Wednesday, November 28, 2007

Nobel Laureates: Edmond Fischer and Edwin Krebs


The Nobel Prize in Physiology or Medicine 1992.
"for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism"

Edmond H. Fischer (1920 - ) and Edwin G. Krebs (1918 - ) received the Nobel Prize in Physiology or Medicine for working out the pathway for regulation of glycogen metabolism. The main feature of this regulation is the phosphorylation and dephosphorylation of enzymes to control their activity [Regulating Enzyme Activity by Covalent Modification].

The Nobel Lectures by Ed Krebs [Protein Phosphorylation and Cellular Regulation I] and Ed Fischer [Protein Phosphorylation and Cellular Regulation II] should be required reading for all biochemistry students. Not only do they show how a fruitful collaboration works, they provide an excellent introduction to fundamental aspects of metabolism and regulation. I wouldn't be surprised if some of the material in these lectures appeared on introductory biochemistry exams.

For this Nobel Prize there's a slide presentation on the Nobel Prize website illustrating the work done by Ed Fischer and Ed Krebs [Illustrated Presentation]. Fischer and Krebs are Professors Emeritii at the University of Washington (USA). They have been friends and collaborators for many years. The first illustration (below) is from the slide presentation.

The Nobel Prize website also has video links to interviews with Edmond Fischer and the transcript of an interview with Edmond Krebs. Here's an excerpt from the interview with Krebs ...

Edwin G. Krebs is a soft-spoken, understated Midwesterner, but there's one thing that gets his goat. Since he turned his attention from medicine to biochemistry, people have been asking him about "his" cycle. They confuse him with Sir H.A. Krebs, the British scientist who won the Nobel Prize in 1953 for elucidating the metabolic Krebs (or tricarboxylic acid) cycle.

One person who made this mistake was the chairman of a clinical department at the UW School of Medicine in 1948, when Krebs started as an assistant professor of biochemistry.

"I must confess that I didn't correct his wrong impression," says Krebs. "I was so uneasy about my status then that I enjoyed being treated with such deference, even for the wrong reason."
The Nobel Prize presentation speech was delivered by Professor Hans Jörnvall of the Nobel Assembly of the Karolinska Institute.
Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,

This year's Nobel Prize in Physiology or Medicine is awarded for discoveries concerning reversible protein phosphorylation. What does that mean and how does phosphorylation work?

Let us start with proteins. They can be compared with workers in our tissues. We are composed of cells, each cell constituting a small community. Constant activity is a characteristic feature both of cells and ordinary communities. There are systems for transportation, energy generation, production, and waste handling. In society all this is handled by humans, in a cell proteins take our place. How do they accomplish their functions? Well, exactly like human workers, they operate by way of interaction with other components. Much in the same manner as a driver or pilot recognizes the controls, proteins recognize "their" partners, binding them to influence the reaction paths.

And now phosphorylation: one or several small phosphate groups are coupled to a protein, changing its properties. If the parallel with our human workers is pursued further, one could perhaps compare phosphorylation with ballet shoes. Despite their small size they have dramatic effects on their wearer! The shape of the foot is altered and after that, work is like a dance. Edmond Fischer and Edwin Krebs, this year's Laureates, described this principle in the ftfties. They showed how muscles liberate an energy-rich form of sugar from its storage form by phosphorylation of a protein. After that, science gradually gained insight into the fact that this constitutes a general principle manifested in all cellular activities. Today, a considerable part of world bioscience involves protein phosphorylation.


Nobel Laureates
Why this regulation via coupling of small groups? One advantage is that the process is reversible, i.e. the shoes can be taken off and put on, a process which can be repeated again and again. Thus, proteins can be regulated in both directions. Another is that the reactions can be carried out in successive steps, creating a cascade that amplifies the end effect. Much like the hydraulic amplification in a brake: a gentle touch of the pedal can stop even a heavy car. In the world of proteins, Krebs and his collaborators paved the way for this knowledge by studying also the preceding protein in the chain of phosphorylations, while Fischer concentrated his efforts along other lines and, as recently as some years ago, reported the purification of a special type of phosphate-removing protein.

Yet another advantage is that the regulation can be affected by different signals. The system that Fischer and Krebs first studied can be activated either by means of a stress hormone released when we become frightened and our muscles prepare us for escape, or by an act of will when we wish to run for other reasons. Phosphate groups are in these two cases attached in response to separate signals, much as they are in all other cellular response systems. What relevance does this have to medicine? The easiest answer is that we all know of the consequences in society from imbalances in economic chain reactions! We are now in a position to start perceiving how illnesses, including common diseases like hypertension and tumors, are accompanied by imbalances in phosphorylations. Relationships initially recognized in connection with glycogen storage in muscles and liver, have thus been proven to pertain to cellular regulatory processes in general. An excellent demonstration of the power of basic research and of the versatility of simple models. The protein system in glycogen storage has given rise, over the years, to several Nobel Prizes, in 1947 to Gerty and Carl Cori for the course of the catalytic conversion of glycogen, in 1971 to Earl Sutherland for mechanisms of action of hormones, and now to Fischer and Krebs for discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism.

Edmond Fischer and Edwin Krebs,

I have tried to describe your field of research and elegant discoveries in your studies of reversible protein phosphorylation, going back to the initial detection of the activation mechanism of phosphorylase, and continuing with protein phosphatases. Over the years, your early observations on a particular system have contributed to the opening up of novel insight into basic protein regulations at all levels and in all cells. On behalf of the Nobel Assembly of the Karolinska Institute, I convey to you our warmest congratulations, and ask you now to step forward to receive your Nobel Prizes from the hands of His Majesty the King.

[Photo Credit: Dept. of Biochemistry, University of Washington]

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