Frank Fenner 1914-2010

It is with great sadness that I report the death of one of my science heroes, Frank Fenner. One of the key people involved in the eradication of smallpox, he was also a prolific researcher in poxvivrology, and discoverer of the virus I study, ectromelia virus. Although I never met him, I have read many of his papers and they have influenced my own research and interests.

Here is the text of the email I received this morning, from Julio Lincio:

“Frank John Fenner AC, CMG, MBE, FRS, FAA (born 21 December 1914,died 22 November 2010) was an Australian scientist with a distinguished career in the field of virology. His two greatest achievements are cited as overseeing the eradication of smallpox during his term as Chairman of the Global Commission for the Certification of Smallpox Eradication, and the control of Australia’s rabbit plague through the introduction of myxoma virus.

Professor Fenner was Director of the John Curtin School from 1967 to 1973. During this time he was also Chairman of the Global Commission for the Certification of Smallpox Eradication. In 1973 Professor Fenner was appointed to set up the new Centre for Resource and Environmental Studies at the Australian National University (ANU). He held the position of Director until 1979.

Professor Fenner has been elected a fellow of numerous faculties and academies, including Foundation Fellow of the Australian Academy of Science (1954), Fellow of the Royal Society (1958), and Foreign Associate of the United States National Academy of Sciences (1977).

During his career Professor Fenner received many awards. Among these are the Britannica Australia Award for Medicine (1967), the Australia and New Zealand Association for the Advancement of Science Medal (1980), the World Health Organization Medal (1988), the Japan Prize (1988), the Senior Australian Achiever of the Year (1999), the Albert Einstein World Award for Science (2000), and the Prime Minister’s Science Prize (2002).

A man of decisive scientific action and strong opinions, Professor
Fenner’s last interview with The Australian is extremely thought provoking and can be found here

A summary of Frank’s remarkable career can be found here


A Universal Flu Vaccine?

The flu comes back year after year, and every season we get vaccinated (well, some of us anyway).  Why do we need to keep getting a new shot for the flu while for others, like measles, we got way back in childhood and are done with it for the rest of our lives?

Our immune response to influenza involves production of antibodies, large proteins that specifically bind to the virus and help clear it out or neutralize it.  It seems like the key to influenza immunity is neutralizing antibodies, antibodies that bind to the virion and prevent it from attaching to the host cell.  You can imagine this large protein just being physically in the way, preventing the virus from binding the host receptor.  The immune response that develops from natural exposure or vaccination generates neutralizing antibodies to HA, a viral envelope protein that is necessary for attachment to the host.  I’ve mentioned HA in a previous post about influenza.  The problem is that last season’s neutralizing antibodies dont bind to this season’s virus.  Although it may be nearly identical to the virus from a past season, the new strain’s HA is slightly different, and those differences are enough to evade existing neutralizing antibodies.

Now a new approach to vaccination has shown that it may be possible to develop a vaccine that illicits broadly neutralizing antibodies, that is, antibodies that will protect against  influenza strains with slightly different HAs.  They used a prime/boost approach, in which a DNA vaccine was used to induce an initial response against HA, and then boosted with a regular seasonal flu vaccine.  The only difference between this and what is currently done is the addition of the DNA vaccine.  However the response seems quite different.  Neutralizing antibodies were generated that can neutralize a variety of different influenza viruses.  It seems the vaccine induced antibodies to a different part of HA.  Antibodies are so specific, the dont recognize the whole HA, but rather discrete parts of it.  The part recognized by these antibodies, called the stem, is highly conserved, meaning it doesnt change season to season.

This raises many interesting questions and possibilities.  Could we soon have a universal vaccine that will protect us for life or at least for many years?  Why did the change in vaccine regimen induce antibodies to a different part of HA?  Why does the current vaccine or natural exposure fail to develop antibidies to the conserved portion of HA? Will the conserved portion of HA eventually change too, if sufficient selective pressure is applied through mass vaccination?


1918 and 2009

The 1918 influenza pandemic (the “Spanish Flu”), by some estimates, killed as many as 100 million people in a very short period of time.  The 2009 “Swine Flu” pandemic didnt kill so many, but it spread rapidly and widely across the globe.  Despite that difference, it turns out the two viruses responsible for these pandemics have some important similarities.

Influenza virus has a protein on the surface called hemagglutinin, or HA, which is used to attach to host cells, allowing the virus to then enter and replicate.  HAs change rapidly, which is partly why influenza keeps coming back.  When HA changes, your antibodies dont recognize it so well, so you get sick again.  It turns out that the HAs of 2009 and 1918 are similar on both the sequence and structure level.  There is a small patch on the HA protein that is 95% identical between 1918 and 2009 but only 70% identical to seasonal strains.  Looking only at the 3D structure, among all influenza HAs, the 2009 HA is most similar to the 1918 HA.  The 1918 and 2009 HAs also lack glycosylation at the tip, while seasonal influenza viruses HAs are sugary.

Why is that interesting? An unusual pattern was noted in the 2009 pandemic: elderly people were not as affected as younger people, the reverse of what is usually seen with influenza.  It was proposed that perhaps some people still had immunity to the 1918 virus, which continued to circulate for many years after 1918, and that immunity was cross-protective.  A recent study shows that this indeed seems to be the case.  Mice immunized with the 1918 virus are protected against the 2009 virus.  The converse is also true: if you immunize mice with the 2009 virus, they are protected against the 1918 virus.  That’s pretty impressive when you consider that one season’s vaccine might not protect you from next season’s virus. It seems the immune system cant really tell the difference between these viruses.  Note that it also tells us how long immunity can last!  The next question is, how and why has this HA structure come back?


Colony Collapse Disorder: Is a virus causing bees to disappear?

My daughter, who is only 4 and has been stung twice, would probably be happy to see all bees disappear.  But bees are important pollinators and we depend on them for many crops.  A very puzzling disorder has been causing bee colonies to collapse in North America: hives that still have abundant resources become abandoned.  The bees disappear and die.  This is odd because, if there were some infectious disease killing the bees you might expect to find lots of dead bees in the hive.  But they seem to just disappear.

Many studies have been done to try to identify the culprit.  Israeli accute paralysis virus, Varoa destructor virus -1, and the fungus Nosema ceranae have all been implicated but eventually ruled out because their presence was not strongly correlated with colony collapse disorder.  A new culprit has been proposed now: a co-infection by the fungus Nosema and a large DNA virus of the family Iridoviridae called Invertebrate Iridescent Virus (IIV).

In a recent post I described the use of metagenomics to sequence all the nucleic acids present in a sample to find the cause of acute flaccid paralysis in South Asia.  Metagenomics had been tried here and failed to identify the true culprit.  In this study they used a different approach called proteomics.  They sequenced protein fragments, rather than nucleic acids, from both healthy and collapsing bee colonies to try to find specific proteins associated with CCD.  What was found were proteins from Nosema and IIV.

There is a strong correlation between the co-infection and CCD, and they went on t show that the co-infection does indeed kill bees.  There are still many unknowns, however.  What is it about the interaction between these two pathogens that results in this odd disorder?  What makes the bees fly away and die rather than die in the hive?  Are they getting lost and confused?  How is it spread and how can we stop it?

(You can also check out the article in the NY TImes).


Discovering new viruses: What is causing acute flaccid paralysis in South Asia?

There are only a few places in the world where polio is still endemic. Polio normally infects the gut and is usually asymptomatic, but sometimes spreads to the nervous system and causes acute flaccid paralysis (AFP).  In South Asia, AFP keeps cropping up, but it turns out many of these cases are not being caused by poliovirus.  So what is causing these cases of AFP?  A recent study did a metagenomic analysis of the virus population from stool samples from AFP cases in Pakistan.  Metagenomics is an approach where you can sequence all the nucleic acid from a particular sample to see whats there.  In this case they filtered samples to remove cells, digested the filtrate with nucleases to destroy free nucleic acids, leaving them with the genetic material of viruses in their protective capsids.

They found lots of bacteriophages (presumably infecting gut bacteria), lots of plant viruses (probably from eating veggies), and lots of animal viruses.  They identified a new genus of picornaviruses, closely related to poliovirus.  This new genus, which they called Cosavirus, appears to be highly prevalent in samples from Pakistan but not in samples from the UK.  But is it the cause of AFP?  Its found in 49% of AFP cases and in 44% of healthy controls.  So are healthy controls asymptomatic infections, like we see in polio?  Are there other causes for the other 51% of AFP cases? Lots of questions obviously remain in understanding the epidemiology of AFP here, but this study is a good start and a very practical application of metagenomics for virus discovery.


Crimean-Congo Hemorrhagic Fever Outbreak

CCHF is disease that is usually transmitted by  contact with blood of infected animals, usually farm animals, or ticks.  As such, most people infected work in agriculture or butchering and tanning.  In rare cases, CCHF transmission has been observed to occur in hospital settings, such as through the use of contaminated instruments or contact with infectious blood.  There appears to be an outbreak in Pakistan and Afghanistan, although at the moment its not clear how the cases are related, if at all.  7 cases were reported in Helmand Province, Afghanistan in June 2010.  Several others have been reported in Pakistan since March and there are several cases of “undiagnosed illnesses” in the area which may be CCHF.  Initial cases were reported in the expected populations: a butcher, a tanner and other agriculture workers.  However the disease appears to be spreading rapidly in hospitals too.    8 individuals at a hospital in Islamabad tested positive for the virus.  A doctor in Abbottabad who died of the disease may have spread it to his brother.

It seems like many of these cases are the result of human-to-human transmission rather than tick bites or from contact with animals.  The reason for prevalence of this unusual transmission pattern in this particular outbreak is not known yet.


TWiV Podcast

TWiV: This Week in Virology.  I love listening to this podcast.  When people see me listening to my iPod, they may think I’m cool and listening to the hip music all the kids are listening to these days, but no, I’m being nerdy and listening to a bunch of scientists talk about viruses.  Its a great resource for learning about virology and just listening in on discussions among scientists gives you a good sense of how science proceeds – lots of questions and curiosity about the world around you.

You can go to the website or download podcasts from iTunes.


Ebola Virus Entry

Viruses can enter cells through a variety of different pathways.  Many enter through endocytosis, and there are actually several endocytic pathways: clathrin mediated, caveolin mediated, phago- and pinocytosis, and the rather mysterious “non-clathrin, non-caveolin mediated endocytosis.”

Ebola virus causes a severe hemorrhagic disease with 90% mortality.  Its an obviously frightening virus which makes it difficult to study, but knowing the details of its replication cycle may provide important clues on how to treat or prevent the disease.  A recent paper demonstrates that Ebola probably uses clathrin-mediated endocytosis.  Clathrin is a protein that forms a polyhedral lattice on the inside of the cell membrane helping to form vesicles.  Virus attachment induces this vesicle formation, giving the virus access to the cell by entering through these vesicles.  Among other experiments, they found that if you use the drug chorpromazine, which inhibits clathrin function, you can block Ebola entry.

The paper raises some interesting questions. First, they didnt actually use Ebola virus.  They used a modified HIV that expresses the Ebola virus glycoprotein involved in attachment and entry.  Does the natural virus enter in the same way?  They used several different cells in culture and found clathrin dependence in all of them, but is it the same in an infected animal?  Finally is the drug chlorpromazine one that could be used clinically?  Presumably not since disrupting clathrin mediated endocytosis would probably have a broadly toxic effect on the host, but it is an interesting lead compound.


Distant Evolutionary Relationships

We’ve been talking about protein structure and folding in my Biol 105 class.  Proteins are made of chains of amino acids and the sequence of amino acids, or primary structure, dictates the way the protein will fold into its final 3D or tertiary structure.  We may assume that two proteins with similar sequences would have a similar structure, and that two proteins with very different sequences would have different structures.  However, this is not true.  Proteins with very different sequences can end up with similar 3D structures.

A great example of this is the structure of capsid proteins from three very different viruses.  Adenoviruses infect animals (eukaryotes), and is one of many viruses that cause colds.  PRD1 is a bacteriphage, a virus that infects bacteria.  STIV (Sulfolobus turreted icosahedral virus) infects Sulfolobus, an archaea that lives in geothermal hotsprings in Yellowstone National Park.  STIV and its host love the 80 degree celsius, pH 3 environment of the hotsprings.  The fact that there are viruses that infect archaea in those extreme environments is cool enough.  But it turns out that the capsid proteins of these three viruses are actually quite similar.  Their sequence differs significantly, but their tertiary structures are highly similar, meaning these very different polypeptides fold into essentially the same shape.

What is the basis of this similarity?  Do all theses viruses share a common ancestor, which would have existed before the three domains of cellular life (eukarya, bacteria, archaea) diverged over 3 billion years ago? Is it convergent evolution?  Was there a horizontal gene transfer event in which a gene moved among all three domains?  The authors of the paper argue for a common ancestor but the other possibilities have not been formally excluded.  We still don’t really know, and it raises interesting questions about the origin of viruses.


Monkeypox and Herd Immunity

In 1980, smallpox was declared eradicated following an intensive global vaccination campaign.  The virus, Variola, has some close relatives that can infect humans, one of which is monkeypox.  Monkeypox isnt nearly the problem that smallpox was; it has a much lower mortality rate and outbreaks tend to fizzle out quickly due to poor human-to-human transmission.

However, a recent paper suggests that monkeypox infections are becoming an increasing problem.  So why is it emerging now?  Its a problem we’ve been anticipating, actually.  Turns out that when you get the smallpox vaccine (or smallpox itself), it also protects you from monkeypox.  So pre-eradication, most people were immune to monkeypox.  If you met up with an infected animal, chances are you were immune and wouldn’t get infected.  If you did somehow get infected, chances are most people around you were immune so you couldn’t transmit it to others.  An immune host is not fertile ground for viral replication, so whenever immune hosts are encountered, the chain of viral transmission ends.  In fact, a highly vaccinated population helps those few individuals that are not vaccinated by greatly limiting the potential of the virus reaching the unvaccinated (“naive”) individual.  Thats called herd immunity.

Turns out herd immunity to smallpox, and therefore monkeypox, is waning.  Vaccinations stopped in 1980 so anyone born after that is naive and therefore there is a major lapse in herd immunity.  Risk of infection with monkeypox virus is now as much as 20 times greater than 30 years ago.  Interestingly, all those old people born before 1980 who were vaccinated have a much lower risk of infection, telling us that immunity from vaccination lasts 30+ years.

So why should we worry about waning herd immunity to a rare and relatively mild disease that is hardly contagious?  Well, variola and monkeypoxviruses are about 96% identical.  We dont know how much  monkeypox needs to mutate to become sustainable in humans or more virulent.


Teaching and Research on the Microbial World in the Liberal Arts

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