Pathfinders in Biology

Professor Oswald T. Avery in his laboratory in the current Medical Center North. The photograph, probably dating to 1948, is inscribed to his associate, Dr. Bertram Sprofkin.
Professor Oswald T. Avery in his laboratory in the current Medical Center North. The photograph, probably dating to 1948, is inscribed to his associate, Dr. Bertram Sprofkin.

Two of the most influential scientists of the 20th century, and perhaps of all time, have worked at Vanderbilt. One performed his last research study in a laboratory at Vanderbilt Hospital; the other, a physicist who began his career in Buttrick Hall, became one of the foremost pioneers in molecular biology and won the Nobel Prize in physiology or medicine. Together, albeit independently, they revolutionized our understanding of genetics.

The first, Oswald Theodore Avery, discovered the nature of the most important substance in living organisms while working at the Rockefeller Institute. Although only a few people recognize Avery’s name—and fewer still know his later connection with Vanderbilt—the revolution Avery began is Darwinian in scope. The substance whose significance he discovered is deoxyribonucleic acid, or DNA.

The experimental model used by Avery to study DNA had been described in 1928 by a British public health officer named Frederick Griffith. The significance of Griffith’s work was recognized by so few people that Avery’s laboratory probably was the only one studying DNA by this technique in the 1930s and 1940s.

Avery did not publish anything about the subject of DNA from 1933 to 1944, and his DNA paper appeared at the end of his career, just before retirement. Its conclusion that DNA was the genetic material in Griffith’s model, and presumably in other living things, was not accepted—in fact, it was bitterly opposed for eight years. Today this paper is generally recognized as the key to our understanding of evolution and how living things are made and work.

Avery studied the change in form and biological behavior inducible in pneumococci, a common and often lethal cause of bacterial pneumonia. Bacteria, like horses and men, breed true, and strains ordinarily do not change in appearance or in ability to produce disease. Griffith, by accident, discovered that avirulent bacteria injected into mice could be changed to virulent forms by adding heat-killed extracts of virulent bacteria. This process was called “transformation,” and the substance responsible was called “the transforming principle.”

The changes induced in the bacteria were stable, passed from generation to generation, and the reason ultimately was shown by Avery and colleagues to be assimilation of DNA from the virulent strain by the avirulent strain.

The major problems in this research program were technical (working with large amounts of virulent bacteria in a pre-antibiotic era), procedural (establishing that only DNA was present in the transforming material), and conceptual (no one believed the heritable material could be carbohydrate-rich DNA, as all essential materials were believed at the time to be proteins).

Working during an 11-year period with two associates, Avery was able to solve all these problems. Ultimately, his lab handled 50 liters of pneumococci at a time when pneumococci were a major cause of death in the United States. A model of transformation was developed that did not involve mouse injections, so all experiments could be done in test tubes.

The second problem—showing that only DNA was present in the transforming material—was more difficult to solve. Advocates of protein as the genetic material insisted that extremely small amounts of protein still might be present despite rigorous attempts at purification.

Max Delbrück on the Vanderbilt campus, sometime in the 1940s
Max Delbrück on the Vanderbilt campus, sometime in the 1940s

The prevailing assumption that the heritable material must be proteinaceous was, perhaps, the reason Avery did not receive the Nobel Prize. Major resistance to acceptance of Avery’s work came from members of the Rockefeller Institute, so personality conflicts with Avery also may have played a role. More important, a study performed at the Rockefeller Institute in the 1930s had refuted work by leading European investigators who had mistakenly concluded that enzymes were carbohydrates. The conclusions of the Rockefeller study—that enzymes were, in fact, proteins—strongly reinforced the perception of the time that all important chemicals, including the one responsible for heredity, must be made of protein. This perception was very much on the minds of Avery and his colleagues as they gradually came to the conclusion that the genetic material in pneumococci was not proteinaceous but was carbohydrate-rich.

Avery’s work was confirmed convincingly in 1952, three years before his death, by experiments involving bacteriophages, viruses that infect bacteria—which brings us to our second pathfinder, Max Delbrück.
This remarkable German scientist possessed an unusual combination of skill in mathematical physics and interest in applying his knowledge to the borderland between biology and physics. The use of bacteriophages to study general biological mechanisms is directly attributable to Delbrück, who won a Rockefeller grant to study in the United States beginning in 1937 and came to Vanderbilt to teach physics in 1940.

Delbrück did teach, but focused his energies on research in biology; he was intrigued by the apparent simplicity of bacteriophages and decided they were ideal for studying microbial genetics. He was at Vanderbilt seven years, based in the Department of Physics, but his research was carried out in the Department of Biology in Buttrick Hall. (His laboratory in Buttrick Hall was in Room 316; a plaque recently placed on a nearby wall commemorates his working there.)

In 1940 he met Salvador Luria, an Italian refugee working at Indiana University, with whom he began a productive collaboration on bacteriophages. Their paper “Mutations of Bacteria from Virus Sensitivity to Virus Resistance” is generally acknowledged to have signaled the birth of microbial genetics in 1943. Delbrück and Luria later collaborated in research with Alfred Hershey, and jointly they received the Nobel Prize in physiology or medicine in 1969.

Delbrück was one of the first to learn in 1943 that Avery had identified DNA as the genetic material in pneumococci. One of the more famous communications in science is a letter written May 13, 1943, from Oswald Avery to his brother, Roy, who was then on the microbiology faculty at Vanderbilt. Now in the Tennessee Archives, this letter summarized in an informal way Avery’s work and thoughts about DNA.

After a long description of the problems involved in purifying the transforming substance, Avery wrote, “In short, this substance is highly reactive and on elementary analysis conforms very closely to the theoretical values of pure deoxyribose nucleic acid type. (Who could have guessed it?)” Later in the letter he speculates, “But today it takes a lot of well-documented evidence to convince anyone that the sodium salt of deoxyribose nucleic acid, protein-free, could possibly be endowed with such biologically active and specific properties, and that is the evidence we are now trying to get. It is lots of fun to blow bubbles, but it is wiser to prick them yourself before someone else tries to.”

Max Delbrück was shown the letter shortly after its receipt, recognized its significance, and much later helped resurrect it from an attic storage trunk in Roy Avery’s home.

In Max Delbrück, Vanderbilt obviously had a world-class biologist on its faculty, a scientist widely known for his tremendous intellect, far-ranging vision and charisma. Delbrück is generally recognized as the fountainhead of molecular biology. Vanderbilt provided a happy and productive environment for him. During his Nashville years he married “Manny” Bruce of Pasadena, and their first child was born at Vanderbilt Hospital.

However, in 1947 Vanderbilt and Max Delbrück parted. He had approached the graduate dean, Dr. Philip Davidson, with a request to set up a new department to be called “molecular biology,” requesting an amount greater than the total budget of the Natural Science Division. The request could not be funded, so Delbrück went to Cal Tech, the institution with which most molecular biologists associate his name and where he remained until his death in 1981. At Cal Tech (and during a summer course at Cold Spring Harbor Laboratory), he spawned and mentored a vigorous and prolific group of microbial geneticists, several of whom ultimately were awarded Nobel prizes.

Throughout his life Delbrück was very appreciative of the opportunities he had at Vanderbilt and in the U.S. to concentrate on science while the world was in turmoil.