Wednesday, July 16, 2008

Nobel Laureate: George Palade

 

The Nobel Prize in Physiology or Medicine 1974.
"for their discoveries concerning the structural and functional organization of the cell"



George E. Palade (1912 - ) received the Nobel Prize in Physiology or Medicine for his contribution to understanding how proteins are synthesized and secreted in eukaryotic cells. He worked mostly on the secretory (exocrine) cells of guinea pig pancreas using a combination of cytological and cell fractionation techniques. As he says in his Nobel lecture, he was fascinated by the organization of these cells with their complex endoplasmic reticulum studded with ribosomes. Palade was among the first to get good electron micrographs of these structures [see below].

The idea was to track the route of newly synthesized proteins from the ribosomes to the exterior of the cell. Part of the solution came from developing techniques for EM autoradiography. This allowed Palade and his group to show that new proteins were first made by ribosomes sitting on the surface of the endoplasmic reticulum (ER). The labelled proteins were immediately seen to enter into the lumen of the ER. Subsequently they passed through internal vesicles and the Golgi until they reached the plasma membrane.

The photographs below show the results of a typical pulse-chase experiment. In the first panel (A) you can see that that with only a short pulse of radioactive amino acids the radioactive proteins—identified by the black squiggles—are localized to the endoplasmic reticulum. For a complete description of the photograph see The American Society for Cell Biology.

The pathway worked out in the 1950s and '60s is now known to be correct and it's a universal pathway found in all eukaryotes.

Palade is credited with being the first one to describe the small particles that later came to be known as ribosomes.

Palade was born in Romania where he obtained his M.D. degree in 1940. He joined the Rockefeller University shortly after World War II and remained there until he took up a position at Yale in 1973. In 1990 he moved to the University of California, San Diego.

Palade shared the 1974 prize with Albert Claude and Christian De Duve.

The presentation speech was delivered in Swedish by Professor Jan- Erik Edström of the Karolinska Medico-Chirurgical Institute


THEME:
Nobel Laureates
Your Majesty, Your Royal Highnesses, Ladies and Gentlemen,

The 1974 Nobel Prize in Physiology or Medicine concerns the fine structure and the function of the cell, a subject designated Cell Biology. There are no earlier Prize Winners in this field, simply because it is one that has been newly created, largely by the Prize Winners themselves. It is necessary to go back to 1906 to find Prize Winners who are to some extent forerunners. In that year Golgi and Cajal were awarded the Prize for studies of cells with the light microscope. Although the light microscope certainly opened a door to a new world during the 19th century, it had obvious limitations. The components of the cell are so small that it was not possible to study their inner structure, their mutual relations or their different roles. To take a metaphor from an earlier Prize Winner, the cell was like a mother's work basket, in that it contained objects strewn about in no discernible order and evidently, for him, with no recognizable functions.

But, if the cell is a work basket, it is one on a very tiny scale indeed, having a volume corresponding to a millionth of that of a pinshead. The various components responsible for the functions of the cell correspond in their turn to a millionth of this millionth, and are far below the resolving powers of the light microscope. Nor would it have helped if researchers had used larger experimental animals: the cells of the elephant are not larger than those of the mouse.

Progress was quite simply at a standstill during the first few decades of this century, but then in 1938, the electron microscope became available, an innovation that held out great promise. The difference between this microscope and the ordinary light microscope is enormous, like being able to read a book instead of just the title. With such an instrument it should now be possible to see components almost down to the dimensions of single molecules. But the early hopes were succeeded by disappointment. It was found impossible to prepare the cells in such a way that they could be used. The book remained obstinately shut, even though it would have been possible to read it.

Albert Claude and coworkers were the first to get a glance inside the book. In the mid-forties they made a break-through and succeeded in preparing cells for electron microscopy. I say a glance, because much technical development still remained to be done, and George Palade should be mentioned foremost among those who developed electron microscopy further, to the highest degree of artistry.

In addition to form and structure it is necessary to know the chemical composition of the cell components in order to understand their functions. It was hardly possible to analyse whole cells or tissues since these consist of so many different components, and so, one would get a confused picture. Each component has to be studied separately and obviously this is difficult when the components are so small. Here a new art was developed, and again Claude was the pioneer. He showed how one could first grind the cells into fragments and then sort out the different components on a large scale with the aid of the centrifuge. This was an important beginning. Palade made further contributions, but it was above all Christian de Duve who introduced brilliant developments within this field.

The functions of the cell could now be mapped with this armoury of methodology. Palade has taught us which components function when the cell grows and secretes. The Prize Winner of 1906, Camillo Golgi, discovered a cell component, the Golgi complex. Palade has demonstrated its role and he discovered the small bodies, ribosomes, in which cellular protein is produced.

Production of organic material must be balanced by scavenging and combustion of waste, even in the tiny world of the cell. de Duve discovered small components, lysosomes, which can engulf and dissolve, e.g., attacking bacteria or parts of the cell itself which are old and worn out. These are real acid baths, but the cell itself is normally protected by its surrounding membranes. Sometimes, however, the lysosomes are converted into veritable suicide pills for the cells. This occurs when the surrounding membranes are damaged, e.g. by ionizing radiation. The lysosomes play a role in many clinically important conditions and the foundations laid by de Duve are of the greatest significance for the interpretation of these states, and, thus, also for prophylactic and therapeutic measure.

To sum up, the 1974 Prize Winners have by their discoveries elucidated cellular functions that are of basic biological and clinical importance. Thus, they cover both aspects of the Prize, Physiology as well as Medicine.

Albert Claude, Christian de Duve and George Palade. During the last 30 years a new subject has been created, Cell Biology. You have been largely responsible for this development both by creating the basic methodology and by exploiting it to gain insight into the functional machinery of the cell. On behalf of the Karolinska Institute, I wish to convey to you our warmest congratulations, and I now ask you to receive the prize from the hands of his Majesty the King.


7 comments :

  1. As I recall, the slices in Palade's EM picture are from pancreatic cells which would be avidly synthesizing proteins for secretion. Nonsecreted proteins are made on cytoplasmic ribosomes. I wonder how many cell biology texts and teachers still state something like "The rough ER is the major site of protein synthesis"? See the prize to Gunther Blobel for working it out.

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  2. Indeed, just about everyone states "The rough ER is the major site of protein synthesis". In my experience, at least.

    Took me to do a postdoc doing things related to secretion to realize it.

    One thing I wanted to understand since is the mechanism by which ribosome components end up in ER as opposed to cytosol (can it really be simple partitioning?)

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  4. dk, maybe I'm misunderstanding, but it was my impression that there are no ribosomes inside the ER--rather, cytoplasmic ribosomes dock reversibly to the "outside" membrane of the ER and insert the translated peptide in through a docking pore of some kind.
    And I think that not only secreted proteins, but also integral membrane proteins get translated at/on ER, then get transported in a vesicle membrane out to the Golgi and plasma mebranes.
    But I am not a cell physiologist!

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  5. sven, your right. Proteins that are being synthesized for excretion, have an early hydrophobic signal section that is bound by a signal recognition particle. This stops the translation and is involved in attaching the ribosome complex to a docking protein on the ~outside~ of the RER. The signal particle then dissociates and the ribosome continues discharging the protein into the lumen of the RER.

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  6. Frank Schmidt asks,

    I wonder how many cell biology texts and teachers still state something like "The rough ER is the major site of protein synthesis"?

    Quite a few, unfortunately. It is, of course, completely wrong. The vast majority of protein synthesis in most cells takes place in the cytoplasm and not on ER-bound polysomes.

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  7. anonymous says,

    Proteins that are being synthesized for excretion, have an early hydrophobic signal section that is bound by a signal recognition particle.

    See The Signal Hypothesis and Signal Recognition Particle.

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