An Interview with Professor Manuel Varela: The Culture of Poliovirus

Sep 28, 2018 by

1) John Franklin Enders is a name that will live on in the annals of science. Apparently, he was the first to have “cultured poliovirus”. Why is this so important?

The 1954 Nobel Laureates Dr. John F. Enders, Frederick C. Robbins, and Thomas H. Weller, were the first scientific investigators, in 1949, to have successfully cultured the poliovirus microbe in the laboratory setting, for the express purpose of developing an anti-polio vaccine. This culturing of the poliovirus result had vastly important ramifications on a worldwide scale, as it ultimately led to the advancement of a vaccine against poliomyelitis, known also as flaccid paralysis, infantile paralysis, or simply polio.

Dr. Enders experimentally demonstrated in the laboratory that, in living host cells, he could culture the microbial causative agent of the polio, an Enterovirus (genus) of the serotype called poliovirus, and a member of the so-called Picornaviridae family of viruses.

This Nobel prize winning discovery by Dr. Enders thus permitted investigators to more closely examine the three forms of the polioviruses, called Types 1, 2, and 3, after producing more of the microbial agents in large quantities. Furthermore, the finding of Dr. Enders allowed investigators to invent new laboratory protocols for the precise identification of the poliovirus types, a useful approach for clinical diagnosis.

The work of Dr. Enders allowed investigators to study how the microbe managed to inflict its cellular damage, a consequence referred to scientifically as the cytopathic effect. Dr. Enders also demonstrated for the first time that, in addition to neuronal cells, which are the prime targets of poliovirus, the virus could also be propagated in other types of host cells, making it easier to grow the microbial agent of polio. 

Importantly, this finding by Dr. Enders that polioviruses could be readily grown in the laboratory thus permitted the rapid development of vaccines for polio. The polio vaccination program turned out to be an overwhelming success towards the elimination of polio from most parts of the world.

2) Now, backtracking, I know polio was a dreaded disease in my parent’s time, but it seems to be ALMOST eradicated now. Am I correct on this?

While the smallpox disease has been definitively eradicated from planet Earth by intensive human efforts on a massive scale, it is widely believed that polio is next in line for the same type of obliteration.

In 1988, an unprecedented polio vaccination program was initiated worldwide and on an enormous scale.  The effort proved to be an astounding success, especially in developed regions of the world. In the U.S., naturally occurring cases of polio ceased to be detected in 1979.  The year 1979 also marks the time in which the polio happened to disappear from both North and South America.  In 2014, India and much of South Asia were declared by the World Health Organization (WHO) to be officially free of the polio disease.

Globally speaking polioviruses types 2 and 3 are considered eradicated.  Type 2 poliovirus was last seen on Earth in 1999 and declared officially eradicated in 2015, while type 3 was declared as such back in 2012. With respect to the type 1 form of the poliovirus, as of this writing, there are small pockets of clinical transmission for cases of the paralytic form of polio remaining in certain parts of the world. In order for an infectious disease to be declared eradicated, no new cases must be observed for a period of three years. When that stage of eradication is reached for polio, only then will an official declaration of its global obliteration finally be affirmed. 

The poliovirus is an RNA-based microbe.  As such, when RNA is replicated, the error rate is higher than in the case of DNA synthesis, making more mutations in the RNA genomes of the virus.  Thus, poliovirus has an elevated chance of mutating into more virulent or contagious forms.  It is feared, therefore, that were type 1 poliovirus not to be ultimately eradicated from Earth, the polio could then remerge to cause more epidemic level cases, possibly becoming terribly difficult to achieve containment the next time.

3) I recall seeing those iron lungs in hospitals. Exactly what was going on with those? What function did they serve?

The graphic images of countless children living in their iron lungs certainly have a compelling effect, especially when one considers the enormity of the polio incidence cases in the 1950s and early 1960s, when the polio numbers reached a record peak. These iron lungs were developed primarily for the most severe cases of polio, the so-called major illness, also called bulbar or paralytic poliomyelitis. 

While the extent of the paralysis to a patient varied tremendously from patient to patient, being frequently mild and temporary, in some of these major illness cases, however, the paralysis exhibited in certain patients could be total, with patients not even able to breathe on their own. Muscular contraction is required for the lungs to intake atmospheric oxygen, in order to supply it to the patient’s tissues.  Without the needed oxygen, the tissue begins to die almost straightaway. The immediate danger to such patients was obviously a swift suffocation and death.

The iron lungs were designed to enable severely paralyzed patients to respire by oscillating the tank pressures, forcing air into and out of the lungs in a periodic manner by invoking positive and negative pressures in the machines. This permitted the patients to breathe on a continual basis.  It did require, however, that the patients remain in their iron lungs on a permanent basis.  Today, while severe cases of the paralytic form of the polio are extremely rare, modern treatments involve smaller and much less cumbersome portable respirators.

While the world’s record for longevity within the iron lung may be disputed, there are indeed numerous documented cases of paralytic polio patients living in the equipment for as long as 50 to 60 years. The Guinness World Records states that the record holder is June Margaret Middleton while other sources attribute Dianne Odell as having lived all of her life in an iron lung, beginning when she was diagnosed at the age of 3 years.

One the most famous American iron lung polio patients was Frederick Snite, Jr., who was diagnosed in 1936 at the age of 25 years. Snite had been born into a family of considerable wealth, and his family was supportive, even making it possible for Snite to frequently travel to various events. One well-known example constituted the Notre Dame Football games, at which Snite had seemingly become a permanent fixture. 

He married Ms. Teresa Larkin in 1939, and together the couple had three offspring.  Fred Snite even got the attention of president Franklin Delano Roosevelt, who also had the paralytic poliomyelitis, but not as severe as Snite’s condition had been.  Snite became a poster child of sorts for the National Foundation for Infantile Paralysis, referring to himself as the “Boiler Kid.”  Snite died at the age of 43 years.

4) What else was John Franklin Enders known for?

John F. Enders was born in West Hartford, Connecticut, in the U.S. on the 10th day of February, in the year 1897.  He was enrolled in elementary school at Noah Webster and attended high school at St. Paul’s School, graduating in 1915.  His university studies had been interrupted by serving in the Great War as an Air Force pilot instructor while holding the rank of ensign. He moved on to take his Bachelors of Science undergraduate degree at Yale College in 1920. Next, he enrolled at Harvard, taking his master’s degree, concentrating in the subject of English, in 1922. Then, he enrolled in the Ph.D. program but found that his dissertation subject had already been largely performed and even published elsewhere. 

About this time, Enders was introduced to Dr. Hans Zinsser, a professor of bacteriology and immunology at Harvard, who inspired Enders to pursue a change in his focus of studies and, thus, work towards a Ph.D. in the topic pertaining to anaphylaxis mediated by bacteria and its relationship to the immune hypersensitivities as mediated by the tuberculin test components. Finding that these two microbiological systems (anaphylaxis versus hypersensitivity) were distinct from each other, Dr. John Enders earned his doctoral degree, in 1930, from Harvard.

With his Ph.D. in the field of microbiology in hand, Dr. Enders stayed on at Harvard in the department of bacteriology and immunology, as a member of their faculty. In 1935, he was promoted to the rank of assistant professor there, and in 1941, he became an associate professor at the institution.

In 1946, Dr. Enders established a new laboratory dedicated to the study of infectious diseases at Boston Children’s Hospital. It is here where Dr. Enders collaborated with Drs. Weller and Robbins to conduct their pioneering work with the cultivation of the poliovirus in living cell cultures, making it ultimately possible for countless of millions to benefit from the consequent development of the polio vaccines by Drs. Sabin and Salk.

Incidentally, Dr. Enders and his colleagues were not actually the very first investigators to have cultured poliovirus in living cells.  In fact, the first scientific study of poliovirus culturing occurred as far early as 1936, with the work of Dr. Albert Sabin and colleague Peter Olitsky, who managed to grow the virus in human embryo neuronal cells. They demonstrated that the virus in these cells could be grown after injection into primate laboratory animals. The work suffered, however, from lack of continuous supply of human tissue and primates needed for their work.

Dr. Enders was also key to other discoveries. For instance, in chick embryonic cells, he was able to culture the mumps virus, a member of the Paramyxoviridae virus family of the genus Paramyxovirus. Furthermore Dr. Enders discovered how cultivate the measles virus, of the genus Morbillivirus.  Each of these historic discoveries in turn led to the development of effective vaccines against both the mumps and the measles.

5) What is going on currently in terms of polio research? Or have we basically eradicated it? Or controlled it?

Despite being tantalizingly close to a planet-wide eradication of polio, there is still much work to be done.  Even after global eradication of polio is achieved, which will no doubt be of historical importance, exploration in this area will most certainly continue.

A PubMed search of poliovirus for the year 2017 shows several hundred publications in that year alone. Biomedical research in the area of polio and poliovirus is still an ongoing endeavor. This is because scientists are also interested in learning how the poliovirus infects hosts at the basic cellular level. 

Virologists are interested in the study of polio. They want to know all of the steps involved in mechanism of cellular infection by the poliovirus.

For instance, they are interested in evaluating how the virus binds to cellular receptors, how the virus enters host cells, how the virus uncoats itself to reveal its RNA, how the virus manages to overtake the nucleic acid and protein synthetic machinery to make and assemble more virus, and how the virus makes its exit from the host cell. Medical pathologists want to know how the polioviruses mediate the cytopathic effect discovered by Dr. Enders. Knowledge of the viral infection mechanism for poliovirus may shed new light on the mechanisms of relatively poorly understood viruses of medical importance.

Immunologists are also interested in knowing how immunity to polio is brought about at both natural and artificial levels. Knowledge of the immune system responses to polio will certainly aid in preventing reemergence of future polio outbreaks and in maintaining current prevention measures for other viruses.  Additionally, knowing the innate, humoral, and cellular immune mechanisms involved in the body’s response to the poliovirus may help us to know how other potentially dangerous viruses and other antigens can be inhibited, in order to prevent other viral diseases.

Previous poliomyelitis patients have been known to suffer from the post-polio syndrome. In this type of medical condition, patients who have had various degrees of paralysis often experience muscle deterioration due to the loss of innervation of affected muscles during polio bouts, even after the patients have recovered from clinical polio. The post-polio syndrome occurs primarily in elderly patients and can become quite debilitating.

With respect to having controlled the polio, microbiologists and biomedical scientists have most certainly won this particular battle with the microbe.  The battle has taken countless lives and cost billions of dollars over the course of centuries and has taken its toll in terms of misery. Eradication is considered imminent, as of this writing. The final clean up, however, will remain to be completed.

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