Part V: Wendell M. Stanley, 1946 Prize in Chemistry
By Joseph Luna
In 1898, a Dutch botanist named Martinus Beijerinck faced a naming conundrum. He reproduced an experiment first performed six years earlier by Russian botanist Dmitri Ivanovsky, who found that a disease of tobacco plants causing a mosaic discoloration of their precious nicotine laced leaves could be transmitted to a healthy plant in an infectious manner. Moreover, like his predecessor, Beijerinck found that after passing through a filter too small for any known bacteria to pass, the juice of infected plants could still be used to infect healthy tobacco leaves. This was a puzzling observation, since any attempt to see the infectious agent under a microscope turned up nothing. Ivanovsky concluded that there must be a tiny living bacterium, smaller than any known, which was responsible for the disease. Beijerinck on the other hand wasn’t convinced and wanted to call this infectious agent something else to reflect its non-bacterial nature. After what must have been some hand wringing, he settled on an old Latin word for “slimy liquid” and named the new agent a virus.
For the next three decades, exactly what a virus was presented a tantalizing mystery. Viruses behaved as if they were alive, they grew and could adapt, and yet some were so small that they approached the sizes of proteins, or other macromolecules that clearly weren’t alive. So which was it? Alive or dead? Beijerinck, for his part, didn’t have a definitive answer, but set a vital tone by referring to viruses as contagious living fluids (“contagium vivum fluidum”). Until the 1930s, as the roster of plant and animal diseases caused by viruses expanded, attempts to categorize them on the basis of size were used to justify the living (i.e. large) from the non-living (i.e. small). Still, others thought this essentialist idea might be missing something entirely.
Wendell Meredith Stanley was among them. Trained as a chemist, Stanley initially came to the Rockefeller Institute in 1931 as a post-doc to work with physiologist Winthrop J. V. Osterhout, but was quickly lured in 1932 by Louis O. Kunkel to be a part of the new division of plant pathology. Housed at the Institute’s outpost in Princeton N.J., the plant pathology group settled in next to the division of animal pathology in its picturesque country setting, and it was here that Stanley probably first met John Northrop, with whom he would later share the Nobel Prize.
No doubt inspired by Northrop’s accomplishment of crystallizing pepsin in 1929, Stanley’s task of trying to crystallize a whole virus seemed just possible, if a bit crazy. But he was in the right place: in addition to famed protein crystallizers Northrop and Moses Kunitz next door, Kunkel’s plant group had geneticists to study plant virus adaptability and the effects of mutations, entomologists to study the lifecycles of insect-borne plant diseases, and a healthy group aimed at working out conditions for plant cell culture in the petri dish, from roots to leaves. Microbiologists, soil chemists, animal virologists, plant physiologists… the variety of disciplines in the new department was as fertile as their verdant greenhouse.
Uniting the group was a long-standing interest in the Tobacco Mosaic Virus (TMV), the same virus studied by Beijerinck, and upon which virology was founded. Much was known by Stanley’s day about TMV, its infectious properties and such, and even a few groups had attempted to get pure preparations of TMV by crystallization. All, however, failed to show that the crystallized virus, when dissolved, remained infectious. Working apocryphally from nearly one ton of infected tobacco leaves, Stanley succeeded in producing a few grams of needle-like crystals that behaved just like TMV when dissolved. He also found that these crystals were overwhelmingly composed of protein, a surprising result, as it mirrored Northrop’s conclusions with much smaller enzymes.
The scientific world was rightfully astonished. Crystals were well known to be ordered, chemical entities that were clearly not living, and yet Stanley’s virus crystals undeniably behaved as if they were alive! The core of biology was broached upon by this discovery, as it prompted scientists to reconsider the very definition of life. For his part, Wendell Stanley remained ever the rigorous chemist, and largely opted not to partake in philosophical discussions, insofar as he interpreted the data pointing beyond a dualist view of life and non-life. Perhaps a virus was both? Perhaps the boundary is arbitrary?
While Stanley’s work raised an almost existential question in biology, it turns out that his results were incomplete. TMV is composed of about 95% protein but it also possesses about 5% RNA by weight, a finding overlooked by Stanley, and now recognized as the key ingredient for a virus’s living nature. What constitutes life at its boundary with non-life makes the virus a unique arbiter in biology in that viruses satisfy both definitions while satisfying none. Or as Stanley’s contemporary and fellow Nobelist Andre Lwoff wrote on the subject, in the end “a virus is a virus!”