Part XIX: Günter Blobel, 1999 Prize in Physiology or Medicine
By Joseph Luna
Let’s start with a fantastical scene: picture a band of Neolithic humans in a hot air balloon overlooking modern New York City. What would they see and experience? Lacking a vocabulary and a mental model of twenty-first century life, our ancient friends would be awestruck at seeing miniscule specks and strangely ordered structures, lines and squares, in green and gray. Perhaps the occasional yellow rectangle from which specks would enter and exit would catch their attention. Or they might ponder a box with flashing lights, speeding its way across a grid. It’s near impossible to imagine being in their shoes, but it’s easy to envision the excitement as they try to describe and make sense of what they saw.
This totally novel experience wasn’t far off from what early cell biologists encountered, as they used the electron microscope (EM) as a sort of hot-air balloon to discover the cities inside cells. By the mid-1960s, they had plotted the geography of all sorts of cellular worlds, had given names to energy-making blobs and recycling vesicles, and with the help of radioactive amino acid labeling, had a basic sense of where proteins were made and where they ended up. But big questions remained such as how did a protein know where it needed to go? For a discipline built on EM observations from high above, this was a challenging question to answer, but it captivated a young German post-doc enough to dream as if he landed his hot air balloon and walked among molecules, where the view was much clearer.
Günter Blobel arrived in George Palade’s laboratory in 1967, shortly after completing his PhD at the University of Wisconsin at Madison. He joined a dynamic group of researchers who had stumbled upon an odd observation concerning the protein factories of the cell, its ribosomes: proteins destined to remain inside the cell were often made from a pool of freely cytoplasmic ribosomes, whereas proteins meant to be exported from the cell quickly associated with ribosomes attached to the endoplasmic reticulum (ER). How a new protein made this decision to stay in the cytoplasm or go to the ER was a mystery.
Within a few years, and overwhelmingly without much evidence, Blobel and a colleague (and Rockefeller University alum) named David Sabatini formulated what became known as “the signal hypothesis” that might explain how proteins got sorted to their proper locations. It represented a truly imaginative and startlingly precise leap, as if one could envision a five digit postal code and a stamp authentication system simply by watching mail trucks from space. Blobel and Sabatini proposed that ER destined proteins contained a special stretch of amino acids that acted like a signal that became apparent the moment the protein was being made at a ribosome. This signal sequence, located at the head of a protein, would be recognized by a factor (or factors) that would, in turn guide the synthesizing ribosome to the ER, where the protein in question could finish being born as it translocated across the ER membrane. Once properly sorted into the ER, the signal sequence was no longer needed and could be removed by an enzyme, even while the protein was still being made. Once finished, the protein could then go and do its job.