather abstract problem in cell biology, funded by decades of federal research dollars, has led to understanding that provides a key tool in combating hereditary disorders. Few long-term investments provide a surer return than investing in knowledge.

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