Several panelists from the recent influenza H5N1 dual-use forum at the New York Academy of Sciences spoke with Brendan Maher of Nature News to discuss their position. Participants in this video include Laurie Garrett, Michael Osterholm, Ian Lipkin, Vincent Racaniello, and Veronique Kiermer.

Update: The New York Academy of Sciences has posted video of the full two hour panel discussion.

On This Week in Virology #169, Michael Walsh and the TWiV team review epidemiology basics, including fatality ratios.

You can find TWiV #169 at www.twiv.tv.

Howard Markel, Professor of the history of medicine at the University of Michigan, in the New York Times:

The censorship of influenza research will do little to prevent its misuse by evildoers — and it may well hinder our ability to stop influenza outbreaks, whether natural or otherwise, when they do occur. In this case, censorship is too little, too late. The data generated by one of the research teams was already presented at a conference in Malta in September, where copies of the paper were distributed. But even if the data weren’t already available, the key details could likely be inferred from other information that is already available.

Dr. Markel also agrees that influenza H5N1 virus would not be a good terrorist weapon:

Even if terrorists got their hands on the new data, it’s not certain they could weaponize the virus: no one knows for certain that the virus’s transmissibility and virulence in ferrets means transmissibility and virulence in humans. In any event, the influenza virus, highly variable in its power and spread, is not an optimal terrorist weapon, not least because no one would know for sure if it was unleashed by a terrorist or natural forces.

The implications of the H5N1 story go far beyond ferrets:

In the years since the 9/11 attacks, we’ve witnessed a disturbing trend in the oversight of sensitive science. [...] Several prominent scientists, including Donald Kennedy, the former editor of Science, have publicly worried that the federal government is thwarting scientific advancement.

The action by the NSABB has propelled us full-tilt into this controversy. Their incorrect decision to censor the influenza H5N1 data not only will inhibit work on this important virus, but will have far-reaching consequences for scientific research. To this day I cannot understand why the NSABB did not more thoughtfully consider not only the data, but the future of science in coming to their decision.

Thanks to Dr. Markel for writing the Op-Ed I’ve been meaning to put together for a long time.

Related:

The NSABB speaks on influenza H5N1

H5N1 facts, not fear

Moratorium on influenza H5N1 transmission research

Palese: Don’t censor live-saving science

N.Y. Times: H5N1 ferret research should not have been done

Should we fear avian H5N1 influenza?

Ferreting out influenza H5N1

The National Science Advisory Board for Biosecurity (NSABB) has published “Adaptations of Avian Flu Virus Are a Cause for Concern”, an explanation of their recommendations with respect to influenza H5N1 research (versions at Science and Nature). It starts with the statement that advances in technology now allow manipulation of microbial genomes in ways that could be misused, leading to global harm. They define dual-use research as “research that could be used for good or bad purposes”.

The authors begin their discussion of influenza H5N1 with the usual incorrect statement about the lethality of the virus:

Highly pathogenic avian influenza A/H5N1 infection of humans has been a serious public health concern since its identification in 1997 in Asia. This virus rarely infects humans, but when it does, it causes severe disease with case fatality rates of 59%.

The reference for this information is a WHO summary of confirmed human cases of H5N1. Both WHO and NSABB ignore the serological evidence for many mild or inapparent H5N1 infections. Omitting these data leads to an overestimation of the virulence of the virus, which has apparently played a large role in the NSABB’s decision.

Next, they engage in extensive speculation:

If influenza A/H5N1 virus acquired the capacity for human-to-human spread and retained its current virulence, we could face an epidemic of substantial proportions.

The virus has been circulating since the 1990s and has not acquired the capacity for human to human spread. This doesn’t mean it never will, but the possibility seems remote. The statement ‘retaining its current virulence’ of course refers to the erroneous 59% case fatality rate. What if the fatality rate is 0.1%, like seasonal influenza?

In discussing influenza H5N1 transmission in ferrets, the NSABB notes the value of the research:

The research teams that performed this work did so in a well-intended effort to discover evolutionary routes by which avian influenza A/H5N1 viruses might adapt to humans. Such knowledge may be valuable for improving the public health response to a looming natural threat.

Many have written that the research should never have been done, and that there are no benefits for human health (New York Times, Tom Inglesby, DA Henderson). Clearly the NSABB believes otherwise.

Next the NSABB describes their consideration of risk assessment of the H5N1 ferret studies. Their conclusion:

We found the potential risk of public harm to be of unusually high magnitude. Because the NSABB found that there was significant potential for harm in fully publishing these results and that the harm exceeded the benefits of publication, we therefore recommended that the work not be fully communicated in an open forum.

But there is no description of how they reached this conclusion. What data did they consider when making this decision? What were the benefits and the potential harms, and how did they weigh them? Apparently we must take the word of the panel that they reached the right decision, even though we cannot know what information they used. To convey their decision in this manner is unacceptable and sends the message that the committee did not consider specific data during their deliberations.

They conclude:

The life sciences have reached a crossroads. The direction we choose and the process by which we arrive at this decision must be undertaken as a community and not relegated to small segments of government, the scientific community, or society.

This is precisely why the decision to redact publication should not have been made by the NSABB or any small group of individuals. I agree that this is an ‘Asilomar moment’, a time when scientists must meet to decide what types of microbial research should be regulated. This should be a discussion among a large group of scientists, not bioterrorism policy analysts.

I understand the need to regulate certain types of experiments on microbes. But when I balance the benefits and risks of the H5N1 ferret transmission experiments, it does not make sense to stamp them as dual use and restrict publication of the results. Let publication proceed and then decide how to decide on how to move forward.

Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit, Alan Dove, and Welkin Johnson

Welkin joins the TWiV team for a discussion of HIV prophlaxis using vectored antibodies, and the influenza H5N1 virus studies in ferrets that were not redacted.

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Peter Palese and Taia Wang have written a compelling article that uses scientific facts to address the controversy over publication of research involving transmission of avian influenza H5N1 in ferrets. In response to calls in the media to destroy the viruses, curtail the research, and protect the public from frightening research, they write that “fear needs to be put to rest with solid science and not speculation”.

The authors begin with the facts: they indicate that the object of ferret-to-ferret passage of avian H5N1 influenza virus was to determine whether sustainable aerosol transmission could be achieved in this animal model. The finding that transmission in ferrets is conferred by a small number of mutations emphasizes the need for continued surveillance of H5 viruses and development of vaccines and antivirals.

Are these studies relevant to humans?

Ferrets are quite susceptible to infection with influenza viruses. However, it is not clear that all virus strains that replicate in and transmit between ferrets necessarily do so in humans. Ferrets are also more likely than humans to have disseminated, multiorgan influenza disease including neurological sequelae….one cannot directly extrapolate from the data to make predictions about humans.

Under the heading ‘fear’, they address the heart of this controversy, the notion that the fatality rate for human H5 infections is greater than 50%:

…in order for a case to be confirmed by WHO, a person must have an acute, febrile respiratory illness with known H5 exposure in the 7 days preceding and have molecular confirmation of H5 infection by a WHO approved laboratory. This definition does not allow for asymptomatic infections and essentially requires that a person actively seek medical help at a hospital that is equipped to draw samples and ship them to an approved laboratory….it seems unlikely that even a small fraction of the total number of infected cases has been accounted for under the WHO surveillance system.

They also review seroevidence in humans for H5 infections:

Of the 10 largest studies of which we are aware…eight report rates ranging from 0.2% to 5.6%….even if only a low percentage of the rural population is asymptomatically/subclinically infected, the case fatality rate that is offered by the WHO – and that is driving this controversy – is likely orders of magnitude too high.

The authors believe that selection of these papers for redaction by the National Science Advisory Board for Biosecurity appears arbitrary, considering what has been published on influenza in the past:

In 2005, the complete sequences for the 1918 pandemic influenza virus were published…in 2006, both Science and Nature published reports of specific mutations that enable the H5 viral hemagglutinin to bind human, rather than avian tissues. In 2012, a report from the CDC that bears striking resemblance, in principle, to the works by Fouchier and Kawaoka was already published in Virology: it describes mutations in an H5N1 virus that confer airborne transmissibility between ferrets.

Finally the address the question: Could the data from these two papers realistically be used to generate an H5N1 biologic weapon?

The answer is simply no.

Everyone should read this article, including anyone who is concerned about the safety of the H5N1 experiments; biosecurity analysts who do not seem to understand the underlying science; and science writers who propagate misinformation about the virus.

Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit, and Alan Dove

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In letters to Science and Nature, the authors of the controversial avian H5N1 influenza virus transmission experiments in ferrets, together with other influenza virologists, have agreed to a 60 day moratorium on transmission research:

…we have agreed on a voluntary pause of 60 days on any research involving highly pathogenic avian influenza H5N1 viruses leading to the generation of viruses that are more transmissible in mammals. In addition, no experiments with live H5N1 or H5 HA reassortant viruses already shown to be transmissible in ferrets will be conducted during this time.

They write that research will continue on assessing the “transmissibility of H5N1 influenza viruses that emerge in nature and pose a continuing threat to human health”.

This research is being halted because of the concerns that ferret-transmissible H5N1 viruses may escape from laboratories. They argue that the finding in two laboratories that viruses with a hemagglutinin (HA) protein from highly pathogenic avian H5N1 influenza viruses can become transmissible in ferrets advances our understanding of influenza transmission. Nevertheless,

We recognize that we and the rest of the scientific community need to clearly explain the benefits of this important research and the measures taken to minimize its possible risks. We propose to do so in an international forum in which the scientific community comes together to discuss and debate these issues.

I agree in principle with this decision, because the argument over this research has become increasingly polarized in recent weeks, with a distressing demarcation between those who believe the work should proceed, and those who feel it should not be done. A dialogue to identify the crucial issues and develop plans to address them, while continuing this important line of research, is certainly welcome.

I am curious to see who will participate in the proposed dialogue. I do hope it will be a balanced forum: a fair mix of microbiologists, especially those working on influenza virus, and those interested in biosecurity. As I have said before, scientists will listen to the policy analysts, but the latter must also understand the science.

Update: Alan Dove has written an honest analysis of the moratorium announcement.

Related:

Palese: Don’t censor live-saving science
N.Y. Times: H5N1 ferret research should not have been done
Should we fear avian H5N1 influenza?
A bad day for science
Ferreting out influenza H5N1

The third annual installment of my virology course at Columbia University, Biology W3310, has begun. This course, which I taught for the first time in 2009, is intended for advanced undergraduates and will be taught at the Morningside Campus.

Until I started this course, no instruction in virology had been offered at the Morningside Heights campus of Columbia University since the late 1980s. This is a serious omission for a first-class University. Sending graduates into the world without even a fundamental understanding of viruses and viral disease is inexcusable.

Course enrollment has steadily increased: 45 students in the 2009, 66 students in 2010, and an amazing 88 students this year. I am gratified that so many students want to learn about the world of viruses. From the photo you can see that the classroom is full, so if interest in the course continues to increase, we will need a larger room.

Most readers of virology blog will not be able to sit in on each lecture – but you can still watch every one of them. You will find a videocast of each lecture at the course website, at my page on Vimeo, and at iTunes University (link pending). An archive of the 2011 version of this course is available online or at iTunes University. I will announce when each lecture is posted on Twitter and Google+. Virology is a rapidly moving field, so rest assured that this year’s version of the course will be different.

The goal of Virology W3310 is to provide an understanding of how viruses are built, how they replicate and evolve, how they cause disease, and how to prevent infection. After taking the course, some of the students might want to become virologists. The course will also provide the knowledge required to make informed decisions about health issues such as immunization against viral infections.

Thanks to the internet, the information in my virology course is accessible to everyone.

After we discussed newly discovered entry factors for ebolavirus and hepatitis C virus on TWiV 166, the New York Times covered part of the story in Key protein may give Ebola virus its opening. Given my recent interest in the case fatality ratio of avian influenza H5N1, I was intrigued by the following introductory statement:

Of the pathogens that keep worried scientists awake at night, few rival Ebola for ruthless efficiency. The virus contains just seven genes, yet it manages to kill up to 90 percent of the people it infects.

Is it true that the fatality rate of ebolavirus is ‘up to 90 percent’? According to the WHO page on Ebola haemorrhagic fever,

Zaïre, Sudan and Bundibugyo species have been associated with large Ebola haemorrhagic fever (EHF) outbreaks in Africa with high case fatality ratio (25–90%) while Côte d’Ivoire and Reston have not. Reston species can infect humans but no serious illness or death in humans have been reported to date.

There have been roughly 1850 recorded cases with over 1200 deaths since ebolavirus was discovered, an average fatality rate of 65%. But have there been only 1850 human infections?

The answer is clearly no. The results of several serological surveys have shown that many individuals have antibodies against Zaire ebolavirus – purportedly the most lethal. The results of one study revealed antibodies in 10% of individuals in non epidemic regions of Africa. A similar seroprevalence rate (9.5%) was reported in villages near Kikwit, DRC where an outbreak occurred in 1995. In addition, a 13.2% seroprevalence was detected in the Aka Pygmy population of Central African Republic. No Ebola hemorrhagic fever cases were reported in these areas.

A more recent study examined sera from 4,349 individuals in 220 villages in Gabon. Antibodies against Zaire ebolavirus were detected in 15.3% of those tested, with the highest levels in forested regions (see map). The authors believe that the seropositive individuals had mild or asymptomatic ebolavirus infection:

The high frequency of ‘immune’ individuals with no disease or outbreak history raises questions as to the real pathogenicity of ZEBOV for humans in ‘natural’ conditions.

These findings indicate that the fatality rates of Zaire ebolavirus that are quoted widely are likely to be vast overestimates. Why the infection is more lethal during outbreak conditions is not known. One possibility is related to the size of the viral inoculum received. During outbreaks the virus is spread by contact with the blood, secretions, organs or other body fluids of infected individuals, which contain very large quantities of virus. In contrast, infections in nature – by contact with contaminated fruit, for example – may involve far less virus.

Whether we are discussing avian H5N1 influenza, ebolavirus, or even the fictitious MEV-1, do not assume that widely quoted fatality rates are correct – check the scientific literature!

Related:

Should we fear avian H5N1 influenza?

Becquart P, Wauquier N, Mahlakõiv T, Nkoghe D, Padilla C, Souris M, Ollomo B, Gonzalez JP, De Lamballerie X, Kazanji M, & Leroy EM (2010). High prevalence of both humoral and cellular immunity to Zaire ebolavirus among rural populations in Gabon. PloS one, 5 (2) PMID: 20161740

The finding of viral nucleic acid sequences in illegally imported wildlife products has attracted the attention of the New York Times, which published an article entitled From the jungle to J.F.K., viruses cross borders in monkey meat. It begins with a scary scenario:

This may read like a passage from a Richard Preston novel, but all an enterprising virus needs to do is jump aboard a traveling human or animal, and bam — the potential for a catastrophe akin to the 1918 Spanish influenza pandemic could emerge. That’s why the Centers for Disease Control and the Wildlife Conservation Society decided to undertake their first surveillance efforts for diseases of animal origins crossing in the United States.

However, the PLoS One paper that is cited in support of this story found short viral sequences, not viruses, in material confiscated at several airports. The authors of this report extracted nucleic acids from confiscated specimens (which included fresh, raw, lightly smoked or dried samples from chimpanzees, mangabeys, guenons, and rats) and screened them for pathogen nucleic acids by polymerase chain reaction (PCR). The authors note that “RNA quality was low with a predominance of degraded, low molecular weight fragments in the samples”. They identified small PCR DNA products from the genomes of simian foamy virus (a retrovirus) and herpesviruses in 15 out of 48 specimens. No complete viral genomes or infectious viruses are reported in the paper.

Perhaps the Times was mislead by the title of the PLoS One paper: Zoonotic Viruses Associated with Illegally Imported Wildlife Products. The abstract is similarly misleading:

Pathogen screening identified retroviruses (simian foamy virus) and/or herpesviruses (cytomegalovirus and lymphocryptovirus) in the NHP samples.

The authors correctly report their results at the end of the introduction:

Here we report finding sequences of simian retroviruses and herpesviruses in bushmeat confiscated at five US airports

Infectious viruses might accompany imported smoked monkey heads, dried bats and rat parts. The presence of small fragments of viral nucleic acids suggests that these materials were indeed once infected. But it is a large leap of faith to suggest that infectious agents are still present. It’s a good idea to use PCR to screen such material, but it is important to be specific when reporting the results. My suggestions for revised titles: Zoonotic viral sequences associated with illegally imported wildlife products (PLoS One) and From the jungle to J.F.K., small fragments of viral nucleic acids cross borders in monkey meat (NY Times). Far less interesting, but factually correct.

Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit, and Alan Dove

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A year has passed since the last reported case of poliomyelitis in India, which occurred on 13 January 2011 in a two year old girl in Howrah, West Bengal. If no additional cases are reported in the next few weeks (some samples are currently being tested for the virus), then it will mark the first time that India has been polio free for one year.

This achievement represents a remarkable turnaround for India, where control of the disease had for years been extremely difficult. As recently as 2009 there were 741 confirmed cases of polio caused by wild-type virus (as opposed to vaccine-derived virus) in India. The tide turned in 2010 with only 42 confirmed polio cases, and in calendar year 2011 there was just one. That is why the 2011 map marking locations of confirmed wild polio cases in India (see figure) shows only one red dot (paralysis caused by type 1 poliovirus) in the country. The blue dots indicate cases caused by type 3 poliovirus.

The challenge now is to keep India free of polio. The map shows why this will be difficult – there are many red dots (cases of type 1 polio) in neighboring Pakistan and Afghanistan. Poliovirus does not respect national borders - China had been free of polio since 1999, but now there are red dots in that country. That outbreak was imported from Pakistan. Even the polio cases in more distant countries such as Africa constitute a threat. As long as there is polio somewhere, all countries must maintain extensive immunization programs. Whether or not that will happen depends upon money, determination, and allowing immunization campaigns to proceed without interruption.

Once polio was eradicated from the United States, the only poliomyelitis was caused by the Sabin vaccine. Consequently this country switched to the use of inactivated vaccine in 2000. As other countries eliminate the disease, vaccine-associated poliomyelitis will become more prominent. If eradication of polio is achieved, the world will have to switch to using inactivated poliovaccine.

Related:

Wild poliovirus in China
Dreaming of inactivated poliovaccine
Poliomyelitis after a twelve year incubation period
Poliovirus vaccine litigation

Renowned influenza virologist Peter Palese has penned an opinion column for the science journal Nature in which he uses his experience in reconstructing the 1918 pandemic influenza virus strain to question the censoring of H5N1 results by the National Science Advisory Board for Biosecurity (NSABB):

My colleagues and I were at the centre of a similar controversy in 2005, when we reconstructed the 1918 flu virus, which had killed up to 50 million people worldwide.

As Palese and colleagues readied a manuscript describing these remarkable findings, the NSABB intervened. Palese explained why publishing the work would allow studies on why the virus is dangerous. The NSABB agreed and allowed publication. That was an important stimulus for work on the virus:

After we published our full paper…researchers poured into the field who probably would not otherwise have done, leading to hundreds of papers about the 1918 virus. As a result, we now know that the virus is sensitive to the seasonal flu vaccine, as well as to the common flu drugs amantadine (Symmetrel) and oseltamivir (Tamiflu). Had we not reconstructed the virus and shared our results with the community, we would still be in fear that a nefarious scientist would recreate the Spanish flu and release it on an unprotected world. We now know such a worst-case scenario is no longer possible.

In light of this positive experience, Palese does not understand why the NSABB today does not want to make public the mutations that allow aerial transmission of H5N1 in ferrets. He believes that knowing the mutations will allow a rapid response if they are observed in nature. His conclusion:

The more danger a pathogen poses, the more important it is to study it (under appropriate containment conditions), and to share the results with the scientific community. Slowing down the scientific enterprise will not ‘protect’ the public — it only makes us more vulnerable.

Why is the NSABB taking a different stance on influenza research today compared with 2005? A major factor may be the perception that the fatality rate of H5N1 influenza virus in humans is 60%, compared with 2.5% for the 1918 H1N1 strain – although the latter is not insignificant. As I have pointed out previously, that assumption is incorrect.

Palese hopes that the scientific community will convice the NSABB to change its mind – otherwise who will enter a field in which you cannot publish your most interesting results?

Science magazine is conducting a live chat about research that produced H5N1 influenza strains that are more easily transmissible between ferrets. Among the topics to be addressed will be the benefits and risks of the H5N1 transmissibility studies and whether they should be published in full; and should experiments that could help aspiring bioterrorists be more tightly regulated.

The guests will be epidemiologist and NSABB member Michael Osterholm, PhD, MPH, Director of the Center for Infectious Disease Research and Policy (CIDRAP), and influenza virologist Andrew Pekosz, PhD, Associate Professor in the Department of Microbiology and Immunology, Johns Hopkins University.

The live chat begins at 3 p.m. EST on Thursday, 12 January. You can join the chat here on virology blog (below) or at the Science website. Questions may be entered in the comment box below before the chat starts.

 

The prominent lead editorial in the New York Times of Sunday, 8 January 2012 is entitled ‘An Engineered Doomsday’. It concerns recent avian influenza H5N1 research, in which scientists in the Netherlands and at the University of Wisconsin found that by passaging the virus in ferrets it could acquire aerosol transmissibility. Let’s determine if the scientific facts warrant the frightening title.

The editorial begins by rebuking the scientists who carried out the experiments on H5N1:

…the research should never have been undertaken because the potential harm is so catastrophic and the potential benefits from studying the virus so speculative.…they created a virus that could kill tens or hundreds of millions of people if it escaped confinement or was stolen by terrorists. …the new virus…ought to be destroyed.

The intent of the experiments was not to create a doomsday virus, but to answer questions about why the H5N1 virus transmits well among birds but not humans. This experiment cannot of course be done in humans, so it was carried out in ferrets, a model for influenza. The results show that aerosol transmissibility in ferrets can be achieved with just five amino acid changes, with no reduction in the virulence of the virus. That result does not mean that the same amino acid changes would have the same effect in humans – it just tells us that achieving aerosol transmissibility in an animal model is relatively easy.

Whether tens or hundreds of millions of people would be killed depends on the ability of a virus to not only transmit among humans, but to retain virulence. There is no evidence that the ferret-passaged H5N1 virus has these properties. In the unlikely event that the virus somehow escaped and began to infect people, its spread could be controlled by vaccines (candidates are under development) and antivirals (existing neuraminidase inhibitors are active against influenza H5N1).

The heart of the H5N1 controversy is encapsulated by the next passage:

Thus far the virus has infected close to 600 humans and killed more than half of them, a fatality rate that far exceeds the 2 percent rate in the 1918 influenza pandemic that killed as many as 100 million people.

This statement refers to the fact that nearly 60% of the 573 WHO-confirmed H5N1 cases have died. This death rate appears staggering until one considers how it is calculated. The WHO case definition for H5N1 influenza states that an individual must have a febrile respiratory illness, known exposure to H5N1 virus in the previous 7 days, and confirmation of infection by virus culture, polymerase chain reaction, or tests for antibodies. These conditions are highly unlikely to be fulfilled in rural populations where most H5N1 infections probably occur. The case fatality ratio can only be calculated by dividing the number of deaths by the total number of infections – and we do not know the latter number. Of ten large studies that have tested for H5N1 antibodies in rural populations, two were negative and 5 reported the presence of H5 antibodies in 0.2 – 5.6% of indiviudals. Much more work needs to be done to determine the actual fatality rate of influenza H5N1, but the WHO estimate is orders of magnitude too high.

Next the Editors weigh in on publication of the ferret results:

The Erasmus team believes that more than 100 laboratories and perhaps 1,000 scientists around the world need to know the precise mutations to look for. That would spread the information far too widely. It should suffice to have a few of the most sophisticated laboratories do the analyses.

As I have argued before, limiting the dissemination of scientific information only serves to impede progress. It is impossible to predict which laboratory is going to do the breakthrough experiment, and picking ‘sophisticated’ laboratories is meaningless.

Then the Editors argue that the research has no value:

Defenders of the research in Rotterdam claim it will provide two major benefits for protecting global health. But it is highly uncertain, even improbable, that the virus would mutate in nature along the pathways prodded in a laboratory environment, so the benefit of looking for these five mutations seems marginal.

I would like to see the studies on which this statement is based. It is well known in virology that mutations selected in laboratory experiments can be been identified in nature. For example, the mutations identified in the H5N1 influenza viruses that transmit among ferrets have indeed been observed naturally in animals. The fact is that no particular viral mutation is improbable, given the enormity of  viral diversity in nature.

The Editors write that the results of the H5N1 studies do not help determine if existing antiviral drugs and vaccines would be effective:

But genetic changes that affect transmissibility do not necessarily change the properties that make a virus susceptible to drugs or to the antibodies produced by a vaccine, so that approach may not yield much useful new information.

Two of the currently used drugs for controlling influenza, Tamiflu and Relenza, act by inhibiting the viral neuraminidase enzyme. Its function is to allow viruses to spread from cell to cell, and could very likely be involved in ferret transmission. If changes in this protein lead to aerosol transmission among ferrets, they could alter sensitivity to the drugs. Other changes in the H5N1 virus might alter its protein profile, making it less sensitive to currently proposed vaccines. These are only two of many reasons why studying this H5N1 virus would yield a great deal of useful information. As noted in A flu virus risk worth taking by Anthony Fauci, Gary Nabel, and Francis Collins in the Washington Post, “…new data provide valuable insights that can inform influenza preparedness and help delineate the principles of virus transmission between species.”

I think it is a good idea to have a public dialogue to understand the goals of influenza H5N1 research. But the discussion should be based on scientific fact, not doomsday scenarios. The Times does everyone a disservice by basing their opinion on science fiction.

Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit, and Alan Dove

Vincent, Dickson, Rich, and Alan answer listener questions about XMRV, cytomegalovirus, latency, shingles vaccine, myxomavirus and rabbits, and more.

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• Human CMV incorporates antibody into virions (Cell Host Microbe)
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• Dr. Eric Schadt talk, Mt. Sinai
• Bacteriophage T4 tattoo
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Dickson – Creation
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Alan – Out of context science
Vincent – The Scientist Top 10 Innovations 2011

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Jim – Christoph Adami: Finding life we can’t imagine (TED)
Tim – Patient Zero (Radiolab)
Mary – Natural Obsessions by Natalie Angier
Jimmy – Science Exchange

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I will be on NPR’s Science Friday this afternoon (6 January, 2 PM EST) to discuss the H5N1-NSABB story. You can listen live, or download the recording which will be available later.

I written three posts (one, two, three) about the ferret H5N1 experiments and why the NSABB should not prevent the publication of these data.

I’m a bit dismayed that Science Friday tweeted about this event earlier today saying “Today, 2-3p ET we’ll talk about the placebo effect. Then, we’ll tackle the debate over research into making influenza more deadly.” I had hoped for a less sensational, and scientifically accurate description from a well-respected science program.

Making influenza virus more deadly is not what this research was about. The over-hyping of the entire H5N1 story (both by scientists and the press) is what has got us into this situation in the first place. On Science Friday I hope to focus on the science which does not support restricting publication of the H5N1 ferret results.

Update: Here is a recording of this SciFri episode (27 MB mp3).

I thought it was interesting that Dr. Henderson discounted the possibility that there is widespread H5N1 seropositivity in rural Asian populations. His reason was that, among all the H5N1 infections, no seropositivity has been observed in their contacts. This would be expected as the H5N1 viruses are known not to be transmitted among humans! Where we would expect to see wide seropositivity is among workers who have frequent contact with poultry, not in the contacts of those who have been infected with the virus.

Dr. Henderson also stated that the experiment done in the Fouchier lab was ‘a little more than passage from ferrets to ferrets’. What he alluded to are the mutations introduced into the starting H5N1 virus to allow it to bind sialic acid receptors found in the mammalian respiratory tract. These types of modifications are widely known in the virology community and could easily be done before passaging the virus in ferrets.

The only thing we have to fear is fear itself – Franklin D. Roosevelt

Why is there such widespread fear of avian H5N1 influenza virus?

Why did Paul Keim, chair of the National Science Advisory Board for Biosecurity (NSABB) say “I can’t think of another pathogenic organism that is as scary as this one”.  What lead Donald McNeil, writing about H5N1 in the New York Times, to conclude that “In its natural form, it is known to have infected only about 600 people since its discovery in 1997, but it killed more than half of them.”

McNeil’s statement is incorrect. Yet it summarizes why Paul Keim, the NSABB, and many others fear the virus.

The problem is that we cannot say with any certainty that the virus has infected only about 600 people. What we do know is that among the 600 seriously ill individuals infected with influenza H5N1 who are admitted to hospital, over half of them die.

To know the fatality rate of avian H5N1 influenza virus in humans, we need to divide the number of fatalities by the number of infections. We do not know that last number – but there are hints that it could be quite large. In a recent study of rural Thai villagers, sera from 800 individuals were collected and analyzed for antibodies against several avian influenza viruses, including H5N1, by hemagglutination-inhibition and neutralization assays. The results indicate that 73 participants (9.1%) had antibody titers against one of two different H5N1 strains. The authors conclude that ‘people in rural central Thailand may have experienced subclinical avian influenza virus infections’. A subclinical infection is one without apparent signs of illness.

If 9% of the rural Asian population has been subclinically infected with avian H5N1 influenza virus strains, it would dramatically change our view of the pathogenicity of the virus. Extensive serological studies must be done to determine the extent of human infection with avian H5N1 influenza viruses.

Until we know how many individuals are infected with avian influenza H5N1, we must refrain from making dire conclusions about the pathogenicity of the virus. Doing so has only lead us down a dangerous path of fearing that H5N1 influenza virus might be used as a weapon of bioterrorism, and restricting the publication of scientific papers on the virus.

Update. A meta-analysis reveals that about 1.3% of over 8,500 study participants had serological evidence of infection with influenza H5N1 (Palese, personal communication).

Khuntirat, B., Yoon, I., Blair, P., Krueger, W., Chittaganpitch, M., Putnam, S., Supawat, K., Gibbons, R., Pattamadilok, S., Sawanpanyalert, P., Heil, G., Friary, J., Capuano, A., & Gray, G. (2011). Evidence for Subclinical Avian Influenza Virus Infections Among Rural Thai Villagers Clinical Infectious Diseases, 53 (8) DOI: 10.1093/cid/cir525

Hosts: Vincent Racaniello, Rich Condit, and Alan Dove

Vincent, Alan, and Rich review ten compelling virology stories of 2011.

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Click the arrow above to play, or right-click to download TWiV 164 (60 MB .mp3, 99 minutes).

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Ten virology stories of 2011:

1. XMRV, CFS, and prostate cancer (TWiV 119, 123, 136, 150)
2. Influenza H5N1, ferrets, and the NSABB (TWiV 159)
3. The Panic Virus (TWiV 117)
4. Polio eradication (TWiV 127, 149)
5. Viral oncotherapy (TWiV 124, 131, 142, 156)
6. Hepatitis C virus (TWiV 130, 137, 141)
7. Zinc finger nuclease and HIV therapy (TWiV 144)
8. Bacteria help viruses (TWiV 154)
9. Human papillomaviruses (TWiV 126)
10. Combating dengue with Wolbachia (TWiV 115, 147)

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Weekly Science Picks

Rich - Fundamentals of Molecular Virology by Nicholas H. Acheson
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Garren – Trillion-frame-per-second video
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For some time I have thought about reviewing this year’s topics on virology blog in 2001, not only to get a sense of what I thought was significant, but more importantly, to highlight areas that need more coverage. I went through all the articles I wrote in 2011, put them in subject categories, and listed them by number of articles. The results are both obvious and surprising.

I wrote most frequently about the retrovirus XMRV and its possible role in chronic fatigue syndrome and prostate cancer. This extensive coverage was warranted because we had an opportunity to learn how disease etiology is established, followed by development of therapeutics. By the end of the year we learned that XMRV does not cause human disease, but the journey to that point was highly instructive.

• Authors retract paper on detection of murine leukemia virus-releated sequences in CFS patients
• Science retracts paper on detection of XMRV in CFS patients
• Chronic Fatigue Syndrome and the CDC: A Long, Tangled Tale (by David Tuller)
• Admit when you are wrong
• Trust science, not scientists
• Murine gammaretroviruses in prostate cancer cell lines
• XMRV is a recombinant virus from mice
• Ian Lipkin on XMRV
• Ila Singh finds no XMRV in patients with chronic fatigue syndrome
• Authenticity of XMRV integration sites
• XMRV infection of Rhesus macaques
• Derek Lowe on how science gets done
• Retroviral integration and the XMRV provirus

The next most frequently visited topic on virology blog was influenza. Writing often about this virus makes sense because it is a common human infection that occurs every year, and controlling it is a continuing goal of virology research.

• A bad day for science
• A $707 million investment in cell-based influenza vaccine
• Ferreting out influenza H5N1
• How good is the influenza vaccine?
• David and Goliath: How one cytokine may take down influenza (by Alexandra Jacunski)
• Gut microbes influence defense against influenza

There were five  posts noting the death of virologists, colleagues, or someone I thought made a substantial impact on my career.

• Steve Jobs, 1955-2011
• Har Gobind Khorana, master decoder
• Bernard F. Erlanger, 88
• Robert A. Weisberg, 1937-2011
• Baruch S. Blumberg, MD, 1925-2011
• Edwin D. Kilbourne, MD, 1920-2011

I wrote more about poliovirus than any other virus except XMRV and influenza. Eradication of poliomyelitis continues to be difficult and faces periodic setbacks.

• Wild poliovirus in China
• Thirty years of infectious enthusiasm
• Transgenic mice susceptible to poliovirus
• Poliomyelitis after a twelve year incubation period

I only wrote three articles about topics in basic virology.

• The Lazarus virus
• Are all virus particles infectious?
• Multiplicity of infection

Like many others, I find the biggest viruses and their virophages compelling.

• Megavirus, the biggest known virus (Jean-Michel Claverie, one of the discoverers of Mimivirus and Megavirus, wrote “Your paper is a well summarized account of the main points raised by the discovery of Megavirus chilensis and its amazing gene content. Great job.”
• Brent Johnson on virophage
• Virophages engineer the ecosystem
• Virophage, the virus eater

The past year saw the release of Contagion, a movie about a virus outbreak. Look for an analysis on TWiV in 2012.

• Contagion: First review
• Contagion: The trailer

The state of science education and science funding is becoming more of a concern. It is not a topic I write about often – I prefer to focus on the science of virology – but for future scientists it is extremely important.

• The dwindling American science majors
• American science and the budget crisis

The other posts covered a variety of topics and viruses, including HIV, human papilloma viruses, hepatitis C virus, and smallpox virus.

• Popularização da ciência através de podcast
• Virologist replaces Steve Jobs at Apple
• The viruses in your food
• Ten seminal virologists
• Microbiology blogs
• Viral desserts
• Women AND men beware: HPV, the culprit behind more than just cervical cancers? (by Bethany DiPrete)
• Virology at the Deutsches Museum
• Infectious salmon anemia virus spread from Norway to Chile
• Live tweeting of the ASV meeting
• Happy as a clam? Maybe not. (by Adriana Lopez)
• Viruses go green (by Ian Blubaugh)
• Canine hepacivirus, a relative of hepatitis C virus
• Not-so-similar fate of identical twins infected with HIV-1 (by Amanda Carpenter)
• Dickson Despommier’s Parasitic Diseases lectures
• Retroviruses and amyotrophic lateral sclerosis
• The press concludes that arboviruses can be sexually transmitted
• Should smallpox virus be destroyed?
• Is Vilyuisk encephalitis a viral disease?
• Replicability of scientific results

What have I learned from looking back? The best covered viruses – XMRV, influenza, and poliovirus – deserve the attention. I am surprised that there were so few articles on important viruses such as HIV, HCV, rotaviruses, and herpesviruses. That shortcoming will have to change. I did not write enough about basic virology. One could argue that teaching a virology course is enough – but I think that concise, informative articles on basic virology are very useful. I’ll try to do more of that in 2012. There is one topic I’d like to write less about, but over which I have little control – the passing of scientists.

Thank you for coming here to learn about virology.

A paper that reported finding retroviral sequences in blood from patients with chronic fatigue syndrome (CFS) has been retracted by the authors. Just four days ago the 2009 Science report of Lombardi and colleagues was editorially retracted. As 2011 comes to an end, so does the hypothesis that retroviruses are etiologic agents of CFS.

Readers of virology blog know that in 2009 Lombardi et al. published a Science report indicating they had detected the new retrovirus XMRV – first detected a few years earlier in prostate tumors – in the blood of a high proportion of patients with chronic fatigue syndrome. Many other laboratories attempted to reproduce this finding, but none were successful.

The next year Alter and colleagues reported finding retroviral sequences in the blood of a substantial number of CFS patients. No viruses were isolated in the Alter study; viral sequences were obtained by polymerase chain reaction (PCR). The viral sequences were not XMRV, but were closely related to endogenous retroviruses of mice called polytropic murine leukemia viruses. (Polytropic means the viruses can infect many species, including mice; xenotropic means that the viruses, though originating in mice, only infect non-mouse species).

The Lo-Alter finding was viewed by many (including myself) as supporting the findings of Lombardi et al., but upon closer inspection it became apparent that they only clouded the situation. The viral sequences reported in the Alter study were not XMRV, and it was not clear why CFS would be caused by such a diverse range of viruses. A second report in 2011 reported MLV-like sequences in a CFS cohort but many other studies failed to find any kind of retrovirus in the blood of CFS patients.

Earlier this year it became clear that XMRV is a laboratory-generated recombinant murine retrovirus: it arose during the passage of a prostate tumor in nude mice in the early 1990s. This finding made it highly unlikely that the virus could be associated with human disease. Lombardi and colleagues then retracted part of the 2009 Science paper that reported viral nucleic acid sequence; they noted that their samples were contaminated with XMRV plasmids. What remained of the paper were serological and virus culture experiments that were not specific for XMRV. Last week the remainder of this paper was editorially retracted by Science.

That left the Lo-Alter findings. The first warning came from the observation made by several laboratories that reagents used to carry out PCR are often contaminated with mouse DNA (an example is Singh’s study). The presence of this adventitious DNA can lead to detection of MLV-like sequences that resemble those found in the Lo-Alter study. The implication was clear: the Lo-Alter findings were wrong, a result of contamination of PCR reagents with mouse DNA.

More doubt came from a report of the Blood XMRV Scientific Working Group, which was assembled to determine if XMRV constituted a threat to the blood supply. In this study, sets of coded samples previously shown to be XMRV positive, as well as samples from healthy controls, were blinded and provided to 9 laboratories for analysis by PCR, virus culture, and serology. Two laboratories reported evidence of XMRV in the coded samples. Only the Whittemore-Peterson Institute identified positive specimens by PCR: two from negative controls, and one from a CFS patient. The Lo laboratory did not detect any positives by PCR, using the same nested assay that they had previously reported in their PNAS paper. The samples tested included 5 specimens that were positive in the Lo-Alter study.

The retraction of the Lo-Alter PNAS paper curiously begins with the assertion that the authors could not detect contaminating mouse DNA in their samples – which was most certainly present and lead to their detection of MLV-like sequences.

Although our published findings were reproducible in our laboratory and while there has been no evidence of contamination using sensitive mouse mitochondrial DNA or IAP assays or in testing coded panels…

This failure remains puzzling and unexplained; but as they report in the next paragraph, they appear to have run out of material to distribute to other laboratories for ‘independent confirmation’.

The authors provide three additional reasons why they are retracting this paper. They note that no one has been able to reproduce their findings, including the Blood XMRV Scientific Working Group. They have not been able to find (along with collaborators) anti-XMRV antibody, XMRV virions, or viral integration sites in patient samples. Finally, they mention their finding from the PNAS paper that a second set of samples taken 15 years later from the same CFS patients also were positive for MLV-like viruses. Phylogenetic analyses revealed that these sequences were clearly not descendants of the original strains. The sequence data used to make this conclusion were available for the PNAS publication, so it is not clear why this evolutionary incompatibility was not noted previously.

The authors conclude:

…in consideration of the aggregate data from our own laboratory and that of others, it is our current view that the association of murine gamma retroviruses with CFS has not withstood the test of time or of independent verification and that this association is now tenuous. Therefore, we retract the conclusions in our article.

The retraction of the Lombardi et al and Lo-Alter papers erases the published evidence suggesting involvement of a retrovirus with CFS. While it is theoretically possible that CFS has a viral origin, at the moment there are no data in support of a specific viral etiology. Some have suggested that gammaretroviruses related to XMRV might be involved in CFS. But I don’t see how a lab contaminant can point you in the direction of a bona fide etiologic agent. Contaminants cloud our vision, they do not improve it.

In light of these developments, the ongoing Lipkin study (sponsored by the National Institute of Allergy and Infectious Diseases, involving analysis of a coded panel of samples from 150 well-characterized and geographically diverse CFS patients and controls) seems less compelling. Many laboratories have failed to find any retrovirus in CFS patients, and the two papers central to this hypothesis have been retracted. Will results from one laboratory clear the matter up further? Whatever the Lipkin study finds, it will have to be validated by others – because we trust science, not scientists.

Update: The retraction has been published at PNAS.

Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit, and Alan Dove

Vincent, Dickson, Rich, and Alan review the 100 year old finding by Peyton Rous of a transmissible sarcoma of chickens, a discovery that ushered in the era of tumor virology.

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• Transmissible sarcoma of the fowl (J Exp Med)
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Bruce Alberts, Editor-in-Chief of Science magazine, writes that the journal is retracting the 2009 paper describing the detection of the retrovirus XMRV in patients with chronic fatigue syndrome:

Science is fully retracting the Report “Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome”.

He writes that the decision was reached because multiple laboratories have failed to reliably detect XMRV or related viruses in CFS patients. He also cites evidence of ‘poor quality control in a number of specific experiments in the report’, and that Figure 1, table S1, and figure S2 have been retracted by the authors. Finally, he notes the omission of information from the legend of figure 2C, specifically that the authors failed to indicate that the peripheral blood mononuclear cells had been treated with azacytidine, phytohemagglutinin, and IL-2. He concludes:

Given all of these issues, Science has lost confidence in the Report and the validity of its conclusions. We note that the majority of the authors have agreed in principle to retract the Report but they have been unable to agree on the wording of their statement. It is Science’s opinion that a retraction signed by all the authors is unlikely to be forthcoming. We are therefore editorially retracting the Report. We regret the time and resources that the scientific community has devoted to unsuccessful attempts to replicate these results.

The virologists who carried out the contentious experiments on influenza H5N1 transmission in ferrets have agreed to remove certain details from their manuscript, according to ScienceInsider:

Two groups of scientists who carried out highly controversial studies with the avian influenza virus H5N1 have reluctantly agreed to strike certain details from manuscripts describing their work after having been asked to do so by a U.S. biosecurity council. The as-yet unpublished papers, which are under review at Nature and Science, will be changed to minimize the risks that they could be misused by would-be bioterrorists.

Apparently a second manuscript on similarly sensitive material, submitted to Nature, has been studied by the NASBB and its details will also be redacted. Members of both scientific groups disagree with the decision.

The article hints that details of the experiments may be made available to influenza virologists ‘with a legitimate interest in knowing them’. Who will decide what constitutes a legitimate interest? And what if a virologist, or another scientist who does not work on influenza virus, has an idea for an experiment and would like the details? Will they be denied because they are not card-carrying influenza virologists? Science often works in unusual ways, and one of them is that difficult problems are often solved by individuals from different areas of research.

I agree with Albert Osterhaus, who noted that this debate could have been held in 2005 when the complete genome sequence of the 1918 pandemic influenza virus strain was released. That H1N1 strain is known to be lethal and transmitted efficiently among humans. In contrast, it is not known if the ferret-passaged influenza H5N1 virus would be transmitted in people and cause disease.

This is a bad day for virology, and for science in general. The decision by the NSABB sets a precedent for censoring future experimental results whose wide dissemination would benefit, not harm, humanity.

Update: A member of the NSABB has written about the committee’s thoughts on this issue. See comments below.

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Vincent, Rich, and Alan continue Virology 101 with a discussion of transcription, the process of making mRNA from a DNA template.

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The United States has provided a large sum of money to pharmaceutical giant Novartis to produce influenza vaccines grown in cell culture. According to CIDRAP:

Novartis’s US efforts have been spurred by two major federal contracts. In 2006 the firm won a $220 million HHS contract to develop cell-based flu vaccines, and in January 2009 HHS awarded a $487 million contract to help build the Holly Springs facility.

The facility consists of six connected buildings with 430,000 square feet of manufacturing, laboratory, and office space on a 167-acre site, Novartis reported in a news release. The company has about 400 employees there now and plans to expand to 500 by the end of 2012. Power said the facility is expected to be ready for full-scale commercial production in 2013.

Is this a good investment of US science dollars? Consider the following points:

• A cell-based vaccine is expected to shorten by a few weeks the time required to produce a vaccine for a new influenza virus strain
• No cell-based influenza vaccine is currently licensed for use in the US
• Cell-based influenza vaccines use the same technology developed 50 years ago for egg-grown vaccine, with the exception that the virus is propagated in a different host
• Inactivated influenza vaccine is not very good – it is 59% effective in individuals 18-65 years of age

We need a completely different influenza virus vaccine, not a retread of the existing process. Promising new approaches include virus-like particle vaccines produced in plants that can be made cheaply, rapidly, and appear to be immunogenic and safe in humans. Influenza vaccines that can protect against all viral strains now seem possible, and these vaccines will probably not be based on growing influenza viruses in eggs or cell culture.

I suspect that contemporary influenza vaccines produced in eggs or cell culture will be replaced with new vaccines within the next decade. With all this in mind, does it make sense to invest $707 million in a vaccine that has such a short life span? Even more money is at stake – according to CIDRAP, “Novartis is one of five companies that received sizable HHS contracts in 2006 to develop cell-based vaccines.” The new Novartis plant will not be able to supply all the influenza vaccine required by the US (and having a sole supplier is not a good idea). Are there enough individuals with severe egg allergies to justify this investment? Or is this a project that seemed like a good idea in 2006 but is now an anachronism?

The mantle of world’s biggest virus has passed from Mimivirus to Megavirus. But in this case, size doesn’t matter. It’s the genes that these viruses share and do not share that make this story important.

The discovery of Mimivirus in a French cooling tower amazed virologists. At 750 nanometers in diameter, it dwarfed all other known viruses and shattered the notion of viruses as ‘filterable agents’. That definition came from using filters that exclude any particle larger than 200 nanometers. The 1.2 million base pair Mimivirus DNA genome was found to encode 979 proteins – more than any other virus. This treasure chest included some proteins never found in any viral genome, such as amino-acyl tRNA synthetases, the enzymes that attach amino acids to transfer RNAs in preparation for protein synthesis. Many other cellular genes were also encoded in the Mimivirus genome, as well as proteins that had never been seen before. This discovery led to the idea that Mimivirus evolved from an ancestral cellular organism by losing genes. The alternative idea is that viruses are ‘pickpockets’ – they began as small pieces of DNA that escaped from cells, acquired a capsid, and then slowly stole genes from other organisms.

The problem with the idea that Mimivirus is a gene loser is that it was the only really big virus of its kind – until Megavirus was discovered in the ocean off the coast of Chile. At 680 nm in diameter, Megavirus is slightly smaller than Mimivirus, but the DNA genome is larger – 1,259,197 base pairs versus 1,182,000. The Megavirus genome encodes 1,120 putative proteins compared with 979 for Mimivirus. What is significant about Megavirus is that its genome resembles that of Mimivirus, including the presence of cellular genes such as those encoding amino-acyl tRNA synthetases. Also important is the fact that 258 of the Megavirus proteins have no counterparts in Mimivirus, including three amino-acyl tRNA synthetases.

When Mimivirus was first discovered, it was not clear if it was an anomaly, or if it would provide information on the emergence of viruses. Other giant viruses were subsequently discovered, but they were either nearly identical to Mimivirus (Mamavirus) or little genome sequence was available (Terra, Courdo, Moumou). The evolutionary distance of Megavirus and Mimivirus is sufficient to allow identification of similar features and the selection forces that lead to their emergence. A comparison of their DNA sequences reveals a set of genes in common between the two viruses, such as those that function during protein synthesis. These observations suggest that Megavirus and Mimivirus arose from a common cellular ancestor – one that could carry out protein synthesis – and lost the genes that were no longer needed. The alternative scenario, that these giant viruses started out small and acquired additional genes, seems unlikely. Seven different gene acquisition events would have been needed to acquire just the genes encoding amino-acyl tRNA synthetases.

More details about how Megavirus and Mimivirus emerged from a cellular ancestor will require the isolation of other giant DNA viruses. Which leads to the inevitable question – what is the biggest virus on earth? Have we reached the limit of viral genome size? Probably not, but I doubt that we will find viruses with much larger genomes that encode almost all the genes needed for independent replication. Such viruses likely evolved from primitive cells a very long time ago, and only the evolutionary descendants remain on Earth today.

If you are wondering how these giant viruses are named, the authors provide revealing background:

We believe it is useful and desirable that the name of a newly isolated microorganism convey some of its most distinctive properties. After the initial naming of Mimivirus (for “microbe mimicking”), already not a very good name because the prefix “mimi” does not convey a helpful scientific notion, newly isolated related viruses are receiving increasingly random/funny names such as “Mamavirus,” “Moumouvirus,” “Courdovirus,” and “Terra”. …we believe the current trend is counterproductive and should give way to more informative names….a distinctive feature of the above giant viruses (or of their close ancestors) is to possess genome in excess of a “megabase”. Hence, the term “Megavirus,” and the proposed family/genus “Megaviridae” that will be proposed… “Chilensis” then refers to the location where this virus was first isolated.

The authors did not incorporate the species of the viral host in the name of the virus. They justify this break with tradition because the natural host of  Megavirus chilensis is not known – it was isolated from the ocean by co-culture with acanthamoeba, a procedure the authors will continue to use to identify giant DNA viruses.

 Arslan D, Legendre M, Seltzer V, Abergel C, & Claverie JM (2011). Distant Mimivirus relative with a larger genome highlights the fundamental features of Megaviridae. Proceedings of the National Academy of Sciences of the United States of America, 108 (42), 17486-91 PMID: 21987820

Hosts: Vincent Racaniello, Rich Condit, Alan Dove, and Gabriel Victora

Vincent, Rich, Alan and Gabriel review the production of antibodies by B cells, and how high affinity antibodies are selected in the germinal centers of lymph nodes.

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• An antibody molecule (png)
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Gabriel – Antibody-based protection against HIV (Nature)
Rich – Contact
Alan – Flu shot dystonia (YouTube)
Vincent – Sciflies and RocketHub

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Neva – Virus and retrovirus
Ayesha – The Life Scientific (BBC)

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A laboratory in the Netherlands has identified a lethal influenza H5N1 virus strain that is transmitted among ferrets. These findings are under review by the National Science Advisory Board for Biosecurity (NSABB) to ensure that they do not constitute a threat to human health. Meanwhile both the popular and scientific press has been calling this a ‘virus that could change world history’. Even the usually restrained Helen Branswell writes that ”…the dangerous virus can mutate to become easily transmissible among ferrets — and perhaps humans…” Should we be frightened?

Details of Ron Fouchier’s experiments are not known because the results have not yet been published. Reports at CIDRAP and Science indicate that Fouchier was attempting to make the H5N1 virus more transmissible in ferrets. This strain of influenza is lethal in birds and humans – there have been over 500 human cases with over 50% mortality. However, the virus is not readily transmitted among humans. The virus is lethal in ferrets but does not transmit among the animals. Fouchier selected a transmissible H5N1 variant by ferret-to-ferret passage. This experiment involves infecting a ferret, harvesting virus from the animal, and infecting another ferret. After ten such passages, the H5N1 variant could spread from one ferret to another by airborne transmission. The two amino acid changes that permit airborne spread among ferrets were identified.

Scientists appear to be responsible for the hype surrounding this experiment. Fouchier called it ‘one of the most dangerous viruses you can make’. Paul Keim, chair of NSABB, ‘can’t think of another pathogenic organism that is as scary as this one’, and Richard Ebright, a molecular biologist at Rutgers University says the experiment should not have been done. Martin Enserink writing in ScienceInsider says that the virus could change world history, and similar proclamations of doom can be found in the popular press.

I cannot fault the press for not having the background to interpret these studies, but scientists should know better than to declare that this is a dangerous virus. First and foremost, ferrets are not humans. Every influenza researcher will say that ferrets are a good model for influenza – they display similar flu-like symptoms, immune responses, and pathological alterations such as elevated temperature, weight loss, and histological changes. But it would be foolish to conclude that ferret influenza is the same as human influenza in all aspects. For example, not all influenza virus strains have the same virulence in humans and ferrets. A good example is the 2009 pandemic H1N1 virus which caused severe infections in some ferret studies, but was relatively mild in humans.

In other words, just because the Fouchier H5N1 virus is transmissible among ferrets does not mean that it will be equally transmissible among humans. The experiment to answer this question cannot be done.

Passage of viruses in a different host is one strategy for reducing the virulence in humans. This concept is explained in this passage from Principles of Virology:

Less virulent (attenuated) viruses can be selected by growth in cells other than those of the normal host, or by propagation at nonphysiological temperatures. Mutants able to propagate better under these selective conditions arise during viral replication. When such mutants are isolated, purified, and subsequently tested for pathogenicity in appropriate models, some may be less pathogenic than their parent.

The possibility that passage of the H5N1 virus in ferrets will attenuate its virulence in humans has been ignored.

In my view, it is highly unlikely that laboratory-modified viruses will be able to cause extensive disease in humans. When humans tinker with viruses, they generally do not know what the virus needs to replicate efficiently, cause disease, and transmit in humans. Consequently, they are likely to introduce changes that attenuate pathogenesis in humans. Nature is far better at producing viruses that can kill – to think that we can duplicate the enormous diversity and selection pressures that occur in the wild is a severe case of scientific hubris.

Another aspect of this story that deserves comment is the review by the NSABB. That body is charged with reviewing experiments that would render a vaccine ineffective; confer resistance to antimicrobial agents; enhance the virulence of a pathogen or make a non-pathogen virulent; increase transmissibility of a pathogen; enable evasion of detection; and enable weaponization of a biological agent or toxin. It is not clear to me how this committee could make some of these conclusions without data from human experiments. Nevertheless, why would the NSABB recommend against publication of Fouchier’s data? Could the sequence of the ferret adapted H5N1 be used for bioterrorism? It seems unlikely: it is not known if the virus would be pathogenic and transmissible in humans. Bioterrorists do not want to carry out an experiment; they want to instill terror. Why use a laboratory modified H5N1 strain when the sequence of the 1918 influenza virus, known to be a lethal and transmissible human virus, is readily available? Ebright calls the 1918 virus “the most effective bioweapons agent now known”.

No one can guarantee that Fouchier’s virus would not be lethal and transmissible in humans. But the same could be said about any number of laboratory modified viruses, none of which have attracted the attention of the NSABB or the press. When dealing with viruses, both caution and restraint are necessary qualities.

This article is based on the conversation with Rich Condit and Alan Dove on TWiV 159 and 160.

Hosts: Vincent Racaniello, Rich Condit, Alan Dove, Dickson Despommier, and Patrick Moore

The TWiV team speaks with Patrick Moore about his discovery, with Yuan Chang, of two human tumor viruses, Kaposi’s sarcoma herpesvirus and Merkel cell polyomavirus.

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• Chang-Moore laboratory at University of Pittsburgh
• Representational difference analysis (Science)
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Patrick – The Theory That Would Not Die by Sharon Bertsch McGrayne
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According to the New York Times (Why Science Majors Change Their Minds), the decline in the number of science majors in the United States has come about in part because the subject matter is too difficult. If this explanation is true, then we have not properly prepared these students in grades K-12. I also believe that the poor state of funding of American science is an important factor. My Columbia University colleague Stuart Firestein expressed this idea in his letter to the Times:

Why do science majors change their mind? They wise up.

Your article makes it sound as if American science students are stupid or lazy, unlike their workaholic Chinese and Indian counterparts. This is glib and insulting.

It is in their second year that students typically join laboratories and see firsthand that their dreams of a scientific career include low-paying and highly competitive professorial jobs, that getting grants for scientific research is increasingly difficult and unpredictable, that they are facing many years of postgraduate work at ridiculously low salaries and that they would have a hard time supporting a family.

Compare this future with that of the economics major (lots of math) who goes to business school and can look forward to million-dollar yearly bonuses.

American students change their majors because they recognize that this country has stopped providing a reasonable future for scientists, with slashed budgets for the National Science Foundation, National Aeronautics and Space Administration and National Institutes of Health.

For Chinese and Indian students, science remains a way out of poverty. For American students, it’s becoming the path into it.

Cliff Mintz at BioJobBlog adds the problem of outsourcing:

…it is important to note that outsourcing and consolidation in the life sciences industry that has occurred over the past decade has all but eliminated the option of industry jobs for those who were unable to secure academic positions. Put simply, there are no longer enough jobs in the US to support the numbers of sciences students that we annually train.

I also agree with Cliff’s idea of eliminating tenure in American universities as a way of infusing new ideas and enthusiasm into the system. The notion of a guaranteed position seems untenable in 2011 and beyond.

Hosts: Vincent Racaniello, Alan Dove, and Rich Condit

Vincent, Alan, and Rich review concern over an influenza H5N1 transmission experiment, and a new host defense protein against RNA viruses.

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Vincent - Chronic fatigue syndrome and the CDC by Dave Tuller

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Judi – Top 7 in Microbiology

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by David Tuller

Note: This account draws from interviews, a close reading of a fraction of the 4608 studies that pop up (as of today; yesterday it was 4606) on a PubMed search for “chronic fatigue syndrome,” and a review of many pages of government documents–in particular the minutes and testimony from meetings of the Chronic Fatigue Syndrome Advisory Committee to the U.S. Department of Health and Human Services, one of many such panels established to provide guidance to federal health officials. Not much here will be a surprise to anyone who has read the better ME/CFS blogs, or Hillary Johnson’s authoritative and prodigiously researched 1996 account, Osler’s Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic. I want to thank Professor Racaniello for letting me invade his space to post this very long story.

David Tuller is coordinator of a new concurrent masters degree in public health and journalism at UC Berkeley. He was a guest on TWiV 119.

In the early 1990s, Mary Schweitzer, a history professor at Villanova University near Philadelphia, suffered through successive bouts of sickness—mononucleosis associated with Epstein-Barr virus, a stomach parasite, repeated episodes of bronchitis. One day, while reviewing student exams in her office, she slumped over and blacked out. Not long after, she received a diagnosis of chronic fatigue syndrome.

In written testimony to a federal advisory committee a few years ago, Dr. Schweitzer described how disabled she eventually became: “On a bad day, I would never get up at all, or would lie in bed curled up under the covers…I experienced pain behind my eyes and in the back of my neck. It felt as if somebody had hit me in the back of the head with a baseball bat, and someone else was trying to unscrew my eyeballs with a pair of pliers.”

Over the years, Dr. Schweitzer has tested positive for multiple viruses. She experiences severe lapses in memory, concentration and other cognitive skills. She suffers from “neurally mediated hypotension,” a form of low blood pressure arising from nerve dysfunction, which causes nausea, loss of balance, and fainting. Her muscle and joint pain can be intense, and she frequently requires a wheelchair. Her white blood cell counts have been way off; her immune system is often out of whack. She left her position at Villanova because of disability and has been unable to work most of the years since.

Like others with chronic fatigue syndrome, Dr. Schweitzer is used to having her illness ignored, mocked or treated as a manifestation of trauma, depression or hypochondria—not only by doctors, colleagues and strangers but by friends, family members and federal researchers, too. So when the U.S. Centers for Disease Control and Prevention reported last year that people with chronic fatigue syndrome are more likely to suffer from “maladaptive personality features”—in particular from “higher scores on neuroticism” and higher rates of “paranoid, schizoid, avoidant, obsessive-compulsive and depressive personality disorders”—Dr. Schweitzer dismissed the research as “incredibly stupid” but “not surprising.” In another recent study, the CDC had reported—also incredibly stupidly, from Dr. Schweitzer’s perspective–that childhood trauma, such as sexual or emotional abuse, was a “an important risk factor” for the illness.

For Dr. Schweitzer, other patients and advocates, and much if not all of the non-CDC research community involved with the illness, those two studies symbolize much of what has gone wrong with the agency’s research program on chronic fatigue syndrome. As the country’s leading public health organization, the CDC has enjoyed remarkable success in the fight against many diseases. But its history with chronic fatigue syndrome, commonly called CFS, is a matter of bitter–and ongoing—dispute.

“We’re talking about a million people who are really, really sick with something,” said Dr. Schweitzer, 61, in one of a series of recent conversations. “And we have been mistreated for years by people who are convinced that it’s just personality disorders or stress or some behavior that we can change and miraculously be well. None of us want to be sick or are doing this to ourselves.”

The CDC’s mandate is to investigate threats to the health and safety of the population; develop ways to prevent, disable or mitigate those threats; and disseminate key information to the public, policy-makers, health care providers and other audiences. Given those varied responsibilities, the CDC’s pronouncements about any topic—in this case, chronic fatigue syndrome–exert an enormous impact on policy, clinical care, insurance reimbursement and public attitudes. Advocates say that when the agency reports that people with CFS suffer from paranoid personality disorder, the public remembers the association, as do other scientists, government officials, health care providers, and insurance adjusters.

In fact, since the CDC first investigated an outbreak of a non-resolving, flu-like illness in the Lake Tahoe area in the mid-1980s, the agency’s CFS program has been marked by financial scandal, an epidemiologic strategy rejected as fatally flawed by the top researchers in the field, and the kind of toxic relationship with much of the patient community that can undermine the trust and cooperation needed for effective policy-making and public health strategies. On a more substantive level, over the past quarter-century, the CDC’s research program has yielded little or no actionable information about causes, biomarkers, diagnostic tests, or pharmaceutical treatments. Nor has the agency done much to track long-term outcomes–such as cancer rates, heart attacks and suicides–among people with the illness.

The reason for those failures, critics charge, is that the CDC has spent years looking in the wrong places. Starting with its 1988 report on the illness, they say, the agency has downplayed or dismissed abundant evidence that CFS is an organic disease, or cluster of diseases, characterized by severe immune-system and neurological dysfunctions as well as the frequent presence of multiple viral infections. Instead, say the critics, the agency has focused major resources on investigating proposed psychiatric and trauma-related factors and associations–the personality disorder and trauma studies were published, respectively, in the journals Psychotherapy and Psychosomatics and Archives of General Psychiatry–even though stress and trauma make people more vulnerable to any number of health conditions.

Moreover, they charge, the CDC’s website on the illness has long been a font of misinformation and has been routinely used by insurance companies to deny legitimate claims for tests ordered by doctors. (After years of complaints from patients and doctors, a paragraph that dismissed the usefulness of many tests, including those for various infectious agents, was finally changed this month.) Critics also note that the CDC website does not incorporate much clinical expertise from doctors who have treated patients for years, but it does highlight a behavioral form of treatment—a gradual increase in exercise, known as “graded exercise therapy”–that is widely discredited in the CFS community. Patient surveys and anecdotal testimony, as well as an increasingly robust body of research, suggest that the therapy might cause severe relapses in CFS patients by encouraging over-exertion.

“The CDC has never taken chronic fatigue syndrome seriously,” said San Francisco writer and former psychotherapist Michael Allen, who suffered a severe flu in the early 1990s and has never recovered his health. “They pay lip service to it being a serious physical illness, but in their hearts they think it’s just a form of mental illness.”

Much of the anger for the CDC’s perceived failings over the years has targeted Dr. William Reeves, an epidemiologist and architect of the CFS research program from 1989 until his abrupt move last year to another division of the agency. With his gruff and sometimes dismissive manner, Dr. Reeves was never popular with the patient community, which came to view him as hostile to the search for viral or other organic causes of the illness; many non-CDC researchers echoed that complaint. When it emerged in the late 1990s that the agency had been diverting funds designated for CFS to other programs and then lying to Congress about it, Dr. Reeves—who was in charge of the program while the financial irregularities were taking place–sought and received whistle-blower protection.

Dr. Reeves also enraged the patient community by his refusal to consider changing the much-hated name of the disease—a name endorsed by the CDC in its 1988 paper and aggressively promoted in a public awareness campaign the agency launched in the mid-2000s. Patients say the name, like the term ‘yuppie flu,’ reinforces stereotypes that they are a bunch of self-entitled whiners and malingerers and that the illness itself is a form of hysteria, the latter-day version of the Victorian malady known as “neurasthenia.” That’s why many doctors, researchers and patients have long promoted a less-stigmatizing clinical name for the illness that predated the selection of chronic fatigue syndrome: “myalgic encephalomyelitis,” or ME, which means “muscle pain with inflammation of the central nervous system.”

It is not possible to exaggerate how much patients despise the name and believe it has hindered public understanding—and how much they fault the CDC and Dr. Reeves for championing it. “If they’d hired a focus group to come up with a name that screams ‘silly’ and ‘meaningless,’ they couldn’t have done a better job than ‘chronic fatigue syndrome,’” said Dr. Schweitzer.

In an interview with The New York Times earlier this year, bestselling author Laura Hillenbrand (Seabiscuit, Unbroken), who has lived with CFS for decades, called the name of the illness “condescending” and “so grossly misleading.” She added: “The average person who has this disease, before they got it, we were not lazy people; it’s very typical that people were Type A and hard, hard workers… Fatigue is what we experience, but it is what a match is to an atomic bomb. This disease leaves people bedridden. I’ve gone through phases where I couldn’t roll over in bed. I couldn’t speak. To have it called ‘fatigue’ is a gross misnomer.”

After Dr. Reeves unveiled a revised epidemiologic method for identifying people with CFS, the CDC estimated in 2007 that there were 4 million people in the U.S. with the illness—a remarkable ten-fold increase over the previous CDC estimate in 2003. Other experts dismissed this dramatic rise as an artifact of the agency’s poor epidemiology. Subsequent research reported that the new CDC approach misclassified people with primary depression as having chronic fatigue syndrome, when they did not; that kind of misclassification could easily lead to increased prevalence rates as well as false and possibly harmful research results.

In the late 2000s, leading patient, advocacy and scientific organizations engaged in an increasingly public revolt against Dr. Reeves’ leadership. In January of 2010, the CDC abruptly appointed him as senior advisor for mental health surveillance in another part of the agency. Dr. Elizabeth Unger, an expert on human papillomavirus who had worked with Dr. Reeves for years, was named to replace him—first temporarily, then permanently–as chief of the Chronic Viral Diseases Branch, which currently houses the chronic fatigue syndrome program.

Now, almost two years after Dr. Reeves’ departure, advocates and researchers say they have seen a shift in tone—some believe it is genuine, others not–but so far little change in substance. (Requests to interview both Dr. Reeves and Dr. Unger, conveyed through the CDC media office, were declined; however, with a press officer acting as intermediary, Dr. Unger responded to questions via e-mail.)

“I’m committed to continuing an aggressive program to address the needs of CFS patients and families for quality medical care and to move CFS into the mainstream of public health,” wrote Dr. Unger. She added that the agency is developing new materials about CFS for medical and health care professionals, and has contracted for studies that will help clarify questions about how to identify the illness.

Dr. Unger has made a point of meeting with patient, advocacy and scientific organizations. In contrast to her predecessor, she has impressed some advocates and researchers with her willingness to listen to their concerns and seek out joint initiatives. But reflecting a widespread view, one activist (who preferred to remain anonymous) said that “overall, I do not feel much has changed under Dr. Unger…I do look forward to changing my mind, though, if appropriate actions are taken.”

Another person with a long history of involvement in the CFS issue offered a similar assessment, noting that Dr. Unger needs to do much more, and do it more quickly, to demonstrate that she’s pursuing a different approach. “I think she has got a window of opportunity, but the patient community is only going to give her so long,” said this advocate. “She can throw off the Reeves mantle and make a break with the past, or she can maintain the past. But there’s not a middle ground here, and she’s got to make a decision.”

Kim McCleary, president and CEO of the CFIDS Association of America, the oldest organization on the illness, said she believes Dr. Unger “is trying to restore some credibility to the CDC’s program.” But, added McCleary, whose organization worked closely with Dr. Reeves for years but ultimately opposed his leadership, “she’s not going to move quickly, she’s not going to do anything bold, she’s going to move pretty methodically along a linear path.”

Although Dr. Reeves’ departure received little public notice, it was a watershed event for patients and advocates, many of whom blame the agency for the prolonged lack of significant progress in CFS research. (They also blame years of inadequate funding from the National Institutes of Health, but that’s another long story; it is worth noting, however, that the NIH online database of spending by disease category indicates only $4 to $6 million allocated annually for CFS in recent years, a small amount compared to other illnesses associated with similar levels of morbidity. While the roles of the CDC and NIH can overlap significantly, the NIH generally focuses more on basic research into disease processes than on epidemiology and the development of public health strategies and interventions.)

The personnel shift at the CDC also occurred during a volatile period in the scientific domain. In October 2009, the journal Science published a headline-grabbing study that linked CFS to XMRV, a poorly understood mouse leukemia retrovirus. The finding thrilled the patient community because it appeared to offer a plausible explanation for the disease and to suggest treatment possibilities. Although a second study found links between CFS and a group of mouse leukemia retroviruses related to XMRV, other research has failed to support the proposed association. The Science report was partially retracted earlier this year, and most researchers now believe the initial findings were an artifact of laboratory contamination. Results expected early next year from a large NIH-sponsored study should settle the XMRV issue, although not the issue of whether another retrovirus might eventually be linked to cases of CFS.

(In the meantime, in a bizarre and unsettling turn of events, the senior author of the original XMRV paper, Dr. Judy Mikovits, is engaged in a fierce legal battle with her former employer, the Whittemore Peterson Institute for Neuro-Immune Disease, at the University of Nevada in Reno. The institute sponsored the XMRV research but has accused Dr. Mikovits, its erstwhile star scientist, of stealing laboratory notebooks and other materials—a charge she has denied. Public feuding between the institute and Dr. Mikovits ratcheted up as the hypothesis they jointly championed appeared to be falling apart. The institute filed a lawsuit against her earlier this month; she has also apparently been charged with “possession of stolen property,” according to a news update in Science. Last Friday, Dr. Mikovits was arrested in California as a “fugitive from justice” and spent the weekend in jail; she was released on bail after a hearing on Tuesday.)

Nevertheless, the heightened focus on CFS during the past couple of years has brought the illness greater attention from a larger group of scientists, including many infectious disease experts who had not previously given it much thought (e.g. the host of this blog, Columbia University virologist Vincent Racaniello). Experts now believe that one or a combination of viral or other infections, or perhaps other physiologic insults such as environmental toxins, can trigger an immune response that never shuts itself off; the immune response itself is likely the cause of many of the symptoms.

Dr. Racaniello said that when he used to question colleagues about chronic fatigue syndrome, they would argue that it was an imaginary illness. “Every time I asked someone about it, they would say it doesn’t exist, it isn’t a real disease, even as recently as the past year,” he said. “But once you start paying attention and reading papers, this looks like a chronic or hyper-immune activation. These patients have a lot of signs that their immune systems are firing almost constantly.” (Note: Dr. Racaniello is on the scientific advisory board of the CFIDS Association of America.)

According to this view, the revved up immune system is actually much less effective at controlling other infections, and studies have found associations between CFS and a grab-bag of pathogens, including members of the herpesvirus, parvovirus, and enterovirus families. Recent research from Norway has also lent support to the hypothesis that at least some people with CFS are suffering from a form of autoimmune disorder, perhaps triggered by one or multiple infections. Neurological impairments are also virtually always part of the complex; a study last year in the journal PLoS One found that people with CFS and a form of Lyme disease have patterns of proteins in their cerebrospinal fluid that clearly distinguish them from each other as well as from healthy controls.

In many cases, additional research has failed to confirm associations from prior studies. Yet there is a reasonable epidemiologic explanation for such divergent results: Most experts believe that there are likely many sub-groups or clusters of CFS patients, with a variety of infectious and possibly environmental exposures; studies that don’t account for such distinctions—and most haven’t–are much less likely to reach consistent results about causation or treatment. Moreover, different research groups have used different methods of identifying people with chronic fatigue syndrome, making it even harder to compare findings across studies—a situation that can encourage speculation that the roots of the illness lie in patients’ psyches.

“This ambiguity over definitions has made it difficult for researchers to pinpoint a biological cause,” wrote Leonard Jason, a professor of community psychology at DePaul University in Chicago and an expert in CFS, in an essay published this year in The Wall Street Journal. “When investigators compare very different samples, it is difficult, if not impossible, to replicate findings from one lab to another. And when consistent biological findings do not emerge, investigators might inappropriately conclude that CFS is only a psychiatric problem.”

In any event, the most promising research into the disease has been taking place not at the CDC or NIH but at academic medical centers; much of the new work is being funded by private donors who have family members with CFS. Researchers from Stanford, Harvard, University of Miami, Columbia, and other leading institutions are all engaged in innovative efforts focused on pathogenesis, diagnosis and treatment, and in particular on such issues as infectious triggers, biological markers, and medical therapies.

Dr. Derek Enlander, a longtime CFS clinician in New York, recently helped to launch an ME/CFS research and treatment center at Mt. Sinai Hospital; his highly regarded team hopes to explore genetic as well as other factors involved in the illness. The center was founded with the aid of a $1 million private donation, said Dr. Enlander, adding that such outside funding allows the group the freedom to pursue promising avenues of investigation. “I believe that an independent organization such as ours, which is not funded by the government or answerable to the government, can be the leader in new research,” said Dr. Enlander.

The Role of Case Definitions

Chronic fatigue syndrome is estimated to afflict about one million people in the U.S., although most remain undiagnosed. Some patients improve over time or have periods of better and worse health, but many remain disabled or even homebound for years. The symptoms include profound exhaustion, especially following minimal exertion, as well as disordered sleep, cognitive impairment, sore throat, and swollen lymph nodes, among others. It is one of a number of so-called “contested illnesses” that have emerged in recent decades to present thorny dilemmas for public policy and medical care; others include chronic Lyme disease, Gulf War syndrome, fibromyalgia, and multiple chemical sensitivity.

These conditions are characterized by shifting patterns of symptoms, a lack of agreed-upon biological markers and diagnostic tests, arguments over the interpretation of evidence, and competing claims of scientific authority. Patients presenting with these illnesses can bedevil doctors, who want to help but have few proven tools at their disposal. They might or might not be willing to try unorthodox strategies; some doctors clearly take advantage of patients who are desperate for relief. Such contested illnesses impact millions of people and their families, cost the U.S. billions in lost productivity, and consume a significant chunk of health care resources—and yet remain poorly understood. With so much at stake, they often emerge as societal and legal battlegrounds, with patients, clinicians, researchers, insurers, health officials and government bureaucrats all seeking to influence and control dialogue, debate and policy.

This conflict often plays out in struggles over a critical epidemiologic tool known as the “case definition”—a set of criteria for research or clinical use that ideally identifies all those who have a condition and screens out all those who don’t. Creating a case definition is easiest when a definitive laboratory test exists, as with HIV or hepatitis C. With an illness like CFS that is identified through symptoms, devising a completely accurate case definition is almost impossible; some people with the illness will always fall outside the parameters of the case definition, and some who have some other condition, or nothing at all, will be misdiagnosed—or will self-diagnose–as having CFS. Yet without a case definition that is as accurate as possible, researchers cannot achieve valid or reliable results.

“If you recognize something is happening, you need a case definition so you can count it,” Andrew Moss, an emeritus professor of epidemiology at the University of California, San Francisco, and an early AIDS investigator, told me for an article I wrote about case definitions earlier this year. “You need to know whether the numbers are going up or down, or whether treatment and prevention work. And if you have a bad case definition, then it’s very difficult to figure out what’s going on.”

Non-CDC researchers say the problem with the agency’s 2005 method for identifying CFS cases is that it mistakenly classifies people with primary depression as having chronic fatigue syndrome instead. Depression and CFS can resemble, overlap and interact with each other in multiple ways; patients with CFS may get very depressed about their situation, and depression often causes fatigue, as can many other ailments. So distinguishing chronic fatigue syndrome from primary depression—in other words, depression that preceded and perhaps caused the fatigue—is important but tricky, and requires nuanced instruments. In epidemiologic studies that conflate the two, treatments that are known to be effective for depression could appear to be effective for chronic fatigue syndrome, even if they might not be.

A case in point is a treatment called “graded exercise therapy,” a slow increase in exercise that has been promoted for CFS patients by the British psychiatric, medical, and insurance establishments; it is also highlighted as a treatment option on the CDC’s website and educational materials.

There is no dispute that exercise can be a very effective treatment for depression. But people with chronic fatigue syndrome generally suffer from a distinctive symptom known as “post-exertional malaise”—a disproportionate depletion of energy following minimal activity that is not a typical feature of depression. (However, the word ‘malaise,’ like the word ‘fatigue,’ is a complete misnomer; post-exertional malaise is much closer to a serious crash or relapse than a Victorian fainting spell.) An emerging field of research—much of it taking place at the University of Utah and University of the Pacific in Stockton, California–indicates that people with CFS suffer from problems with oxygen consumption, energy production and muscle recovery. So it’s not surprising that increasing activity levels could lead in some or many cases to a prolonged resurgence of their symptoms rather than the improvement predicted by proponents of graded exercise therapy.

Patients with CFS are very familiar with post-exertional malaise. Many report having recovered for a period of time, then pushing themselves too hard and suffering a devastating set-back, repeating the cycle multiple times before learning to adjust their pace. When Mary Schweitzer experiences post-exertional malaise, she said, she loses her formidable communications skills.

“I get close to incoherent,” she wrote in a recent e-mail. “I can’t make sense, and nobody can make much sense out of what I say. I am used to it now and try to make a joke out of it, but it’s sad.” As a result, she wrote, she has learned what people with CFS call ‘envelope theory,’ based on published work from Dr. Jason’s research group at DePaul University: how to harness their energy by recognizing their limits, and not pushing beyond them. That approach is essentially the antithesis of graded exercise therapy.

“You learn what will bring on a crash–sitting upright at a restaurant, for example–and you just don’t do it,” wrote Dr. Schweitzer. “You live in what we call your ‘envelope.’ Then if something special comes along like a birthday, you push the envelope, and if you get a push-back, you know you still have the same boundaries.”

Like Laura Hillenbrand, Mary Schweitzer is an author (although the book she wrote from her doctoral research at Johns Hopkins, Custom and Contract: Household, Government, and the Economy in Colonial Pennsylvania, has undoubtedly never reached Seabiscuit-y heights in Amazon’s rankings). She grew up in Richmond, Virginia; boogied in the mud at Woodstock; wooed her future husband, Bob, with home-cooked lasagna (he was the teaching assistant in an economics course she as an undergraduate at Duke); and was teaching, conducting research, and raising two kids when CFS whacked her life upside down.

Dr. Schweitzer said she could never have managed through the years without the support and devotion of her husband, a professor of finance and economics at the University of Delaware. But she has also improved significantly on intermittent treatment with Ampligen, a drug that appears to be effective for some people with CFS. The drug hasn’t been approved by the U.S. Food and Drug Administration, but Dr. Schweitzer currently receives it as part of an ongoing clinical trial. She travels twice a week from her home in Delaware to her doctor’s office in Manhattan for infusions of Ampligen; unlike in most clinical trials, she has to pay for the drug, which costs her $16,000 a year.

When off Ampligen, she has suffered major crashes; at one point several years ago, she tested positive for four herpesviruses—Epstein-Barr, cytomegalovirus, HHV-6A, and HHV-7—and Coxsackie B, an enterovirus. Whenever she can, she addresses public forums, in particular the twice-yearly meetings of the Chronic Fatigue Syndrome Advisory Committee, one of many committees created to offer guidance to the U.S. Department of Health and Human Services; she estimates that she has testified to date at thirty hearings, conferences or meetings. When she speaks, in a public forum or one-to-one, she is articulate, passionate, loud, tender, demanding, funny and fierce. In one of her many statements to the federal advisory committee, Dr. Schweitzer described one of her severe relapses.

“I lost the ability to walk normally and we had to bring the wheelchair back up from the basement,” she wrote. “I dropped things, and when I tried to load the dishwasher I crashed one glass against another…It made no difference that now I knew the names of the various symptoms–ataxia, expressive aphasia, short-term memory loss, central auditory processing dysfunction, etc. My brain had disappeared.”

A Bit of History

The conflict over the nature and definition of CFS–between the CDC and the patient community, as well as between the agency and other researchers–dates back to the initial investigations of an outbreak in Incline Village, Nevada, near Lake Tahoe, of a mysterious illness, possibly associated with Epstein-Barr virus. The outbreak was one of many reports in the mid-80s of what was already being called “chronic Epstein-Barr syndrome” or “chronic mononucleosis.” (Epstein-Barr virus causes most cases of mononucleosis).

In its 1988 paper on the illness, a CDC-led team of researchers cast doubt on the Epstein-Barr hypothesis and rechristened the phenomenon “chronic fatigue syndrome” to discourage unproven assumptions about viral origins. (Ironically, because CFS began as a suspected viral illness, the research program has remained housed in the agency’s viral section.) The paper proposed a complicated case definition requiring six months of unexplained fatigue, plus either six of eleven “symptom criteria” (mild fever, sore throat, painful lymph nodes, muscle weakness, muscle pain, prolonged fatigue post-exercise, headaches, joint pain, neuropsychological complaints, sleep disturbances, and sudden onset of the illness) and two of three “physical criteria” (fever, sore throat, and palpable or tender lymph nodes, documented by a physician twice, at least one month apart); or eight of the eleven symptom criteria, without the physical criteria.

In retrospect, for many patients the CDC’s first big blunder was in not calling the Tahoe illness myalgic encephalomyelitis in the first place. Benign myalgic encephalomyelitis has long been recognized by the World Health Organization as a synonym for “postviral fatigue syndrome,” which is listed as a neurological illness. The term was coined to refer to a similar flu-like outbreak at a major London hospital in the 1950s (although “benign” has since dropped out of common usage.) In practice, many patient and advocacy groups now combine the two terms as CFS/ME or ME/CFS, or use ME alone.

Dr. Reeves was not on hand for the original investigation, but joined the CDC in 1989 as chief of what was then called the Viral Exanthems and Herpesvirus Branch. Dr. Reeves received his B.A. in 1965 from the University of California, Berkeley, where his father was a renowned expert in mosquito-borne illnesses and served as dean of Berkeley’s School of Public Health; he studied medicine at University of California, San Francisco, earned a masters in epidemiology at the University of Washington, and worked at a major medical research center in Panama for a dozen years before joining the CDC in 1989.

A Harvard-led research team described the Tahoe outbreak in far more serious terms than the 1988 CDC report: the patients, they reported in 1992 in the Annals of Internal Medicine, had abnormal MRI brain scans, significant alterations in white blood cells counts and functioning, and signs of active infection with a recently discovered pathogen, HHV-6. The illness, they wrote, was likely a “chronic, immunologically mediated inflammatory process of the central nervous system.”

In a letter to the journal listing more than a dozen purported methodological flaws, the CDC—with Dr. Reeves as the lead author—dismissed the Harvard study and its findings in unusually blunt terms. “We conclude that the disease…described is not the chronic fatigue syndrome or any other clinical entity and that they showed no association with active HHV-6 replication,” wrote Dr. Reeves and his colleagues.

A pattern appeared to have been established. In a subsequent episode in the early 1990s, chronicled in detail in Osler’s Web, the CDC failed to confirm other researchers’ reports of a retroviral link to chronic fatigue syndrome. These and other contradictory results gave rise on both sides to claims and counter-claims and counter-counter-claims (etc.) of methodological flaws, unjustified assumptions, and other scientific sins of omission or commission.

In the early 1990s, a CDC-led team reviewed the complex 1988 case definition and published a revised and somewhat simplified version. According to these 1994 guidelines, a diagnosis of CFS required the presence of six months of disabling, medically unexplained fatigue, along with at least four of eight other symptoms: impaired memory or concentration, disordered or unrestful sleep, muscle pain, joint pain, headache, tender lymph nodes, sore throat, and post-exertional malaise. Although the definition relied on self-reported symptoms rather than biological tests or standardized instruments to measure levels of fatigue and disability, it soon became the most widely used set of criteria in both research and clinical settings.

The Financial Scandal

Two years after the CDC issued its 1994 case definition, Osler’s Web was published to strong reviews. The book documented how the CDC routinely diverted money slated for CFS research to other projects because of lack of concern about the illness. (The CDC did not officially comment on the book at the time, according to a CDC spokeswoman.) Two years later, Dr. Reeves leveled similar charges against his superiors, noting that the CDC lied to Congress about how it spent CFS funding; he received whistleblower protection.

In his statement, he reported that, for example, in 1996 the agency spent $1.2 million for laboratory equipment and supplies for measles and polio and charged it to the CFS account. In 1995, he reported, the agency charged the CFS program $2.6 million for funding spent on unrelated studies. He had, he stated “attempted to rectify this within CDC” before going public.

“I believe that CDC has intentionally misrepresented monies allocated to CFS research and I cannot ethically support this,” wrote Dr. Reeves in his public statement. “The misrepresentations involve systematically charging between $400,000 and $2 million incurred by unrelated activities to CFS between 1995-97 and reporting to DHHS [Department of Health and Human Services], Congress and patients that the monies were used for CFS research.”

A 1999 report from the inspector general of HHS found that of the $22.7 million the CDC charged to its CFS program between 1995 and 1998, less than half was clearly spent on the illness. The report noted: “CDC spent significant portions of CFS funds on the costs of other programs and activities unrelated to CFS and failed to adequately document the relevance of other costs charged to the CFS program…As a result of these inappropriate charges, CDC officials provided inaccurate information to Congress regarding the use of CFS funds.”

The inspector general’s report found that $8.8 million was spent on non-CFS projects and that the documentation on an additional $4.1 million was so poor that it was impossible to determine whether they were used to support CFS research or not. Even as the CDC shortchanged the CFS program, the report noted, it disregarded Congressional requests to support important research initiatives. As an example, the report noted that Congress had urged the CDC to expand its surveillance of CFS among adolescents and to hire a neuroendocrinologist “to enable expansion of its research efforts and pursue promising findings from other Federal agencies and the private sector.”

At the time of the inspector general’s report, however, the CDC had halted an ongoing adolescent study and had not hired an endocrinologist—even as allocated money wasn’t being spent. The report noted: “Internal correspondence… indicated that delays were forced due to a ‘lack of available funds.’ Yet, we found that large portions of budgeted CFS funds had been held in reserve by the Division Director during the year, and were not released until after the deadline for obligations had passed. Thus, while important enhancements were not being implemented, more than $850,000 of FY 1998 budgeted funds were never made available to the program.”

In the wake of the scandal, Dr. Reeves’ boss left his position; the agency agreed to reform its accounting practices and restore more than $12 million to the CFS program over the next several years. Although Dr. Reeves’ whistleblower status effectively solidified his position at the CDC, his statement didn’t answer all outstanding questions. Given the revelations from Osler’s Web in 1996, it seemed unlikely to many patients and advocates that key officials at the agency could have been unaware of accounting irregularities–especially since they apparently continued through 1998, according to the federal investigators.

A subsequent investigation in 2000 from the U.S. General Accounting Office (now called the Government Accountability Office) found that communication between the CDC and the NIH about CFS research programs and priorities was poor. The limited coordination, as well as the CDC misspending, had hampered progress in the search for answers to the illness, the investigators reported.

The financial scandal left many CFS advocates, patients and researchers with a lingering distrust toward the CDC. In the following years, however, some of the CDC’s work in chronic fatigue syndrome—funded by the millions restored to the budget–received praise.

In 2003, Dr. Reeves’ study of CFS in Wichita, Kansas, yielded a disease prevalence of 235 per 100,000 percent of the adult population, or about 400,000 overall in the U.S. That figure was below the generally accepted estimate of one million sufferers, derived from a community-based study in the Chicago area by Dr. Jason’s research group at DePaul University. Yet the new figure was accepted as far more accurate than the agency’s earlier estimates, from research in the 1990s, that less than 20,000 people had the illness; that research had been criticized for relying on doctors’ reports of patients with CFS, a far less effective epidemiologic method of assessing prevalence than community-based surveys. The Wichita research also provided a sense of the societal burden of CFS; the CDC team reported that the illness cost the economy $9.1 billion a year in lost productivity, and people with CFS lost an average $20,000 annually in earnings.

Also praised was the CDC’s partnership with Australian researchers on a study reporting that more than 10 percent of a cohort suffering from acute viral illnesses went on to develop CFS–one of the agency’s few successful efforts to document viral links. And in 2006, the CDC published—with great fanfare–a set of 14 studies in the journal Pharmacogenomics, which found significant variations in CFS patients of gene expression and activity related to how the body handles and adapts to physical and emotional challenges and stress.

Much of the research focused on genes associated with the hypothalamic-pituitary-adrenal axis, which regulates the body’s stress responses, among other functions. At a press conference introducing the studies, Dr. Reeves outlined his understanding of the illness: “The working hypothesis is that the HPA axis and the brain is a plastic organ which changes its actual physical architecture depending on stresses accumulated over the lifetime,” he explained. “So as people experience stress, and that can be childhood abuse, it can be childhood infections, it can be multiple injuries…to some extent the genetics determine how you are going to react to them, they determine how your allostatic load [a stress-related indicator] may accumulate, and more importantly, they actually determine your subsequent reaction to stress applied at a later time during the lifespan.”

Dr. Reeves himself declared the illness to be a matter of great public health concern and expressed empathy for patients. “People with CFS are as sick and as functionally impaired as someone with AIDS, with breast cancer, with chronic obstructive pulmonary disease,” he told me in 2007, when I wrote my first story about the disease for The New York Times.

Some advocates welcomed the genetics studies for providing evidence that the illness had a biological basis and was not a figment of patients’ imaginations. But a news article in Science about the Pharmacogenomics papers reported that other scientists had raised serious methodological questions about the CDC’s approach, with one prominent researcher calling the new findings “meaningless.” Others in the CFS community feared that the focus on stress and trauma as major factors left the door open for the CDC to focus on a wide range of psychologically and behaviorally oriented approaches in the search for both causes and treatments—and they note the recent personality disorder and childhood abuse studies as proof of their concerns.

 The Rejected Empiric Criteria

Other CDC efforts, such as the multi-million-dollar public awareness campaign to brand the name “chronic fatigue syndrome,” dismayed much of the patient and advocacy community, given ongoing and fervent attempts to have the illness officially renamed ME. And in a highly controversial move, Dr. Reeves spearheaded in 2005 the creation of the new, purportedly more precise method of identifying patients; critics feared the approach would wreak havoc with epidemiologic studies by mixing a lot of people with depression but not CFS into samples of people all presumed to have chronic fatigue syndrome.

During the 2000s, researchers—including many clinicians who actually treated patients and understood how seriously ill they could be—had continued to be dissatisfied with the 1994 case definition, which they felt imprecisely described the condition. For one thing, the definition allowed for but did not require the presence of post-exertional malaise (reminder: read “relapse” or “crash,” rather than “malaise”). Yet it was increasingly apparent that post-exertional malaise, and not fatigue alone, was a cardinal symptom for many if not most patients, and one that clearly helped distinguish CFS from primary depression, as well as other chronic illnesses. The CDC definition also allowed for but did not require the presence of cognitive and neurological problems, although these appeared to afflict almost everyone with the condition.

Other research groups were using their own case definitions, making it hard to compare results. The “Oxford criteria” developed in Great Britain required only the presence of six months of disabling fatigue; that single-symptom criterion was criticized as so broad that it was likely to identify many people with primary depression rather than CFS. A more detailed 2003 case definition developed in Canada focused on post-exertional malaise as a cardinal symptom of what it called ME/CFS. Required symptoms also included disordered sleep, pain, and neurologic symptoms, as well as signs of dysfunction in the immune, endocrine and autonomic nervous systems.

Earlier this year, a team of top researchers—not surprisingly, without any participation from the CDC–published a new “international consensus” case definition, which adopted the name myalgic encephalomyelitis and abandoned chronic fatigue syndrome altogether. Using the Canadian definition as a jumping-off point, the new international definition also dropped the construct of “fatigue” in favor of requiring post-exertional malaise, which they renamed “post-exertional neuroimmune exhaustion.” Other required symptoms include neurological and energy production impairments.

In contrast, the 2005 effort by the CDC to “operationalize” the earlier 1994 case definition–by introducing standardized questionnaires and measurement scales to assess levels of fatigue and functional impairment—has found no support outside the CDC itself. In suggesting specific instruments and scales, Dr. Reeves and his research team proposed cut-off points to represent sufficient grounds for identifying CFS.

Yet when the CDC researchers applied these new “empiric” criteria, as they called them, to a population in Atlanta in 2007, they found a prevalence of 2.54 percent of the adult population. Extrapolated nationwide, that meant that four million people—in other words, ten times the CDC estimate from its Wichita research just four years earlier, and four times the widely accepted figure of about one million—had the illness. Dr. Reeves and his co-authors defended the new numbers, attributing the increased prevalence estimates to a broad sampling strategy and “application of more sensitive and specific measures of the CFS diagnostic parameters.”

Others outside the CDC dismissed the new numbers as absurdly inflated and argued that the empiric criteria, like the Oxford criteria but unlike the 2003 Canadian case definition, blurred and expanded rather than clarified the disease boundaries. While some advocates believed the increased estimates would focus more attention on the illness and should therefore be embraced, many others—including leading epidemiologists–believed that the expanded category could make it harder to isolate physiological correlates; that failure, in turn, would make it more likely that others would continue to perceive it to be largely a psychiatric illness.

One study from Dr. Jason’s research group at DePaul University, frequently cited by advocates, found that 38 percent of a group suffering from major depression but not chronic fatigue syndrome were misdiagnosed as having CFS using the new empiric case definition. The researchers reported that the scales, measurements and cut-off points indicated by the CDC group did not sufficiently distinguish between emotional and physiological sources of fatigue and disability; in other words, someone could be identified as having CFS under the new method solely because of fatigue or disability arising largely from psychological causes, such as depression.

“Given the CDC’s stature and respect in the scientific world, this new definition might be widely used by investigators and clinicians,” wrote Dr. Jason and his co-authors. “This might result in the erroneous inclusion of people with primary psychiatric conditions in CFS samples, with detrimental consequences for the interpretation of epidemiologic, etiologic, and treatment efficacy findings for people with CFS.” The authors also noted pointedly that the population prevalence for CFS calculated using the empiric definition was close to that for major depressive disorders.

Although the empiric case definition was published six years ago, it has not found any favor outside the CDC, raising questions about the comparability of CDC data derived from its use to results from other studies. Dr. Unger wrote in her e-mail response that she knew of no other researchers who had adopted the empiric criteria, although she noted that “others have started applying case definitions using instruments as tools, recognizing the improved ability to get consistent results.” Three major ongoing CDC studies have samples selected through use of the empiric criteria.

Dr. Unger appeared reluctant to whole-heartedly endorse the estimate, based on the empiric criteria, that 4 million people in the U.S. have CFS, but she did not back away from it either. “No single study or approach can be considered sufficient to determine the true population prevalence of an illness as complex as CFS,” she wrote. “Like all studies, the 2007 prevalence estimates of CFS based on the Georgia surveillance study are subject to the limitations of the study design. However, the Georgia study, along with those from other investigators, does demonstrate the public health importance of CFS and it is the CDC’s most recent study on the prevalence.”

Dr. Unger indicated that the agency “is in dialogue with other investigators about instruments and methods to best characterize and stratify CFS patients.” The agency is also launching studies with several investigators to enroll and characterize patients from seven clinical practices headed by leading CFS physicians to help clarify issues involving the case definition as well as the name.

“We are planning to collect standardized data on all the domains of illness included in the Canadian Consensus Criteria of CFS/ME, the 1994 CFS definition and the newly proposed International ME definition,” she wrote. “We anticipate that this data will assist researchers and clinicians in considering further refinements of the case definition.” With regards to the name of the illness, she wrote: “Opinions of advocates, clinicians and researchers remain divided about whether CFS and ME are the same or different entities. However, we are following the discussions with interest and would consider any consensus that is reached by patient groups and the scientific community going forward.”

The Website Conflict

Another conflict that has dogged the agency involves its CFS website. Advocates and patients have long complained that it conveys serious misinformation, in particular on aspects of diagnosis, treatment and management of the illness. For example, until this month the website included the following language: “No diagnostic tests for infectious agents, such as Epstein-Barr virus, enteroviruses, retroviruses, human herpesvirus 6, Candida albicans, and Mycoplasma incognita, are diagnostic for CFS and as such should not be used (except to identify an illness that would exclude a CFS diagnosis, such as mononucleosis). In addition, no immunologic tests, including cell profiling tests such as measurements of natural killer cell (NK) number or function, cytokine tests (e.g., interleukin-1, interleukin-6, or interferon), or cell marker tests (e.g., CD25 or CD16), have ever been shown to have value for diagnosing CFS. Other tests that must be regarded as experimental for making the diagnosis of CFS include the tilt table test for NMH, and imaging techniques such as MRI, PET-scan, or SPECT-scan.”

Advocates and patients appealed to the CDC many times over the years to remove the language. They acknowledged that these and other tests were not diagnostic for CFS but insisted that wasn’t the point; even though the tests couldn’t be used to confirm that a patient had CFS, they were important weapons for disease management. Experienced clinicians, like Dr. Enlander at Mt. Sinai and Dr. Nancy Klimas, a top researcher at the University of Miami, have long used tests such as these to identify CFS sub-groups and individualize treatment strategies, given their patients’ histories of immune dysregulation and viral infections. Yet clinicians report that they have received letters from insurance companies citing that paragraph in rejecting claims for tests they have ordered, in some cases as recently as last summer.

The agency finally removed that language this month, after an advisory group reviewed the website and requested a host of changes. “They [the reviewers] provided useful feedback in early October and CDC is incorporating this feedback into our ongoing efforts to improve the CFS website,” wrote Dr. Unger. Replacing the old language is a new passage that suggests that some of the same tests once disallowed for diagnosis of CFS can be useful for disease management—as advocates have been saying all along. Patient groups welcomed the change, but some advocates said it was minimal and long overdue, given that many insurance claims had been rejected unfairly in years past.

Another major complaint about the website has been the agency’s longstanding promotion of two treatments developed and championed in the United Kingdom: graded exercise therapy and cognitive behavior therapy. In the U.K, mental health professionals have dominated research into and treatment of chronic fatigue syndrome; they use the Oxford criteria, requiring only six months of unexplained fatigue. A major British study using this case definition and published earlier this year indicated some improvement with graded exercise therapy and cognitive behavior therapy. But U.S. experts on the illness, at least those outside the CDC’s immediate orbit, generally believe that the U.K. case definition—like the CDC’s empiric definition–is likely to define a cohort that includes a lot of people with depression, and not actual CFS, as their primary complaint.

To those convinced that CFS is a condition of psychogenic and not organic origin, it probably doesn’t matter if people with depression are mixed up in a study sample. In the framework of chronic fatigue syndrome endorsed by the British medical establishment, the prolonged fatigue and associated illness are largely considered to be caused by the patient’s inability or unwillingness to maintain an active lifestyle—an avoidance triggered by some form of stress, psychological issues or perhaps even an infectious illness. That avoidance of activity then leads to a physiological deconditioning that impacts multiple body systems and organs.

“It’s a psychological model,” said Dr. Jason of DePaul University, of the British view of CFS. “It’s an illness that might be caused by some kind of virus or trauma, but what’s maintaining it is that you have some sort of phobic avoidance of activity. The idea is your bone and muscle mass decrease, you become weak. So if you can get a person to slowly increase the amount of activity that they do, they will break this phobic avoidance.”

In the U.K. framework, graded exercise therapy is often paired with cognitive behavior therapy in the treatment protocol for CFS. Cognitive behavior therapy is a treatment modality with widespread application, and is likely to be useful to many people undergoing major stresses–whether from cancer, a back injury, an existential crisis, fear of sex, migraines, a bad divorce, or cognitive fatigue syndrome. However, the kind of cognitive behavior therapy prescribed in Great Britain to treat people with CFS—as Dr. Jason and other researchers have repeatedly noted–is largely geared toward convincing patients to overcome their avoidance phobia and increase activity levels; in other words, to encourage them to participate in something very much like graded exercise therapy.

But for people who experience post-exertional relapses of their symptoms, graded exercise therapy could be harmful, not helpful; in addition to the emerging research about post-exertional malaise, patient surveys in the U.K. have indicated a high degree of unhappiness and increased morbidity among those who have been through a course of graded exercise therapy. And, say critics, cognitive behavior therapy could also be harmful, if the goal is to convince patients to engage in graded exercise therapy or otherwise ramp up activity levels.

Dr. Unger wrote in her response that she was aware of patient concerns about including information on graded exercise therapy and cognitive behavior therapy on the website, and that the agency was reviewing those sections. The goal of the information, she wrote, was to let patients know about treatment options they could discuss with their health care providers. “Though these approaches may not work for everyone, the scientific literature shows that they provide some benefit to some patients,” she wrote.

However, Dr. Unger declined to comment specifically on the contested scientific literature from the U.K. that actually reported the modest benefits from these therapies, noting that “as a rule, CDC doesn’t comment on research not conducted by CDC.”

The View from the Chronic Fatigue Syndrome Advisory Committee

The growing dismay about Dr. Reeves’ leadership and the agency’s problematic CFS research program are evident in the minutes and testimony from the twice-yearly meetings in the late 2000s of the Chronic Fatigue Syndrome Advisory Committee of the Department of Health and Human Services. The mandate of the committee, with a rotating membership of clinicians, researchers, patients and advocates, is to offer guidance and recommendations to the department. In 2007, the committee requested financial records from the CDC’s CFS program. Dr. Jason, a member of the CFSAC, and Dr. Reeves, an ex officio member as the CDC’s representative, sparred publicly over access to the records.

By the time of the next CFSAC meeting, in October of 2008, Dr. Reeves had been replaced as the CDC’s ex officio member (although he retained his CDC position). Another CDC official at the meeting said he hoped the change would help “to leave behind past tensions to make a fresh start.”

At that meeting, however, Kim McCleary, the head of the CFIDS Association of America, testified that the CFS program, based on a review of the CDC financial documents that the committee had sought, suffered from “shameful scientific leadership, zero accountability, invisible outcomes and millions and millions of dollars stuck in suspended animation, if not wasted…Only the government contractors seem to be benefiting from millions spent for which there are no worthwhile outcomes for American taxpayers, or CFS patients.”

The largest chunk of the program’s funding, reported McCleary, went to a single private research organization, Abt Associates in Cambridge, Massachusetts, in sole-source or no-bid contracts for the epidemiologic research that was being widely criticized by other scientists. At least $2.7 million committed to Abt was “in limbo”–obligated to specific projects but remaining unspent—and work on other projects was proceeding slowly and at great cost, she testified. The financial mismanagement, testified McCleary, “has resulted in program management coming often to this committee and telling other investigators that no funds are available for new projects or collaborations.”

(The CFIDS Association of America had been criticized by some other advocates over the years for its previous close association with Dr. Reeves. The organization had provided essential public support for Dr. Reeves during the accounting scandal in the late 1990s; in the mid-to-late 2000s it implemented the agency’s controversial multi-million-dollar CFS public awareness campaign at a time when others were seeking to change the disease name. McCleary’s public rebuke of Dr. Reeves’ leadership, therefore, was viewed as a significant blow to the CFS program and found a welcome audience.)

McCleary’s report further shredded support for Dr. Reeves among committee members; some were researchers struggling with their own funding issues. The financial accounting appeared to confirm a frequently heard complaint about the CDC and Dr. Reeves—that they were not taking full advantage of opportunities to collaborate with outside scientists at academic research centers.

Christopher Snell, a professor of sports sciences at the University of the Pacific in Stockton, CA, and a committee member, stated, according to the minutes: “As somebody who works on a shoe string budget, when I start to look at some of these numbers, I was somewhat appalled… It just does not seem to be the best use of the funds. The thing that we asked for at a couple of previous meetings was for the CDC to consider more collaboration with outside entities. We meant people who work a lot cheaper. It would seem that there are people out there with great ideas who would love to work with the CDC for much less money.”

Dr. Klimas, also a committee member, noted that she had been collaborating with the CDC on a study comparing people with CFS and Gulf War illness, and that the agency had failed to finish its testing on samples, citing funding problems. She also unleashed another common charge: that the CDC was simply not interested in the role of pathogens. According to the minutes, “Dr. Klimas said that CDC has made it known that the agency has no intention of looking for infectious agents. She added that other research organizations are pursuing identification of pathogens and that CDC should be embarrassed not to be looking for them as well…despite the evidence, the CDC is still saying that viruses don’t matter in the illness even though people are already being treated for them. She said that the science is there to provide options way beyond the CDC’s recommended behavioral treatment and exercise.”

At its meeting in May 2009, the committee unanimously voted to recommend “progressive leadership” for the CFS program; although the recommendation, in an apparent nod to decorum, did not cite Dr. Reeves by name, the intent was clear. The request for a top personnel change—essentially a vote of no-confidence in the current leadership–was considered an aggressive move for this kind of federal advisory committee. At the same meeting, the International Association for CFS/ME, a leading scientific and research organization, endorsed the call for new leadership.

In October of 2009, Dr. Reeves committed what many in the CFS world regarded as a major public gaffe: an off-hand remark to a New York Times reporter (not this one) about the mouse retrovirus research that had just sparked a wave of excitement. In the interview, which occurred shortly after the publication of the Science paper reporting the link between XMRV and CFS, Dr. Reeves said his research team would look for the retrovirus but that they were unlikely to find anything. He told the Times: “If we validate it, great. My expectation is that we will not.”

For a scientist to predict his team’s outcomes in a contested field of research during a highly public and volatile debate is not the best way to demonstrate impartiality and open-mindedness (notwithstanding that the XMRV hypothesis appears not to have panned out). Even more so for someone like Dr. Reeves, who was already facing coordinated calls for his ouster from almost every corner.

At the CFSAC meeting later that month, the committee again approved a recommendation for new leadership and emphasized the urgency of the issue. According to the minutes: “CFSAC considers that recommendation important and would like to get some feedback, including whether or not the recommendation is being considered. This has become more important because of certain quotes that have been made in The New York Times concerning the retrovirus by the person in charge of the CDC program.”

The committee also formally rejected the CDC’s empiric case definition—the centerpiece of Dr. Reeves’ epidemiologic approach—and recommended support for “a national effort to arrive at a consensus definition of CFS that is accurate, standardized, and reflective of the true disease.”

Within months, Dr. Reeves was gone from his position, although no public explanation for the move was offered. For the most part, the elements of the CFS program that Dr. Reeves championed—the empiric criteria, the name of the illness, (most of) the disputed website information, etc.—remain in place under Dr. Unger.

Reaction to Dr. Unger’s efforts appears decidedly mixed so far. Yet some members of the research community express optimism about being able to develop, with Dr. Unger, the kind of cooperative framework that many felt was absent when Dr. Reeves ran the program. Dr. Fred Friedberg, president of the International Association for CFS/ME, said that Dr. Unger was “way more responsive” than Dr. Reeves, noting that she had attended the association’s annual conference this fall in Ottawa.

“We reached out to her and she has been very accommodating and engaged in conversation to talk about some joint efforts,” said Dr. Friedberg, a professor of psychology at Stony Brook University Medical Center. “It remains to be seen what goals she’s going to set up and what kind of studies she’s going to do exactly. So this is kind of a work in progress, but the level of cooperation is pretty good. For the first time in years, there’s an opening.”

For those who do not read Portuguese, the title of this post is “Popularization of science through podcast”. During my visit to Brazil last month, I was interviewed by a Ph.D. student, Luiza Montenegro Mendonça, from the Federal University of Rio de Janeiro. Luiza is taking a course on scientific divulgation, and students are required to produce a podcast each week which is published on the course website. Luiza’s brief (~5 min) conversation with me can be found on the ICB (Instituto de Ciências Biomédicas) website, and it’s available in both English and Portuguese. If you read Portuguese, you should also check out the home page of the ICB website.

Luiza is very interested in teaching the public about science, but does not feel that podcasting is right for her. Instead, she plans to write a science blog in Portuguese. When her blog launches we will be sure to note it here.

Hosts: Vincent Racaniello, Rich Condit, Alice Telesnitsky, and Kathy Spindler

Vincent and Rich visit the Microbiology and Immunology Department at the University of Michigan Medical School, and speak with Alice and Kathy about their work on HIV genome dimerization, and packaging and pathogenesis of mouse adenovirus.

Model of poliovirus bound to CD155 made by Stefan Taube.

Please help us by taking our listener survey.

Click the arrow above to play, or right-click to download TWiV 158 (52 MB .mp3, 87 minutes).

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, by email, or listen on your mobile device with the Microbeworld app.

Links for this episode:

• Mouse adenovirus infection of macrophages (Virology)
• Breakdown of blood-brain barrier by mouse adenovirus (J Virol)
• Major locus for mouse adenovirus susceptibility (J Immunol)
• Structures in HIV 5′-end that regulate genome packaging (Science)
• Packaging of host RNAs by murine leukemia virus (J Virol)
• What, how, when, where, and why of retroviral genome dimerization and packaging (PLoS Path)
• Virologist replaces Steve Jobs at Apple
• TWiV on Facebook
• Letters read on TWiV 158

Weekly Science Picks

Alice – Banvard’s Folly by Paul S. Collins
Kathy – The world at seven billion
Rich – The Princess Bride
Vincent - Center for the history of microbiology

Listener Pick of the Week

Tim – Dead Ends to Somewhere by Richard L. Ward
Don – Ben Goldacre: Battling bad science (TED)

Send your virology questions and comments (email or mp3 file) to twiv@twiv.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

Arthur D. Levinson, Ph.D., Chairman of Genentech, has replaced Steve Jobs as Chairman of the Board of Apple, Inc. During his scientific career, Levinson did research on different viruses, including adenovirus, retroviruses, and hepatitis B virus. His first virology paper came from his Ph.D. research with Arnold Levine, and is entitled “In vivo and in vitro phosphorylation of the adenovirus type 5 single strand-specific DNA-binding protein”. He moved to the University of California, San Francisco for postdoctoral work with Harold Varmus and Michael Bishop. There he published on the transforming gene of the retrovirus avian sarcoma virus. This PubMed search string will return Levinson’s publications on viruses, of which there are approximately 35. Levinson left virology to work at Genentech in 1980, but clearly could be called a bona fide virologist. Who would have known that Steve Jobs would be replaced by a virologist?

Thanks to Alice Telesnitsky for pointing out this story.

Hosts: Vincent Racaniello, Rich Condit, Alan Dove, Dickson Despommier, Jeremy Luban, and Gabriel Victora

A large TWiV panel remembers Ralph Steinman, and considers a new innate sensor of retroviral capsids.

Photograph of a dendritic cell (green) interacting with T cells (cyan) near a blood vessel by Gabriel Victora.

Please help us by taking our listener survey.

Click the arrow above to play, or right-click to download TWiV 157 (90 MB .mp3, 125 minutes).

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, by email, or listen on your mobile device with the Microbeworld app.

Links for this episode:

• HG Khorana obituary
• DC discovery: four seminal papers (one, two, three, four)
• Ralph Steinman videos from Lasker Award
• TRIM5 is an innate immune retroviral sensor (Nature)
• TWiV on Facebook
• Letters read on TWiV 157

Weekly Science Picks

Dickson – Eats, Shoots & Leaves by Lynne Truss
Rich – Battlestar Galactica
Alan – Coleman LED quad lantern
Gabriel – A History of Immunology by Arthur M. Silverstein
Jeremy – Principles of Virology by Flint, Enquist, Racaniello, Skalka
Vincent - Principles of Molecular Virology by AJ Cann

Listener Pick of the Week

David – Carl Sagan’s Pale Blue Dot (YouTube)

Send your virology questions and comments (email or mp3 file) to twiv@twiv.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

Most students of elementary biology will have seen the table at left that depicts the genetic code. HG Khorana was one of several scientists who determined, in the 1960s, the amino acids specified by each three-letter combination of bases. As long as I have been at Columbia University I have had a copy of this table on my office wall.

Khorana reminisces how the finding that genes are nucleic acids set the stage for his work on decoding:

While it is always difficult, perhaps impossible, to determine or clearly define the starting point in any area of science, the idea that genes make proteins was an important step and this concept was brought into sharp focus by the specific one gene-one enzyme hypothesis of Beadle and Tatum. The field of biochemical genetics was thus born. The next step was taken when it was established that genes are nucleic acids. The transformation experiments of Avery and coworkers followed by the bacteriophage experiments of Hershey and Chase established this for DNA and the work with TMV-RNA a few years later established the same for RNA. By the early 1950’s it was, therefore, clear that genes are nucleic acids and that nucleic acids direct protein synthesis, the direct involvement of RNA in this process being suggested by the early work of Caspersson and of Brachet.

The first triplet to be decoded was UUU, which specifies the amino acid phenylalanine. This work was done by Nirenberg who found that an RNA consisting of repeating U residues could be translated into a protein containing only phenylalanine. Codons for lysine (AAA) and proline (CCC) were similarly discovered using RNAs containing only A or C. Khorana used both enzymatic and chemical synthesis of oligonucleotides to decipher much of the remaining code. A good account of his work can be found in his Nobel lecture (pdf).

Khorana, together with Robert Holley (structure of tRNA) and Marshall Nirenberg, received the Nobel Prize in Physiology or Medicine in 1968 for their work on deciphering the genetic code.

Hosts: Vincent Racaniello and Dickson Despommier

Vincent and Dickson discuss immune evasion by the cruzain protease of T. cruzi, and novel tetraspanin antigens of S. japonicum.

Click the arrow above to play, or right-click to download TWiP #32 (65 MB .mp3, 90 minutes).

Please help us by taking our listener survey.

Links for this episode:

• NF-kappaB: Nuclear Factor binding kappa enhancer in B cells
• Immune evasion by T. cruzi cruzain (PLoS Pathogens)
• Novel tetraspanins in S. japonicum (Acta Tropica)
• Intravenously administered malaria vaccine (Science)
• TWiP on trypanosomes (#15) and schistosomes (#26)
• Monsters Inside Me
• Futures in Biotech with Dr. Jack Horner, advisor for Jurassic Park
• Dickson’s Pick: Labcoats in Hollywood by David Kirby
• Letters read on TWiP 32

Contact

Send your questions and comments (email or mp3 file) to twip@twiv.tv.

Subscribe (free)

Subscribe to TWiP (free) in iTunes, at the Zune Marketplace, by the RSS feed or by email

At the recent Brazilian Virology Society meeting George Rohrmann gave me a copy of his book, Baculovirus Molecular Biology. Baculoviruses are double-stranded DNA containing viruses that infect insects and other arthropods. Early in the first chapter of George’s book I learned that baculoviruses may be present on uncooked cabbage leaves:

…in one study it was found that cabbage purchased from 5 different supermarkets in the Washington D.C. area were all contaminated with baculoviruses to such an extent that each serving (about 100 cm² of leaf material) would contain up to 10⁸ polyhedra of an NPV pathogenic for the cabbage looper, Trichoplusia ni!

We ingest many other non-animal viruses regularly with foods. In TWiV #79, Red hot chili viruses, we discussed the finding of pepper mild mottle virus, one of the major pathogens of chili peppers, in human feces as well as in pepper or spice-containing food products. Metagenomic analysis of the RNA viruses present in human feces revealed that most viral sequences are similar to plant viruses.  Of 36,769 sequences obtained, 25,040 (91%) resembled plant viruses. In this study, the most abundant human fecal virus was pepper mild mottle virus, present in concentrations of up to 10⁹ virions per gram of dry fecal matter.

The plant (and perhaps insect) viruses that we ingest on a regular basis do not appear to replicate or cause disease in humans. Might they play important roles in development of the immune system, as do the commensal bacteria in our gut?

Zhang, T., Breitbart, M., Lee, W., Run, J., Wei, C., Soh, S., Hibberd, M., Liu, E., Rohwer, F., & Ruan, Y. (2006). RNA Viral Community in Human Feces: Prevalence of Plant Pathogenic Viruses PLoS Biology, 4 (1) DOI: 10.1371/journal.pbio.0040003

Hosts: Vincent Racaniello, Rich Condit, and Dickson Despommier

Vincent, Rich, and Dickson review a meta-analysis on influenza vaccine, a killer virus in fungi that selects against RNAi, and the use of armed and targeted poxviruses for oncolytic virotherapy.

Please help us by taking our listener survey.

Click the arrow above to play, or right-click to download TWiV 156 (57 MB .mp3, 94 minutes).

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, by email, or listen on your mobile device with the Microbeworld app.

Links for this episode:

• Efficacy and effectiveness of influenza vaccine (Lancet)
• Flu vaccine not as effective as thought (MPRNews)
• Blog posts on flu vaccine meta-analysis (virology blog, alandove, viva)
• Killer virus explains RNAi deficient fungi (Science)
• Poxvirus-based oncotherapy (Nature)
• Jennerex
• TWiV on Facebook
• Letters read on TWiV 156

Weekly Science Picks

Rich – Google’s self-driving car (story one and two)
Dickson – Wild Russia and Wild China TV series
Vincent – Baculovirus molecular biology by George Rohrmann (free)

Listener Pick of the Week

Jim – Lee Cronin: Making matter come alive (TED)

Send your virology questions and comments (email or mp3 file) to twiv@twiv.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

I hear from many readers that they routinely get the flu vaccine every year, yet they often contract the disease. I usually tell them that the vaccine is not perfect: it doesn’t protect everyone who gets it. Now we have the numbers to back up this statement, and they are not pretty.

There have been 5,707 studies since 1967 on how well influenza vaccine protects against infection. Many of them did not properly assess whether individuals were infected with influenza, leading to overestimation of the protective effect of vaccines. In many studies a four-fold increase in serum hemagglutinin antibodies were used to confirm infection. Immunization also increases these antibodies, making it difficult to confirm viral infection.

A review of the influenza vaccine studies was done by focusing on reports in which viral infection was confirmed by viral culture or polymerase chain reaction (PCR). The results of 31 studies show that the trivalent inactivated influenza vaccine is overall 59% effective in individuals 18-65 years of age. That means of every 100 individuals immunized, 41 will be susceptible to influenza. This number is far too low – it should be above 90%. The infectious, attenuated vaccine fared better – it is overall 83% effective but only in children 6 months to 7 years of age. It was not significantly effective in protecting individuals 18-49 years old.

Perhaps even more telling is those age groups in which there are no efficacy data for influenza vaccines. No trial results for the inactivated vaccine in 2-17 year olds or adults 65 years and older were considered adequate for inclusion in this study. Furthermore, there were no acceptable data for the attenuated vaccine in the 8-17 year group. Nevertheless, seasonal influenza vaccine is recommended by the Advisory Committee on Immunization practices for all people over 6 months of age.

The 65 and older age group is a main target for influenza immunization to prevent serious illness and mortality. However, there are few data for this age group on the ability of influenza vaccine to reduce illness or death. The infectious attenuated vaccine was shown to have significant efficacy in this age group in only one study, but it is not licensed for use in adults 50 years old or more in the US.

This study sends a strong message that better influenza vaccines must be developed. Why does the inactivated vaccine confer such poor protection? This vaccine is produced by inactivating the virus with formalin and disrupting it with detergents. In this dissociated state it not only does not replicate after intramuscular injection, but it lacks many of the components that induce a strong inflammatory response. Consequently the antibody response is weak. The attenuated influenza vaccine, which replicates in the respiratory tract, is more protective (83%) in the 6 month-7 year age group. If shown to be efficacious in other age groups it would make sense to increase the use of this vaccine, which currently accounts for only 9% of vaccine given in the US. But we should aim for greater than 90% protection and that may require developing entirely new vaccine approaches using novel antigens, delivery systems, and adjuvants.

These findings will provide a rationale for those do not feel it is necessary to be immunized against influenza. But the study authors do not condone abandoning the inactivated influenza vaccine:

…We should maintain public support for present vaccines that are the best intervention available for seasonal influenza.

In other words, it’s better than nothing, surely not a ringing endorsement. I suspect that the results of this study will lead to a decline in influenza immunization rates in the US.

Update: Alan Dove has a slightly different view of this study.

Osterholm MT, Kelley NS, Sommer A, & Belongia EA (2011). Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. The Lancet infectious diseases PMID: 22032844

In my recent keynote address to the Brazilian Virology Society entitled The World of Viruses, I presented my list of ten seminal virologists. The idea to include such a discussion came from David Baltimore, who sent me the following note:

Since you have been thinking about the history of virology, I thought I would share a list with you. Someone asked me to list the 10 most important virologists in history. I came up with 12. But I wondered if you had to make such a list, who you would include.

David Baltimore’s list included the following individuals:

• Jenner– the father of vaccination
• Beijerinck– discovered the first virus
• Rous– discovered tumor viruses
• Enders– father of the polio vaccine, discovered how to grow viruses in cell culture
• Lwoff– demonstrated latent infections with bacteriophage lambda
• Stanley– first virus crystals
• Klug– with Casper, described the principles of virus construction
• Dulbecco– established the plaque assay for animal viruses, allowing quantitation– also found that tumor viruses integrate into host DNA
• Delbruck– established viral genetics and, with Luria, was a father of molecular biology
• Temin– suggested that there was a DNA intermediate in the growth of RNA tumor viruses and found the reverse transcriptase
• Baltimore– found the first RNA-dependent RNA polymerase and the reverse transcriptase and established biochemical methods of virus investigation
• Hilleman– made most of the vaccines in use today while working at Merck

Obviously such lists are very personal and will certainly differ (although there would likely be names in common). Here is the list of ten seminal virologists:

• Beijerinck
• D’Herelle – discovered bacteriophages
• Theiler – produced the first infectious attenuated viral vaccine, yellow fever
• Delbruck
• Lwoff
• Hershey – showed, with Martha Chase, that DNA carries the genetic information of bacteriophages
• Enders – propagated an animal virus, poliovirus, in non-neural cell cultures
• Klug
• Baltimore
• Doherty – discovered MHC restriction of T cell killing

I sent my list to David, who replied:

I suppose this is a discussion that could go on endlessly but I find Doherty a very odd choice (more an immunologist than virologist) and Hershey a surprising choice, although he makes sense for having shown that the guts of a virus is its nucleic acid. And I miss Rous and Stanley very much. When Stanley crystallized TMV he brought together chemistry and virology, made life a continuum from the inorganic and put viruses at the cusp. Then Hershey makes sense because he got inside the virus and found the key chemical. Rous, you might argue, did more for cancer research than for virus research but I still think that the link of viruses to cancer changed the trajectory of virus research.

Interesting discussion.

Rich Condit and Alan Dove also have their own lists of ten virologists, which we’ll share on an upcoming TWiV. Making such lists stimulates valuable discussion about discoveries that set the future course of virology. It’s very much like the discussion about whether or not viruses are alive – the answer is not as important as the thoughts involved in getting there.

Who would be on your list of ten seminal virologists?

Thanks to TWiV listener Janet for transcribing episode #154, ‘Symbiotic safecrackers’. A pdf file of the transcript can be found on the post for that episode. A list of the episode transcripts is also available.

TWiV transcripts are all listener-generated, for which we are extremely grateful. If you would like to transcribe an episode, please let me know at twiv@twiv.tv, to avoid duplication of effort. We will provide a TWiV coffee mug as a token of our gratitude.

Hosts: Vincent Racaniello, Grant McFadden, Eurico de Arruda Neto, Paulo Eduardo Brandão, Francisco Murilo Zerbini, and Janice Reis Ciacci Zanella

Vincent, Grant, Eurico, Paulo, Francisco and Janice discuss their work on bocavirus, infectious bronchitis virus, begomoviruses, and circoviruses at the Brazilian Virology Society meeting in Atibaia, São Paulo, Brazil.

Click the arrow above to play, or right-click to download TWiV 155 (56 MB .mp3, 93 minutes).

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, by email, or listen on your mobile device with the Microbeworld app.

Links for this episode:

• Program of the XXII Brazilian Virology Meeting (pdf)
• Sociedade Brasiliera de Virologia
• Journal of the Brazilian Society for Virology
• Photographs from the meeting at TWiV Facebook or Picasa
• TWiV on Facebook
• Letters read on TWiV 155
• Video of this episode – view below or download 640×480 .mp4 file

Weekly Science Picks

Vincent – AAM Colloquium Program
Grant – The Disappearing Spoon by Sam Kean

Listener Pick of the Week

Antonio – 2011 Nobel Laureates Lectures at Lindau

Send your virology questions and comments (email or mp3 file) to twiv@twiv.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

I was honored to present the Keynote Address at the XXII meeting of the Brazilian Virology Society on 23 October 2011. In my talk entitled The World of Viruses, given to an audience of 640 virologists, I shared my enthusiasm for these amazing microbes by discussing ten seminal virologists and ten compelling virology stories of recent years.

Before I began the presentation, I asked the audience to smile and took the photograph at left. Within a few minutes there were no empty seats in the room.

Watch the video of The World of Viruses below, or download the .mov file to your computer in two different sizes: 640 x 400 (109 MB) or 1280 x 800 (295 MB). Right-click the links and select save as to download.

Hosts: Vincent Racaniello, Alan Dove, and Rich Condit

Vincent, Alan, and Rich are very enthusiastic about two studies that show how gut bacteria help viral invaders.

Click the arrow above to play, or right-click to download TWiV 154 (46 MB .mp3, 77 minutes).

Subscribe to TWiV (free) in iTunes , at the Zune Marketplace, by the RSS feed, by email, or listen on your mobile device with the Microbeworld app.

Links for this episode:

• TWiV154 transcript (pdf)
• Retrovirus transmission dependent on commensal microbiota (Science)
• Intestinal microbiota promote enteric virus replication (Science)
• TWiV 3D timeline (9 MB .mv4 – thanks, Ricardo)
• Faleye’s photos at VirusTalk
• TWiV on Facebook
• Letters read on TWiV 154

Weekly Science Picks

Alan – SciWriteLabs
Vincent – Take as directed

Listener Pick of the Week

Tony – Introduction to AI online course

Send your virology questions and comments (email or mp3 file) to twiv@twiv.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twiv.

Hosts: Vincent Racaniello and Dickson Despommier

Vincent and Dickson discuss the promising results of a phase III trial of a malaria vaccine in African children.

Click the arrow above to play, or right-click to download TWiP #31 (50 MB .mp3, 70 minutes).

Links for this episode:

• First results of RTS,S/AS01 phase III trial (NEJM)
• Development of RTS,S/AS malaria candidate vaccine (Vaccine)
• Chandler’s dog images (one, two - jpg)
• Schistosomiasis hieroglyphics (pdf)
• TWiP on malaria (#9, #10, #11)
• Letters read on TWiP 31

Contact

Send your questions and comments (email or mp3 file) to twip@twiv.tv.

Subscribe (free)

Subscribe to TWiP (free) in iTunes, at the Zune Marketplace, by the RSS feed or by email

Hosts: Vincent Racaniello, Michael Schmidt, Stanley Maloy and Elio Schaechter.

On episode #18 of the podcast This Week in Microbiology, Vincent, Michael, Elio, and Stanley explain how to make the human intestinal commensal and benign laboratory bacterium Escherichia coli K-12 into an invasive organism, and the unearthing of century-old spores in New York City.

Click the arrow above to play, or right-click to download TWiM #18 (54 MB, .mp3, 74 minutes).

Subscribe to TWiM (free) on iTunes, Zune Marketplace, via RSS feed, by email or listen on your mobile device with the Microbeworld app.

Links for this episode:

• Conversion of E. coli K-12 to an invasive form (mBio)
• Pedigree of E. coli K-12 (pdf)
• The facade of E. coli K-12 (Small Things Considered)
• Unearthing of century old bacteria in NYC (ABC News)
• Bacteria in 30,000 year old salt crystals (Geology)
• Old bacteria in ice
• Old, small, cold… (Small Things Considered)
• IP6 mediated autoprocessing of bacterial toxins (PloS Path)
• Letters read on TWiM #18

Send your microbiology questions and comments (email or mp3 file) to twim@twiv.tv, or call them in to 908-312-0760. You can also post articles that you would like us to discuss at microbeworld.org and tag them with twim.