Wednesday, September 12, 2007

Nobel Laureates Max Delbrück, Alfred D. Hershey, Salvador E. Luria


The Nobel Prize in Physiology or Medicine 1969.
"for their discoveries concerning the replication mechanism and the genetic structure of viruses"
Max Delbrück (1906-1981), Alfred D. Hershey (1908-1997), and Salvador E. Luria (1912-1991) received the Nobel Prize in Physiology or Medicine for founding the phage group and stimulating hundreds of scientists to study molecular biology. That's not exactly what the citation says but nobody is fooled. This is an unusual Nobel Prize. While the work that these three men did is impressive there's no real breakthrough or discovery that links all three. In a sense, they are getting the Nobel Prize for being teachers and mentors. That is entirely fitting and proper.

Their influence was enormous. Delbrück especially was the man behind the curtain throughout most of the 50's and 60's. His name comes up repeatedly in biographies and memoirs. Recall that the book Phage and the Origins of Molecular Biology was dedicated to him [Waiting for the Paradox].

The photograph on Monday's Molecule #42 shows a bacteriophage particle that has burst and spilled its DNA onto the electron microscope grid. It's a fitting symbol of the phage group that Delbrück, Luria, and Hershey founded.

The Presentation Speech was given by Professor Sven Gad of the Royal Caroline Institute.
Your Majesty, Your Royal Highnesses, Ladies and Gentlemen.

Man, animals, plants, microorganisms, they are all preyed upon by viruses. Even bacteria have their own viruses, somewhat misleadingly called bacteriophages - "bacteria eaters". These were discovered at the time of the first world war but the subsequent 25 years of research did not contribute much to our knowledge of their true nature. However, about 1940 Max Delbrück became interested in bacteriophages and soon thereafter so did Salvador Luria and Alfred Hershey. Their aim was to study the most fundamental of all vital processes - replication. They expected to find in the bacteriophages a model, sufficiently primitive to permit an attack on this problem with hopes for success.

The constellation was promising: one physicist, Delbrück, one physician, Luria, and one biochemist, Hershey. With their different backgrounds and approaches they were able to launch truly concentric attacks on the fundamental problems. They worked independently but in close contact. Early on they formed their own school and the stimulating intellectual climate they created attracted talented scientists from many different fields and with many different attitudes. Under their direction the development proceeded with explosive speed.

The honour in the first place goes to Delbrück who transformed bacteriophage research from vague empiricism to an exact science. He analyzed and defined the conditions for precise measurement of the biological effects. Together with Luria he elaborated the quantitative methods and established the statistical criteria for evaluation which made the subsequent penetrating studies possible. Delbrück's and Luria's forte is perhaps mainly theoretical analysis, whereas Hershey above all is an eminently skillful experimenter. The three of them supplement each other well also in these respects.

The research proceeded along the lines Delbrück had set for a little more than ten years. During this period the bacteriophage life cycle was mapped out in detail. The various phases of the replication process were dissected and studied separately. The final picture of the sequence of events was briefly as follows.

A bacteriophage particle consists of a core containing nucleic acid, enveloped in a protein shell. The shell contains an enzyme that reacts specifically with a substance in the cell wall and which produces an erosion in the cell surface through which the bacteriophage core enters. The protein shell remains outside and does not further participate in the process of infection. With the entrance of the bacteriophage core the activity of the cell is radically changed. Its chemical tools remain intact but its regulating center is switched off. Instead the bacteriophage core takes command and directs the chemical activity exclusively towards production of new bacteriophage particles. The various components of the virus, nucleic acid and several proteins, are produced separately and only in the terminal phase are they put together to form "mature" particles. When this stage is reached the cell wall is dissolved and the newly formed virus is released. This process proceeds with almost inconceivable speed. One virus particle may in 10 to 15 minutes give rise to more than a thousand new particles.

New nucleic acid is formed in principle through repeated duplications. On rare occasions a synthetic error may occur, resulting in the appearance of a unit with a structure that at some point differs from that of the others. If the error is not sufficiently serious to make the new unit non-functional, it will be repeated at subsequent duplications and the final harvest of bacteriophages will contain a number of particles with properties that differ from those of the parental type. Through a "mutation" a new variant has appeared.

One and the same cell can be simultaneously infected by two or more related virus particles. If so, an exchange of parts may take place between two units in a so-called recombination process. In this fashion new variants are formed with the characteristics of the original types in various combinations. An analysis of the properties of the recombinants may give information on the genetic structure of the virus. The rapid multiplication of the bacteriophages has made it possible in a short time to collect numerous mutants and to perform systematic crossing experiments. By this means their genetic structure has been established in ever finer detail.

Such was the situation at the beginning of the 1950's. The biological phenomena had been sorted out and placed in correct relations. The picture of the nature and mode of action of the virus which was thus obtained differed essentially from previous concepts. Most important perhaps are the evidence of an interaction between the virus and the host cell and the fact that the regulation of the cellular activity can be affected by the introduction of foreign, genetically active structures.

These discoveries have decisively influenced the development within many fields of biological research. The charting of the fundamental processes in the life cycle of the bacteriophages was a necessary condition for attempts to define them in chemical terms, on the molecular level. At first the scientific community in general had struck a reserved attitude to bacteriophage research. It was considered to be of interest as a curiosity but of little importance to biology in general. Gradually this attitude has changed. It is now clearly evident that in principle the same mechanisms regulate the activities of bacteriophages, micro-organisms and more complex cellular systems. Therefore, Delbrück, Hershey and Luria must in fact be regarded as the original founders of the modern science of molecular biology.

Their discoveries have also had great importance for the geneticists. It is mainly through studies of bacteriophages that the mechanisms of the genetic regulation of the vital processes have been revealed.

Last but not least, bacteriophage research has given us the better insight in the nature of viruses which is necessary for the understanding and combat of virus diseases of higher beings. A long time has passed since the discoveries were made. However, their general biological and medical importance was only gradually recognized and only in later years has the wide range of their applicability become fully evident.

Max Delbrück, Alfred Hershey, Salvador Luria.

Thirty years ago you embarked upon a research project which to most members of the scientific community must have appeared as overambitious. You set out to solve the most fundamental of all biological problems, that of self-replication. By making the lowly bacteriophage your subject you probably also raised many eyebrows. However, by your sense for the importance of strict scientific methodology, your brilliant experimental skill and above all your imaginative approach you succeeded in making the impossible feasible. The realization that bacteriophage after all is a respectable representative of all living matter was slow in coming. Today, however, the general applicability of the principles you established is beyond doubt and the full impact of your achievements is finally felt. You have been awarded this year's Nobel prize in physiology and medicine for your discoveries concerning virus replication and genetics and we hereby acknowledge the importance of your contributions to the biological and medical sciences. On behalf of Karolinska Institutet I beg you to accept our heartfelt felicitations.

I now ask you to receive your prize from the hands of His Majesty the King.

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