Bollenbach

Polio Biology III

What About If We Need The Virus Later?

Eddie Bollenbach

A Lincolnshire Post-Polio Library Publication

23rd April 1999

Viruses are tricky creatures. We don’t understand everything about them. Until recently we didn’t even know how polio got inside the cells it infects. But we are learning new things all the time. Polio virus is one of the most cultured (grown) viruses for laboratory study. And yet, there are aspects of its life cycle which remain puzzling. For example, how are the virus’s protein subunits assembled after they are produced, inside cells, during infection? Or, what is the effect of a mutation (change) in one of the protein subunits that assemble to produce the case inside which the genes of the virus reside? One thing we do know is that polio virus mutates a lot during infection. Its small component of genes is simply too little to contain the “Proof Reading” enzymes found in larger cells with larger genomes. When polio is eradicated from this earth, which may happen soon, should we keep this virus to continue studying it or should we discard it and allow it to crumble inside the steel of autoclaves throughout the world? This is not a question that will come without controversy.

The World Health Organization recommended in 1996 that the World’s known stocks of Smallpox Virus, held by the U.S. Centers for Disease Control and Prevention and the Russian State Research Center of Virology and Biotechnology, be destroyed. The last known outbreak of Smallpox was in Somalia in 1977. So the destruction of laboratory stocks seems like a fitting end to this historical scourge. But what if we learn about a new disease in the future which involves smallpox infection. Suppose smallpox is now dormant inside some people? What if the virus is being held by rogue states that plan to use it as an agent of biological warfare? Or what if we simply want to study it to learn more about viral diseases? These considerations have resulted in President Clinton balking on WHO’s directive to destroy smallpox stocks by June 1999. The US will keep its laboratory stocks of Smallpox.

Despite the fact that wild polio infection has not been seen in the Western Hemisphere for quite a few years, we are continuing to learn more about how polio may be harming those it infected 40 years ago. The Pasteur Institute is involved in studies centering on the molecular aspects of a polio infection and

have discovered that inside the spines of those of us with PPS polio virus genes (and likely proteins) persist. As we gather more evidence it will become important to find out the mechanism of this persistence. The protein case that surrounds the virus will be a target of much of this research. The polio virus is so small that a big chunk of its genetic material is devoted to the protein case. If a virus loses a gene to make the properly shaped protein for the case it would be impossible for the virus to assemble itself and spread. This could be what allows polio virus to persist. This aspect of virus biology could help explain the Post-Polio Syndrome. At this moment the two main contenders for explaining PPS are the

“Wear out Theory” and the “Viral Persistence Theory”. One doesn’t need a live virus to explain our woes; the other does.

So, I guess I would side with President Clinton’s ideas on maintaining Smallpox stocks. The world is safe from smallpox and we can only learn more by studying the virus. We just don’t know enough about them even though we seem to have eliminated the future threat of new epidemics.

The Lincolnshire Post-Polio Network

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An Information Service for Polio Survivors and Medical Professionals

All enquiries, book requests, medical article requests, membership fees, items for newsletters and donations to

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PO Box 954, Lincoln, Lincolnshire, LN5 5ER United Kingdom

Telephone: +44 (0)1522 888601

Facsimile: +44 (0)870 1600840

Email: info@lincolnshirepostpolio.org.uk

Web Site: www.lincolnshirepostpolio.org.uk

The Lincolnshire Post-Polio Network takes great care in the transcription of all information that appears at this site. However, we do not accept liability for any damage resulting directly or otherwise from any errors introduced in the transcription. Neither do we accept liability for any damage resulting directly or otherwise from the information available at this site. The opinions expressed in the documents available at this site are those of the individual authors and do not necessarily constitute endorsement or approval by the Lincolnshire Post-Polio Network.

© Copyright Eddie Bollenbach 1999 2000

© Copyright The Lincolnshire Post-Polio Network 1999 – 2010.

Copyright is retained by The Lincolnshire Post-Polio Network and/or original author(s). Permission is granted to print copies of individual articles for personal use provided they are printed in their entirety. Links from other Internet WWW sites are welcome and encouraged. We only ask that you let us know so that we can in future notify you of critical changes. Reproduction and redistribution of any articles via any media, with the exception of the aforementioned, requires permission from The Lincolnshire Post-Polio Network and where applicable, the original author(s).

Document preparation: Chris Salter, Original Think-tank, Cornwall, United Kingdom.

Created: 23rd April 1999

Last modification: 21st January 2010.

Polio Biology II

Post-Polio Syndrome’s Elusive Etiology

Eddie Bollenbach

A Lincolnshire Post-Polio Library Publication

3rd January 1999

In science, self-satisfaction is death. Personal self-satisfaction is the death of the scientist. Collective self-satisfaction is the death of the research. It is restlessness, anxiety, dissatisfaction, agony of mind that nourish science.

Jacques Monod, 1910-1977, New Scientist, 1976.

Monod is someone to listen to. He and his colleagues gave us the first model explaining how a gene can turn on when it is needed and off when it is not. And so, although I don’t need a lot of pushing in the direction of questioning ideas, I do think it is of value to be skeptical, especially when someone gives us an unequivocal answer as to the cause of a complex process like Post-Polio Syndrome.

So, the bells went off the other night when I visited the Web Pages of the National Institutes of Health in the States. I scrolled around until I got to Post-Polio Syndrome. And I found a rather authoritative pronouncement that it was caused by the recovery from polio. That the Syndrome can be completely understood in the loss of regenerated fibers, which compensated for the original damage of disease. And that this regression is the result of overcompensation and years of overwork of the nerves that “carried the day” thirty plus years ago. But why? What actually happens? And, although it sounds very plausible, where is the evidence for this?

Why do some people with a lot of polio damage not experience Post-Polio Syndrome? Do their overworked neurons remain stable for some unknown reason? Why is there new brain pathology (if there is) with Post-Polio Syndrome? And, if there is, do brain neurons just happen to lose connections and die at the same time as motor neurons by coincidence, even though they attach to one another and not to muscle that overwork them? I need a deeper understanding of this. Answering that motor neurons “wear out” begs the question: why, what is the mechanism?

Sometimes when an answer is given, as above, the effect is to stifle further research. If there is to be any deeper understanding, we have to comprehend the mechanics of how neurons “wear out”. I’d like to offer some food for thought without endorsing what follows, but rather present it to try to convey how complicated interactions between host (us) and parasite (polio) can be biologically. And, as a consequence of this complexity, how difficult it can be to find an ultimate cause.

Polio virus is very small. It is classified with this in mind: Picornaviridae. The particle itself is composed of two parts: a protein case, called a capsid, and the genetic material inside: Ribonucleic Acid (RNA). The

capsid is made of repeating units called capsomers, and each capsomer (a triangular piece like a part of a soccer ball) is made of protein subunits called protomers. Each protomer is the same. So you put together a polio virus by assembling protomers into capsomers, and capsomers into a twenty sided (icosahedron).

The genetic stuff (RNA) is inside. The RNA contains very few genes and is unusually small. Unlike larger DNA viruses, polio has no way of fixing mutations when they happen. This would require a larger genome. And mutations do happen during an infection. What I am saying is that when the genetic material duplicates inside an infected cell there is not always perfect fidelity between the parent molecule and its daughter molecule. Pairing mistakes are made. Considering how small polio virus is there can be a million or more duplications within a single cell. We must conclude that there are plenty of mutant genomes (RNA’s) produced during the life cycle of polio virus within a motor neuron.

Now, the presence of mutant RNAs would likely interfere with the proper reproduction of normal genomes. First of all, viral genes shut down the cell’s normal functions, selfishly requisitioning these materials for its own reproduction. We can assume that there would be competition between the normal genomes and mutant RNA inside an infected cell. Many of the mutant RNAs would be unable to produce proteins which could assemble into a complete viral particle. Some of these RNA’s would remain inside the cell, which would present opportunities for them to survive by evading the immune system. The normal viruses outside would be subject to attack by the immune system. So mutant genomes of polio virus could very well be selected for and be capable of surviving within a cell while normal viruses succumbed.

Another question I’ve thought about recently is why doesn’t polio virus completely decimate all motor neurons? Why do some survive? Bodian’s work in the 1940’s showed that most all of the neurons appeared abnormal during the acute polio infection. Yet some survive, why? Does the infection with virus allow some neurons to modify themselves resulting in an effective defense mechanism against infection? Does the nerve cell surface change, or is there some other biochemical change which may persist after infection, which, ultimately shortens its life cycle and may result in PPS down the line?

Or do cells have within them now bits of polio virus RNA, which have survived all these years because of their evolutionary fitness in competition with all viral progeny? If so these RNAs surely make proteins within the cell and these proteins, no doubt, migrate to the cell’s surface. There, they can be recognized by the immune system and attacked. Has this been going on very slowly? Naked RNA (without the virus capsid) can infect adjacent cells but this is very inefficient compared to intact polio virus. Has this been going on for 30 plus years? Are some or all of these proposed mechanisms in place and do they explain why post-polio motor neurons “wear out”.

There is precedent justifying these questions. Coxsackievirus is a Picornavirus too. It is very similar to polio. One single gene mutation of coxsackievirus B3 can convert it into a virus, which damages the heart. [1]

The progression of HIV virus to AIDS is not clearly understood. The evolving virus, within cells, results in mutants at astonishingly high rates. This virus is highly adaptable and cannot as of yet be exterminated within a patient.[1] And highly mutated polio virus RNA was found in a study of a small number of patients with PPS. One half of patients with PPS (5) had recoverable highly mutated polio RNA. While none who had paralytic polio but no signs of PPS had recoverable mutated RNA. Was this due to damaged neurons that “wore out” releasing the RNA that the control group had? Or was the presence of this RNA causal to Post-Polio Syndrome?[2]

My advice mirrors Monod’s at the start of this essay: don’t embrace any of these ideas, be skeptical, question, and wait for evidence to arrive. Just think about it.

References

1. Quasispecies Structure and Persistence of RNA Viruses Esteban Domingo,* Eric Baranowski,* Carmen M. Ruiz–Jarabo,* Ana M. Martín-Hernández,† Juan C. Sáiz,‡ and Cristina Escarmís*Centro de Biología Molecular “Severo Ochoa,” Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain; †John Innes Center, Norwich, United Kingdom; ‡Universitat de Barcelona, Barcelona, Spain , in Emerging Infectious Diseased, December 1998. The entire article can be found at: www.cdc.gov/ncidod/eid/vol4no4/domingo.htm
2. J Clin Microbiol 1996 Aug;34(8):2023-6 Evidence of presence of poliovirus genomic sequences in cerebrospinal fluid from patients with postpolio syndrome. Leparc-Goffart I, Julien J, Fuchs F, Janatova I, Aymard M, Kopecka H Laboratoire de Virologie, Centre National de Reference des Enterovirus, Lyon, France. leparc@cismsun.univ-lyon1.fr [PubMed Abstract]

The Lincolnshire Post-Polio Network

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An Information Service for Polio Survivors and Medical Professionals

All enquiries, book requests, medical article requests, membership fees, items for newsletters and donations to

The Secretary, Lincolnshire Post-Polio Network

PO Box 954, Lincoln, Lincolnshire, LN5 5ER United Kingdom

Telephone: +44 (0)1522 888601

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Email: info@lincolnshirepostpolio.org.uk

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The Lincolnshire Post-Polio Network takes great care in the transcription of all information that appears at this site. However, we do not accept liability for any damage resulting directly or otherwise from any errors introduced in the transcription. Neither do we accept liability for any damage resulting directly or otherwise from the information available at this site. The opinions expressed in the documents available at this site are those of the individual authors and do not necessarily constitute endorsement or approval by the Lincolnshire Post-Polio Network.

© Copyright Eddie Bollenbach 1999 2000

© Copyright The Lincolnshire Post-Polio Network 1999 – 2010.

Copyright is retained by The Lincolnshire Post-Polio Network and/or original author(s). Permission is granted to print copies of individual articles for personal use provided they are printed in their entirety. Links from other Internet WWW sites are welcome and encouraged. We only ask that you let us know so that we can in future notify you of critical changes. Reproduction and redistribution of any articles via any media, with the exception of the aforementioned, requires permission from The Lincolnshire Post-Polio Network and where applicable, the original author(s).

Document preparation: Chris Salter, Original Think-tank, Cornwall, United Kingdom.

Created: 3rd January 1999

Last modification: 21st January 2010.

Polio Biology I

An Introduction to the Virus

Eddie Bollenbach

A Lincolnshire Post-Polio Library Publication

22nd August 1998

It may surprise you to know that we don’t understand where viruses originally came from. Yet for every life form on the planet there is some virus somewhere that can penetrate and infect its cells. All viruses infect by following a similar process: they attach to a cell, penetrate it, reproduce, and propagate. The propagation step often involves bursting and killing the infected cell and the release of hundreds of new viruses. Polio does this to the cells it infects.

No virus will naturally infect a cell unless there is a receptor on the surface of the cell that the virus can “recognize”. The receptor combines with the virus by attaching to it. This attachment is analogous to a hand slipping into a tight glove. Cells without the proper receptor are not naturally infected. Hence, polio only infects humans and closely related primates, and, only infects cells within those species that have receptors for polio virus. In humans, polio receptors can be found in the upper and lower throat, gut, brain, and on the motor nerve cells (polios-denoting gray matter) of the spinal cord.

Before the advent of the trivalent polio vaccines, polio virus was abundant within our environment. It passed from person to person by ingestion of extremely small bits of fecal material. This could happen through swimming, through food handlers who failed to wash hands properly, or through poor general

sanitation. Polio virus is one of the smallest viruses and can be readily transmitted, in large numbers, easily. If the number of virus particles a person ingests is large enough (infectious dose), the virus strain infective enough (virulent), and the resistance of the person low enough (susceptible), the virus attaches to receptors and enters cells in the gut faster than the immune system can clear the virus from the body. Soon, as propagation proceeds, great numbers of virus particles are released into the blood. When virus is in the blood, the condition is called viremia. Eventually viruses find their way to the parts of the brain and spinal cord which have receptors for them. These cells then, unwittingly, take virus in. During propagation within the Central Nervous System, nerve cells (neurons) are killed and cannot divide to replace themselves. Within a couple of weeks the infectious stage ends but virus shedding from fecal material can continue for a few more weeks.

For most of us permanent damage resulted this way. Nevertheless, most of us recovered some function. Recovery involved a number of separate adaptations. For example, we substituted muscles that were less damaged (by nerve loss) for necessary tasks, we sprouted new end fibers from surviving nerves, confering on them a burden for which evolution had not prepared them. The ratio of muscle fiber types changed: the proportion of endurance fibers vs. strength fibers was altered in favor of the endurance type. These

adaptations served us well for a long time. Some are failing us now. This is the simplest and most understandable explanation for Post Polio Syndrome. Perhaps, because we are losing more endurance type muscle, manual strength tests on many of us fail to demonstrate the severity of muscle fatigue we experience. Anyway, these are the most likely explanations for the onset of PPS.

Questions do remain however. Why do some polio survivors and not others experience PPS? Is PPS a disease process which is a natural consequence of having polio? Can you have polio with the damage and repair adaptations and remain stable for life? If so, why? To complicate the legacy of our biological interaction with polio virus is the recent discovery of polio virus genes inside the spinal cords PPS patients. These genes are not present in polio survivors without PPS. This seems to be telling us something. And, the obvious question is “do these fragmments of virus cause PPS?”

It is possible to remove the outer protein shell from a polio virus by treating the virus with phenol. When this was done in the 1940’s it was found that the genes inside were infectious without their outer coat. Virus genes could enter cells but were a thousand times less infective than whole virus. We can also assume polio’s genes, in the cords of PPS patients, are defective. That is, they have mutated and are not propagating normally by bursting cells. Perhaps, as foreign viral parts, these genes can trigger inflammation, or interfere with nerve cells in another way. New research may resolve these questions. In the meantime polio virus biology remains ineluctably entwined with our own.

The Lincolnshire Post-Polio Network

Registered Charity No. 1064177

An Information Service for Polio Survivors and Medical Professionals

All enquiries, book requests, medical article requests, membership fees, items for newsletters and donations to

The Secretary, Lincolnshire Post-Polio Network

PO Box 954, Lincoln, Lincolnshire, LN5 5ER United Kingdom

Telephone: +44 (0)1522 888601

Facsimile: +44 (0)870 1600840

Email: info@lincolnshirepostpolio.org.uk

Web Site: www.lincolnshirepostpolio.org.uk

The Lincolnshire Post-Polio Network takes great care in the transcription of all information that appears at this site. However, we do not accept liability for any damage resulting directly or otherwise from any errors introduced in the transcription. Neither do we accept liability for any damage resulting directly or otherwise from the information available at this site. The opinions expressed in the documents available at this site are those of the individual authors and do not necessarily constitute endorsement or approval by the Lincolnshire Post-Polio Network.

© Copyright Eddie Bollenbach 1998 1999 2000

© Copyright The Lincolnshire Post-Polio Network 1998 – 2010.

Copyright is retained by The Lincolnshire Post-Polio Network and/or original author(s). Permission is granted to print copies of individual articles for personal use provided they are printed in their entirety. Links from other Internet WWW sites are welcome and encouraged. We only ask that you let us know so that we can in future notify you of critical changes. Reproduction and redistribution of any articles via any media, with the exception of the aforementioned, requires permission from The Lincolnshire Post-Polio Network and where applicable, the original author(s).

Document preparation: Chris Salter, Original Think-tank, Cornwall, United Kingdom.

Document Reference: <URL:http://www.zynet.co.uk/ott/polio/lincolnshire/library/bollenbach/biology1.html> Created: 22nd August 1998

Last modification: 29th April 2021st January 2010.00