Leaving Koch behind

parvovirusFor the past 40 years, certain laboratory mice in Australia and the US have been unexpectedly dying in middle age, but the cause has remained elusive. A novel member of the parvovirus family appears to be the culprit.

These unexpected deaths of laboratory mice are caused by kidney disease, as these organs appear shrunken and fibrotic upon histologic examination, with tubular necrosis, interstitial fibrosis, and intranuclear inclusion bodies. Sequence analysis of RNA from diseased kidneys revealed a 4,442 nucleotide genome with homology to parvoviruses. This new agent was called mouse kidney parvovirus (MKPV).

Parvoviruses (illustrated) are small viruses with single-stranded DNA genomes. They cause the human rash diseases erythema infectiosum (fifth disease) and arthritis, and serious infections in dogs and cats. There are also parvoviruses that infect mice, but these do not cause disease. MKPV is very different from these parvoviruses; it is more related to isolates from Old World fruit bats and vampire bats and are likely part of a new genus within the family. Whether MKPV is present in mice in the wild is unknown.

Co-housing experiments show that MKPV is transmitted among mice via feces and urine. After transmission the virus can be detected in serum and urine within 50-80 days, after which mice lose weight and die from kidney disease. The virus replicates within tubular epithelial cells in the kidney, and the abundance of viral genome sequences correlates with histological disease severity. Disease is mainly observed in immunodeficient mice, in which virus replicates to ten fold higher levels than in immunocompetent mice.

Chronic kidney disease in humans may have a variety of causes, including diabetes mellitus, hypertension, and virus infections. The latter are problematic in organ transplant recipients, in which polyomavirus-associated nephropathy is a major cause of death. The severity of interstitial fibrosis is a determinant of renal failure, but measuring fibrosis in patients is difficult. Several urine and serum biomarkers have been identified and some are found in mice infected with MKPV. Infection of mice with MKPV might therefore be a useful model for studying kidney interstitial fibrosis.

The authors conclude that MKPV is the cause of inclusion body nephopathy in mice. But Koch would be turning over in his grave: the authors did not fulfill his postulates, because they did not isolate MKPV, propagate it in culture, reintroduce it into mice, show that mice developed the same disease, and reisolate the virus from these diseased mice.

However, we are in a new age far beyond Koch where many viruses are discovered in silico (as was MKPV) and cannot be propagated in culture. Indeed, the authors indicate that they were unable to grow MKPV. A new set of Koch’s postulates are required for this new age, as outlined by Fredericks and Relman and previously discussed on this blog. Authors claim they have fulfilled most of these new requirements:

  • MKPV was found only in diseased mice, and mainly in kidneys, the only organ to display disease.
  • MKPV viremia was detected before disease, and viral DNA copy number correlated with disease.
  • Parvoviruses assemble in the cell nucleus, consistent with the observation of inclusion bodies in the kidney epithelium.
  • Viral sequences were detected in affected but not normal cells of the kidney

It seems likely that MKPV causes IBN in mice. Nevertheless, I am certain that the authors continue to try to propagate MKPV in cell culture, so they will one day allow Koch to remain at rest in his grave.

By David Tuller, DrPH

Here’s a video of back-to-back presentations from last month in Newry, Northern Ireland. On October 2, Brian Hughes, a professor of psychology at the National University of Ireland, Galway, and I both spoke at an event organized by Hope For ME & Fibro Northern Ireland. The title of the event: “The PACE Trial: ‘The Greatest Medical Scandal of This Century'”

Thanks to the organizers, volunteers, attendees and viewers!


By David Tuller, DrPH

I have written many posts about BMJ Open’s 2011 school absence study,
which reported that school absence records could be useful in identifying children with chronic fatigue syndrome. However, for reasons not yet adequately explained, the investigators exempted the study from ethical review on the grounds that it qualified as “service evaluation.” To support the claim, they cited a 2007 letter from the regional research ethics committee (REC), which was unrelated to the study in question.

Studies involving data from human subjects are often categorized as either “service evaluation” or “research.” Those in the former group are generally supposed to evaluate the provision of health care or other services through analyses of anonymous data; they are exempt from ethical review. If a study is testing a hypothesis, produces generalizable conclusions and/or involves data collected from participants known to the investigators, it falls under the category of “research,” not “service evaluation,” and requires ethical review.

The school absence study was conducted by investigators from the University of Bristol. It featured a formal hypothesis, generalizable conclusions, and in-person collection of data from participants. It was clearly “research,” as understood by the Health Research Authority, the arm of UK the National Health Service that serves as the arbiter of research ethics. The study should never have been defined as service evaluation and published without ethical review. Yet BMJ Open has repeatedly defended the decision to publish it.

As it turns out, the 2007 REC letter has been cited to exempt at least ten other studies from ethical review as service evaluation. (In some cases, the claimed exemption was only for part of the study.) Perhaps exemption from ethical review could be justified in some instances. But given the Bristol investigators’ inappropriate decision to cite the 2007 REC letter in exempting the school absence study from ethical review, further scrutiny of these studies would seem to be warranted. (A smart source introduced me to the issues involving the 2007 REC letter.)


Here’s the background:

In 2007, the North Somerset and South Bristol REC approved a request to add questionnaires to those already being used during pediatric care at the Bath CFS/ME clinical service. At the time, the clinical service was conducting assessments with several questionnaires at entry and at twelve months. The REC application sought approval for the Bath CFS/ME clinical service to add further assessments at six weeks and six months, arguing that this would be useful for measuring and improving the delivery of care.

In the documents, the title of the research project associated with the application was: “What happens to children with CFS/ME? The study of a longitudinal cohort of children who access a paediatric CFS/ME service.” After reviewing the application, the North Somerset and South Bristol REC sent a letter dated May 1, 2007. Here’s the operative phrasing from this letter: “Members [of the REC] considered this project to be service evaluation. Therefore it does not require ethical review by a NHS Research Ethics Committee or approval from the NHS R&D office.”

The 2007 REC letter referred to “this project”—i.e., the expanded schedule of pediatric assessments at the Bath CFS/ME clinical service. It did not present itself as a precedent for avoiding ethical review for future, as-yet-undescribed projects. Yet that is how members of the Bristol team of investigators seem to have used it.

Besides the school absence study, here are the other papers (in no particular order) that have cited this 2007 REC letter to claim exemption from ethical review:


Some of these studies involved data from adults, so it is hard to understand why they would be considered exempt from ethical review based on an REC letter related to routine pediatric questionnaires. Five of the exempted studies were published in BMJ journals—three in Archives of Disease in Childhood and two in BMJ Open, including the school absence study. This doesn’t surprise me. For almost a year, I have been criticizing both journals for lax oversight.

In the case of Archives of Disease in Childhood, our ongoing discussion involves an unrelated study from members of the same team of investigators—a trial of the Lightning Process as a pediatric treatment for children with chronic fatigue syndrome. This trial violated BMJ’s strict policy on prospective registration but is still in the literature. In the case of BMJ Open, the issue has been the school absence study and its lack of ethical review. That study helped trigger my interest in how the same 2007 REC letter was used to exempt other research from ethical review.


Besides the BMJ Open school absence paper, BMJ published four more studies that specifically cited the 2007 REC letter. None seem to meet the criteria for service evaluation of pediatric care.

The second BMJ Open paper on the list involved data from adults as well as children and included this explanation of the finding of the 2007 REC letter: “The North Somerset and South Bristol Research Ethics Committee decided that collection and analysis of CFS/ME patient data constituted service evaluation and did not require ethical review by a NHS Research Ethics Committee or approval by NHS Research and Development offices.”

This expansive reading of the 2007 REC letter would seem to go beyond the meaning and intent of the letter’s finding that “this project”—the collection of specific pediatric data for a longitudinal cohort study–qualified as “service evaluation.” Ethics declarations from other papers in the group use similarly broad terms in describing the 2007 REC letter to exempt themselves from ethical review on the grounds of service evaluation.

The three studies published in Archives of Disease in Childhood and exempted from ethical review on service evaluation grounds do not seem to have focused on the evaluation of pediatric services. Instead, they presented generalizable conclusions about children with the illness.

One of the studies concluded this, for example: “Depression is commonly comorbid with CFS/ME, much more common than in the general population, and is associated with markers of disease severity. It is important to screen for, identify and treat depression in this population.” Studies with generalizable conclusions are normally categorized as “research” and require ethical review.

It is unclear why a narrowly written 2007 REC letter about a particular pediatric research project at one clinical service seems to have been treated as something of an invitation to bypass ethical review in a range of pediatric and adult studies. Bristol University should assess whether each study in this group was or was not appropriately exempted from ethical review based on the finding from the 2007 REC letter. The university should also determine whether members of its faculty commonly use this method to exempt their studies from ethical review.

For its part, BMJ has an independent responsibility to explain why it published multiple studies that exempted themselves from ethical review on questionable grounds, all citing the same 2007 REC letter. Editors need to ask themselves some tough questions. Here are a few:

*What lapses in procedures for assessing and reviewing manuscripts might have allowed these studies to slip through? What red flags were missed?

*What is current policy about fact-checking ethics declarations, especially when they are used to exempt studies from ethical review?

*In the case of the 2011 school absence study, the abstract itself provides sufficient evidence to determine that this was “research” requiring ethical review and not “service evaluation.” Why doesn’t BMJ Open apologize for making an error in judgement and address the issue honestly?

*What steps can BMJ take to prevent such potential embarrassments in the future and to bolster public confidence in the integrity of its editorial decision-making?

The TWiVomers review a potential role for herpes simplex virus type 1 as a cause of Alzheimer’s Disease, including the finding that amyloid-beta acts as an antiviral by enveloping virus particles.

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herpesvirusAlois Alzheimer was the first to propose that an infection might play a role in the disease named after him. Herpes simplex virus type 1 (HSV-1) has been most frequently linked to Alzheimer’s Disease (AD), and a clinical trial is in progress to determine if antivirals ameliorate its development. What is the evidence that HSV-1 is involved in AD?

[continue reading…]

By David Tuller, DrPH

Below is an exchange between members of the Australian ME/CFS community and Professor Michael Sharpe. The open letter from patients and advocates was prompted by a tweet this week from Professor Sharpe that many considered offensive. He has since deleted it. This post includes the initial tweet as well as the open letter and Professor Sharpe’s response.


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By David Tuller, DrPH

This morning I sent the following letter to Fiona Godlee, editor-in-chief of The BMJ and editorial director of BMJ. I cc-d Carol Monaghan MP, Darren Jones MP, and Nicky Morgan MP.


[continue reading…]

hershey virus

Vincent travels to Penn State College of Medicine in Hershey, PA to speak with Nick Buchkovich and Leslie Parent about their careers and their work on human cytomegalovirus and retroviruses.

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Viral Defenses In Plantae


Tobacco mosaic virus-infected tobacco leaf. Image credit: Principles of Virology, 4th Edition, ASM Press.

By Gertrud U. Rey

Post-transcriptional gene silencing (PTGS) is an RNA regulation pathway in eukaryotes that depends on the presence of double stranded RNA (dsRNA) in the cytoplasm of cells. As stated by Nels Elde in TWiEVO 8, dsRNA in the cytoplasm has an effect synonymous to “blood in the water” for the innate immune system, triggering a cascade of events that leads to the degradation of complementary mRNAs. In plants, this pathway has been thought to serve as the predominant mechanism of antiviral defense.

[continue reading…]

Brianne and Vincent tackle two studies that utilize infectious viruses to examine zoonotic potential of Bombali virus, a new ebolavirus from an insectivorous species in Sierra Leone, and a human mumps-like virus from an African flying fox in DRC.

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