A huge multinational plot will soon be stopping the polio research of Dr. Vincent Racaniello, Higgins Professor of Microbiology.
The sentence above is true but the reality is not so sinister. The World Health Organization is expected to declare the world free of poliovirus in a few years and, as part of its polio eradication program, most laboratory stocks of the virus must be destroyed.
During his Dean's Distinguished Lecture on March 21, Dr. Racaniello eulogized the virus and discussed its contribution to his career and to virology. As a scientist, Dr. Racaniello has worked intimately with poliovirus for more than 20 years and answered basic questions about its life cycle, including how the virus infects cells and travels to the central nervous system.
Polio has probably been with us since our early human beginnings, but it flared up in the first half of the 20th century. Although 99 percent of infections never resulted in more than a fever, every summer between 1900 and 1960, a polio outbreak crippled thousands of children when the infection spread from the intestine to the central nervous system. Others lost control of breathing muscles and were immobilized in iron lungs. Some died from the disease. But the fear of polio disappeared by the 1960s, when the Salk and Sabin vaccines eradicated the disease from industrialized countries.
When Dr. Racaniello started work on poliovirus in the late 1970s, it was the best-known virus in microbiology, but studying its infection and disease progression was slow and expensive since the virus only infects primates. To learn more about the virus, Dr. Racaniello deciphered the RNA genome of the poliovirus in 1981 and then tried to infect human cells with a DNA clone of the viral genome.
Although he didn't think the DNA clone would infect cells, it did. Virulent poliovirus popped out of cells transfected with the DNA copy of the viral genome. We're still not sure why it works, Dr. Racaniello says. Poliovirus never uses DNA in its life cycle.
Dr. Racaniello used the infectious DNA to compare vaccine viral strainswhich infect the intestine but are too weak to infect the nervous systemwith wild type strains to find out which part of the genome causes virulence. But the clone didn't allow him to address the question he wanted to answer: How does the virus actually enter human cells? By this time, Dr. Racaniello was an assistant professor at P&S and one of his first graduate students, now Dr. Cathy Mendelsohn, searched for a receptor.
The molecule she founddubbed PVR for poliovirus receptorwas unique among known viral receptors. Instead of acting like a hook and simply holding the virus near the cell membrane while other proteins removed the viral genome, PVR holds the virus and unzips the outer coat itself. Now plenty of receptors are known to be unzippers, including the receptor for the virus that causes the common cold.
With PVR in hand, Dr. Racaniello inserted the gene into mice and made the first transgenic mouse model for a viral disease of animals. Mice injected with the poliovirus came down with the same symptoms humans display and let researchers answer basic questions about how the virus causes disease. Using this model, Dr. Racaniello discovered the virus travels to the brain from infected muscle cells through the axons of neurons.
But other questions still remain unanswered. An outstanding question about polio is what really kills the neurons, Dr. Racaniello says. Though the virus can kill cultured nerve cells directly, in the body the most important cell-killer may be the immune response, which destroys infected nerve cells in an attempt to destroy the virus.
How polio kills nerve cells is an important question for all viruses because if the immune response is causing the disease, you can devise therapies to reduce the destruction of nerve cells without compromising the body's ability to clear the virus, Dr. Racaniello says.
I would love to use polio to get the answers to these remaining questions because it's a good model, he says. But it's hard to convince students and postdocs to do the work when the virus may be gone in two years. Instead, his lab is trying to use its knowledge of poliovirus to understand other viruses that cause colds, heart disease, and eye hemorrhages.
Although Dr. Racaniello is resigned to losing poliovirus, he's unhappier the World Health Organization's plan calls for a stop to worldwide vaccination soon after the wild virus is eradicated. For a few years after vaccination stops, vaccinated immune-compromised people will continue to shed live virus into the environment. If some of this virus has mutated back to virulence, unvaccinated children can acquire the virus through untreated water supplies. A virulent vaccine-derived poliovirus was responsible for a polio outbreak last year in the Dominican Republic, seven years after the island was certified polio-free. It's not clear to me you can ever stop vaccinating, Dr . Racaniello says.