Could ancient host proteins contribute to the replication of a modern virus? The answer is, not very well (link to paper).

Viruses are obligate intracellular parasites, which means that they have to get inside of a host cell to produce more viruses. The genomes of all viruses, even the biggest ones, do not encode anywhere near the number of proteins that are needed to replicate. The cell provides thousands of proteins that are involved in energy production, membrane synthesis, protein synthesis, transport, and so much more.

The difficulty in studying ancient proteins is that none of them exist. But we can make good guesses about what very old proteins might look like, by examining modern proteins, seeing how they vary among organisms, and calculating how they might look like billions of years ago. The field of predicting what ancient proteins might look like is quite active.

Investigators have predicted what ancient versions of a cell protein called thioredoxin might have looked like. They have synthesized such ‘ancient’ thioredoxins and shown that they are stable and active. Thioredoxins are found in nearly all organisms, where they act as antioxidants.

Ancient thioredoxins that have been synthesized include those from the last common ancestors of bacteria; of archaea; and of archaea and eukaryotes (all around 4 billion years old); the last common anestor of cyanobacterial, deinococcus, and thermus groups (about 2.5 billion years old);  the last common ancestor of gamma-proteobacteria; of eukaryotes; and of fungi and animals (around 1.5 billion years old).

These ancient thioredoxins work in a modern E. coli. This bacterium has two thioredoxin genes, and if they are both deleted, growth occurs, but very slowly. If genes encoding ancient thioredoxins are introduced into these mutated bacteria, they can compensate for the growth deficiency. The older thioredoxins (4 billion years) compensate less well than ones that are closer in time (1.5 billion years).

It’s amazing that an ancient protein can work in a modern E. coli. But could ancient thioredoxins support viral growth?

Thioredoxin from E. coli is an essential part of the DNA polymerase complex of the bacteriophage T7 (pictured – image credit). This virus does not form plaques on E. coli lacking the two thioredoxin genes. The only ancient thioredoxin gene that allows phage T7 plaque formation is from the last common ancestor of cyanobacterial, deinococcus, and thermus groups, which is about 2.5 billion years old and has 57% amino acid identity with the E. coli enzyme. But the effienciency of plaque formation was very poor – about 100 million times worse than on regular  E. coli. None of the older thioredoxins worked.

Why would an ancient thioredoxin work for E. coli but not for bacteriophage T7? Over billions of years, thioredoxin evolves but it must still be able to carry out its function for E. coli. The viruses that infected bacteria 4 billion years ago were very different from contemporary viruses, and so the ancient thioredoxin does not work for modern viruses. Today’s thioredoxin could change so that it would not support T7 replication – as long as the enzyme still works for E. coli.

The authors of this work view it as a proof of principle: that virus growth is not supported by an ancient version of a modern protein required for virus replication. They would like to apply this approach to produce plants that are resistant to viruses, which have serious effects on global agricultural productivity.

I think the work is amazing not only because an ancient protein can be made, but it supports growth of the host and not that of a virus. It might therefore be possible to reconstruct the host-virus arms race, starting from ancient proteins. In this race, the gene encoding an essential cell protein can evolve so that it no longer supports virus replication. Next, the viral genome changes to adapt to the altered cell protein. And so the game goes back and forth.

The authors have shown that they can select mutant bacteriophage T7 isolates that replicate in the present of an ancient thioredoxin. This result suggests that it might be possible to reconstruct host-virus arms races beginning with an ancestral host protein. If we can make an ancient protein, could we also make an ancient virus? Why not?

By David Tuller, DrPH

This month, the U.K. organization currently assessing whether to update the clinical guidelines for the illness it calls CFS/ME is seeking input from “stakeholders” in the process. Unfortunately, that’s not good news—it’s bad news.

Why? The National Institute for Health and Care Excellence, or NICE, is an independent body that operates under the sponsorship of the U.K. Department of Health and establishes guidelines for clinical practice. NICE created its current guidelines for CFS/ME, called CG53, in 2007. These were heavily influenced by the cognitive behavior therapy/graded exercise therapy (CBT/GET) paradigm, which was already dominant in Britain before the first PACE results were reported in The Lancet in 2011.

NICE is in the process of reviewing whether it should take a fresh look and update CG53. The guidelines cover a range of areas, including clinical presentation and diagnosis as well as management strategies. The organization has asked those who have registered as stakeholders, such as advocacy groups, to submit comments between July 10th and July 24th.

But in a recent exchange of e-mails with NICE, the ME Association clarified that the request for stakeholder input means the organization has already reached a preliminary decision that no revisions to the 2007 guidelines are necessary at this time. The two-week comment period therefore offers, at best, a formal opportunity to change the minds of people who have already indicated that their minds are made up. Since the available evidence has not yet persuaded them that recent events have rendered obsolete the old recommendations for CBT and GET, stakeholders have an enormous challenge in seeking to effect any change in their perspective.

The NICE solicitation of input from stakeholders comes right as the U.S. Centers for Disease Control has suddenly stopped recommending CBT and GET for what it calls ME/CFS. In early July, mention of the two treatments vanished from the CDC website. The website still suffers from multiple issues; the agency says more changes are forthcoming. But the removal itself should signal to NICE that the tide has shifted against both the CBT/GET ideology and the science purportedly proving that these treatments are effective. A decision to ratify the current NICE guidelines, as if nothing has changed since they were promulgated, will be greeted with dismay from many in the international scientific community.

What is obvious, but what NICE appears to overlook, is that the CBT/GET literature is plagued by two overarching flaws. The first is that these are mostly open-label trials with subjective outcomes—a study design rejected in other fields of medicine because it is so prone to bias. The second is that many of the studies, especially older ones, rely on the use of the Oxford criteria or other broad case definitions that yield heterogeneous samples because they conflate chronic fatigue and chronic fatigue syndrome. These studies simply cannot provide credible evidence about treatments for the specific disease that patients prefer to call ME. (PACE, of course, suffers from many other flaws besides these two.)

Some have argued that it is better to be able to provide patients with some recommendations rather than none. It is therefore important to stress that a recommendation should not be kept just because there are no better recommendations to make. If a recommendation is based on results from studies that promote bias, or on results that have been inflated through outcome-switching or have been derived from heterogeneous samples or are inaccurate for other reasons, then the recommendation needs to be rescinded, even if there is not sufficient current evidence to suggest other proven treatment approaches. That is especially the case when patient surveys and biomedical evidence raise concerns that a recommended strategy—in this instance, a steady increase in activity levels–is causing serious harm rather than benefit.

The fact that NICE decided to reconsider the 2007 guidelines this year seemed like a potentially promising development, but it was unclear what new information the agency would consider. For example, would the surveillance review include only reports from clinical trials of therapeutic interventions? Or would it also include findings of physiological abnormalities, most from research produced outside the U.K., which undermine the deconditioning theory that supports use of CBT and GET?

Other questions: Would the review consider the conclusion of the 2015 report from the U.S. Institute of Medicine (now the Academy of Medicine) that “exertion intolerance” was a cardinal symptom, which raises questions about whether GET is contra-indicated? Would it consider that the U.S. Agency for Healthcare Research and Quality found little or no evidence for CBT and GET after removing Oxford criteria studies from its analyses? And would it include the reanalyses of the reported PACE “recovery” and “improvement” findings, which were dramatically boosted by post-hoc outcome changes?

NICE’s “surveillance proposal consultation document” for CG53, recently posted on its website, provides answers to many of the questions. This 56-page report offers details about the NICE surveillance review and the reasons for the agency’s provisional decision not to change the guidelines. The review was apparently conducted by a NICE “surveillance team” with input from an unidentified number of unidentified “topic experts.” (I have filed a freedom-of-information request with NICE for the names of the experts it consulted. NICE has 20 working days to respond. The ME Association is also seeking the names, and the Countess of Mar has asked the Department of Health for the same information.)

The consultation document indicates that the surveillance team and topic experts did in fact take notice of the recent controversies and the new literature, including the reanalyses, before concluding that the guidelines should remain the same. The document noted that some upcoming research could impact the guidelines down the line, and identified specifically a study of online CBT for kids—an apparent reference to FITNET-NHS. This study exemplifies some of the problems common in this field of research, as I described on Virology Blog months ago. (Professor Esther Crawley of Bristol University, the trial’s lead investigator, subsequently referred to that blog post as “libelous” in a slide she showed during at least two speeches. She has not documented her charge.)

The consultation document also notes that only study abstracts, not the studies themselves, were reviewed. This is a surprising methodological choice given the significance of the issue. Abstracts can be seriously misleading and incomplete; studies themselves obviously provide a much more authoritative and nuanced picture. It does not seem too much to expect that those responsible for establishing enormously influential clinical guidelines should have taken the time to examine the actual research on which they were basing their recommendations. To learn that they did not is rather shocking.

In response to the controversy over the PACE trial, the document notes more than once that the investigators themselves have responded to criticisms, citing the FAQ on the trial website and other publications. The surveillance team appears to accept these responses at face value–as thorough and honest explanations. Perhaps no one has examined them closely enough to realize how empty and full of half-truths they are. The PACE investigators have certainly tried to defend their work. But there are no reasonable answers to many of the concerns, so their responses to date have only satisfied their ideological companions and those who know little about the debate.

The consultation document contains some troubling inaccuracies in its discussion of the PACE trial. For example, it reports that “the PACE authors note that…changed thresholds for recovery were pre-specified.” But it is simply false to call the revised thresholds “pre-specified.” The recovery thresholds for physical function and fatigue—two of the four recovery criteria in the 2013 paper published in Psychological Medicine–were the same as the “normal range” thresholds included in the 2011 Lancet paper. In that earlier paper, these thresholds were presented as part of post-hoc analyses, so it is hard to understand how the same thresholds could also be “pre-specified” under any standard definition of the term.

Besides that, all four recovery criteria were weakened, so it was self-evident that each change, whether pre-specified or not, would boost the numbers that the investigators could report had achieved “recovery.” Moreover, the 2013 paper does not cite any oversight committee approval for the major changes to the “recovery” definition–an oversight that should have raised alarm bells for Psychological Medicine. (Since the NICE surveillance team only reviewed abstracts and not actual papers, it would not have noticed this unusual lack of oversight committee approval.) And the consultation document fails to mention the fact that 13 percent of the PACE participants were already “recovered” for physical function at entry—an anomaly that should have prevented publication.

In another inaccurate (or at least highly disingenuous) statement, the consultation document notes that the investigators “have re-analysed the main outcome measures according to the original protocol with similar results to those in the primary PACE results paper i.e. reduced fatigue and increased physical function.” But it is stretching the truth beyond recognition to claim that the results of the reanalysis were “similar.” In the 2011 Lancet paper, the investigators reported that around 60 percent “improved” with CBT and GET; in the 2016 reanalysis, which used the original PACE protocol’s definition of “improvement,” the figure fell to around 20 percent.

Proponents of PACE have cited the 60 percent improvement rate as evidence of the effectiveness of CBT and GET. So a two-thirds decline in improvement rates should change any reasonable observer’s assessment of the effectiveness of the interventions. For NICE to accept the PACE investigators’ argument that this dramatic drop represents “similar results”–presumably because they were still able to report some very modest “improvement”–suggests that the surveillance team and topic experts are assessing the data with preformed opinions.

The topic experts seem to have enabled some of the NICE surveillance team’s own poor instincts. For example, after noting concerns raised about the Oxford criteria, the consultation document dismisses the significance of the issue this way:

“Trials using Oxford criteria were eligible when developing NICE guideline CG53, and topic experts had no concerns about the inclusion criteria of trials in CFS. It was also noted by topic experts that there is no gold standard definition of chronic fatigue syndrome. There is currently insufficient consistent evidence about diagnostic methods for CFS/ME to determine an impact on the guideline recommendations.”

Hm. So they used these studies the first time around ten years ago, and therefore it must be okay to use them again; something about that logic escapes me. And the topic experts expressed “no concerns,” shrugging off the case definition problem because there is “no gold standard.” But this thorny issue is at the core of the current controversy, and failure to address it is not a viable option. Scientists outside the influence of the CBT/GET ideological brigades understand very well that the populations generated with the Oxford criteria cannot yield actionable findings about an illness that should be defined much more specifically.

The consultation document also states that NICE will encourage Cochrane to update a 2008 review of CBT so that it can include the reported results from the PACE trial. “A further review of the guideline may be considered following publication of the updated Cochrane review,” stated the document. In other words, the NICE surveillance team is not only not deterred from considering the PACE results but is taking steps that would amplify their impact on the recommendations.

In fact, by citing Cochrane’s reviews as key evidence to support keeping the guidelines in place, the consultation document highlights the major role of these analyses in bolstering the entire CBT/GET enterprise. Cochrane takes the same problematic approach to assessing studies as NICE, accepting the results of open-label trials with subjective outcomes even though these are known to suffer from serious bias. In addition, Oxford criteria studies dominate the Cochrane reviews. In short, the body of research being used by both Cochrane and NICE, including but not limited to PACE, suffers from fundamental flaws. (Perhaps if Cochrane removed responsibility for the illness from the “common mental disorders group,” where it doesn’t belong, a new set of reviewers would demand higher-quality evidence.)

The provisional decision to not revise the guidelines at present has alarmed patients and advocates. The ME Association has launched an online petition, which notes that the intention is “to offer the patient community the chance to demonstrate to NICE just how unhappy it is with the current guideline.” The petition states:

“As stakeholders, the ME Association believes that the current guideline is not fit for purpose and that we are not being afforded a fair opportunity to help produce a better version.

We believe the guideline should be improved to reflect international biomedical research and medical opinion and the overwhelming evidence against current treatment recommendations – specifically in relation to graded exercise therapy.

We also feel recent re-analysis of PACE Trial data and growing international concern about the efficacy of this research, and those therapies it examined, should result in a reappraisal of their use in this guideline.”

The petition’s specific demands include, among others, a “complete and proper review” of the current guidelines, recognition of CFS/ME as a neurological disease in accordance with UK health agencies, removal of the GET recommendation in particular, and the highlighting of pacing as a strategy widely used by patients. The ME Association petition has so far collected more than 11,600 signatures.

NICE will presumably consider the stakeholder input before making its final decision. I guess the topic experts will also be given another chance to weigh in. I hope there’s a real chance to change the outcome.

**********

The CDC (Sort of) Explains

I sent the CDC a few questions last week after the agency had removed CBT and GET from its web pages, among other changes. I wanted to know what had prompted the changes, whether the removal of CBT and GET constituted an acknowledgement that there was no reliable evidence to support recommending the therapies, and whether the agency would apologize for having gotten it wrong. I also asked if the CDC would actively disseminate information about the changes.

Here’s what I heard back:

Dear Dr. Tuller,

Thank you for your interest in CDC’s recently updated ME/CFS web pages.

Thanks again for your continued interest in this important public health topic.

This statement from the CDC is disappointing. The agency apparently does not plan to make a public announcement at this time that it has dropped CBT and GET, even though these therapies remain widely prescribed in the U.S. The agency will also not acknowledge that there is little or no credible evidence to support the treatments, and that it was wrong to recommend them for so long. The most it will concede is that “there has been confusion about what we recommend related to exercise and therapy.”

This is nonsense. Patients and advocates did not complain about the CDC website because they didn’t understand what it was recommending. They complained because it specifically recommended GET and CBT, citing PACE. After removing references to PACE from the website, the agency then claimed that CBT and GET were generic management strategies, unrelated to PACE. This claim was untrue. What other illness is GET recommended for? In what other illness is CBT supposed to alleviate you of the misguided belief that you have the illness in the first place?

Until early July, that is where things stood. Now the CDC seems to want to pretend it was all a big misunderstanding. To be clear: Patients are not against activity or exercise per se. They recognize that people with the illness should move their bodies to the extent they can without over-exerting themselves; that is a basic concept behind the self-management strategy called pacing. It is the “graded” aspect that patients find alarming—the idea that activity levels need to be steadily increased to reverse the deconditioning that is wrongly hypothesized as causing the symptoms. Similarly, patients are not against psychotherapy as a tool for coping with the demands and stresses they confront. They are against the specific form of CBT that has been created to treat their illness.

So patients were never confused by what the CDC’s recommendations meant. They understood that the recommendations meant the CDC bought into the CBT/GET paradigm, despite the PACE trial’s glaring flaws. In maintaining that it made the changes to prevent “confusion,” the CDC is weaseling out of admitting the obvious–the country’s top public health officials got this one wrong for years. The PACE trial–the crown jewel of CBT/GET research–has been authoritatively discredited. But the CDC won’t say so.

CBT and GET have been the de facto standards of care for this illness in the U.S. A major reason is that the CDC endorsed the therapies. Now the agency has abruptly un-endorsed them. That’s a big, big deal, not a minor tweak. For the sake of public health awareness and understanding, CDC officials have an obligation to provide a direct, transparent, and credible account of why they made these major changes. The statement I received from them does not demonstrate those qualities.

Ben tenOever joins the TWiVoli to discuss the evolution of RNA interference and his lab’s finding that RNAse III nucleases, needed for the maturation of cellular RNAs, are an ancient antiviral RNA recognition platform in all domains of life.

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I just love it when long standing mysteries in virology are suddenly solved, typically by the use of new technologies. In this story, the long standing mystery was why poxvirus mRNAs have a stretch of poly(A) in their 5′-noncoding regions. The answer is that it allows the ribosome to preferentially translate these viral mRNAs over those of the host (link to paper).

Ribosomes, the sites of protein synthesis, are very large assemblies of RNAs and proteins. A ribosome-associated protein called RACK1 is the major player in this story. This protein was previously found to be important for translation of viral RNAs by internal ribosome entry, a process in which ribosomes bypass the 5′-cap structure on mRNAs.

Cells lacking the gene encoding RACK1 seem to be just fine – they grow normally. This result would suggest that RACK1 is not needed for translation of mRNAs via the 5′-cap structure. But the translation of mRNAs of vaccinia virus, a poxvirus, is blocked in cells lacking RACK1. More specifically, the viral mRNAs produced later in infection cannot be translated.

This effect of RACK1 on vaccinia virus mRNA translation prompted a closer look at the protein in virus infected cells – which revealed that it is phosphorylated by a viral protein kinase. Phosphorylation of RACK1 makes the ribosomes preferentially translate vaccina virus mRNAs – an effect that is completely dependent upon the poly(A) in the 5′-untranslated region! Transfer of this poly(A) sequence to a non-viral mRNA enhanced its translation in cells in which RACK1 is phosphorylated.

The amino acid sequence of RACK1 that is phosphorylated is within a loop that contacts the 18S ribosomal RNA subunit. An examination of RACK1 proteins from different species reveals that in plants, unlike in mammals, this loop contains a stretch of negatively charged amino acids. Because a phosphate is negatively charged, it made perfect sense to see if the plant loop sequence, when transferred to mammalian RACK1, could stimulate translation of poly(A) containing mRNAs. It did!

In other words, phosphorylation by a vaccinia virus protein kinase makes RACK1 plant-like! Which is why the authors called their paper ‘Trans-kingdom mimicry underlies ribosome customization by a poxvirus kinase”. Exactly what RACK1 protein is doing in plants is a burning question, as is how RACK1 recognizes mRNAs containing a poly(A) leader.

Phosphorylation of RACK1 by the vaccinia virus kinase explains why viral mRNAs with poly(A) leader sequences are preferentially translated in infected cells (late viral mRNAs have this unusual leader). The presence of poly(A) in the 5′-ends of late vaccinia virus mRNAs is considered to be a consequence of polymerase slippage – but it is clearly not a mistake. At one time, long ago, a polymerase might have slipped for the first time, but the resulting poly(A) in the mRNA conveyed a selective advantage that remained. Today I would no longer call the addition of poly(A) to vaccinia virus mRNAs an error!

Why did it take so long to figure out the role of poly(A) at the 5’-end of vaccinia virus mRNAs? The right technology was not available – the key ones were the ability to knock out specific genes in cells, to knock down mRNA levels with RNA interference, and to identify the sites of RACK1 phosphorylation by mass spectrometry. These are not only recently developed techniques, but they have become widely accessible. But don’t forget the use of long-ago isolated vaccinia virus mutants of the protein kinase that were an essential part of this story.

Rich Condit, a poxvirologist, joined Nels Elde (also a poxvirologist, though he dabbles in other systems) and me to discuss this very cool paper on episode #21 of TWiEVO, This Week in Evolution. Rich had some very good insight on this paper; plus he bristled twice during the episode. You’ll have to listen to find out why.

Image credit.

By David Tuller, DrPH

This is the beginning of a new phase for “Trial by Error.” I initially assumed that my work on PACE and ME/CFS (or ME, or CFS/ME, or CFS) would be a one-off investigation, and then I’d move on to other projects. But after my 15,000-word series was posted on Virology Blog in October of 2015, the story kept going and going. I couldn’t stop myself—there was always more to write about. But it was all very complicated and I didn’t know where it would lead.

And then the issue gained traction and momentum, especially after the release last year of the trial data, which revealed how much the investigators had inflated their findings by relaxing their outcome measures. The data release itself occurred thanks to the heroic efforts of Australian patient Alem Matthees, who doggedly pursued his freedom-of-information request and defeated Queen Mary University of London’s high-powered legal team. Despite this success, there’s still more work to do, and I’m glad to have the opportunity to pursue the issue further. I owe that opportunity to all the amazing contributors to the crowdfunding campaign, and to the support of Professor Vincent Racaniello, the host of Virology Blog, and my colleagues at the School of Public Health at the University of California, Berkeley.

Going forward, I will drop the word “Continued” from the headline of this series and just use “Trial by Error.” I decided to keep “Trial by Error” because, well, I really like the name. And I think it accurately describes both the PACE trial specifically and the larger effort to impose the CBT/GET paradigm on this patient population. I have relied on my friends Valerie Eliot Smith and Robin Callender Smith for their legal insight throughout this effort, but I also need to thank them again for suggesting this perfect title two years ago.

Other than that, I expect things will more or less continue as before–some investigating/blogging on Virology Blog, some writing for other publications, some orchestration of open letters from academics, some use of social media, etc. Overall, the project should cover about half my work time. I have previously mentioned some things I want or plan to examine. Unforeseen topics will also emerge, of course—before Esther Crawley libeled me, who knew I’d write multiple blogs about her unscholarly behavior?

I won’t manage to do everything, but I hope to get enough done to help further blunt the authority and credibility of the CBT/GET ideological crusaders. Their position has been considerably weakened, given the willingness of many in the international scientific community to criticize the PACE study’s conduct and methodology. Yet the PACE investigators still present themselves as victims of an organized campaign of anti-science zealots, as Professor Michael Sharpe implied recently in his abstract for an “ethics” talk at Oxford. (Professor Sharpe’s position was artfully deconstructed last week on Virology Blog by Northwestern University law professor Steven Lubet.)

I can understand why the PACE investigators might have trouble acknowledging that the theory to which they have devoted decades of their lives has been undermined by the evidence of their own highly promoted trial. But the dereliction of editorial responsibility by The Lancet and other prestige journals, which have enabled the PACE/CBT/GET charade by publishing poor-quality work, is perhaps even more disturbing. It is not surprising that The Lancet has just published another flawed study from this school of research, a trial of self-help graded exercise for what the researchers still call “chronic fatigue syndrome.” In effect, The Lancet was doubling-down on its defense of PACE.

The Lancet editor, Richard Horton, has invested his reputation in the proposition that the PACE trial was methodologically sound and that the critics were not only wrong and irrational but were in fact harming the scientific enterprise. Yet he has also recently positioned himself as a high-profile scourge of poor-quality science. Given that, his refusal to acknowledge the flaws with the PACE/CBT/GET approach promoted by his journal represents enormous hypocrisy or a great talent for self-delusion.

In fact, The Lancet’s publication of the self-help graded exercise paper has occurred as the CBT/GET paradigm continues to lose ground elsewhere. Early this month, the Centers for Disease Control revised its website for the illness, in the process eliminating recommendations for these therapies (more on that below). In contrast, Dr. Horton and his journal remain mired in this swamp of bad science. So does the rest of the U.K. academic and medical establishment.

**********

Just as The Lancet has published more “evidence” for graded exercise, the CDC has moved decisively in the opposite direction. In revamping the information on the part of its website geared toward the general public, the agency has “disappeared” all mention of CBT and GET as treatment or management strategies. Patients and advocates have long pushed for this step, as did Julie Rehmeyer and I in a New York Times opinion piece in March. Although the revised text is dated as having been reviewed on May 30th, it apparently went live sometime during the first week of July. (The CDC has still not revised the pages designed for health care providers, although old information has been removed. The agency calls the illness ME/CFS.)

For advocates, the CDC’s removal of the CBT/GET recommendations represents a major victory. “I think it’s huge,” said Mary Dimmock, an advocate who has long pressured the CDC to revise its website. Given the agency’s stature, she added, the decision could have widespread impact, not just in the U.S. but internationally as well. Many health care providers and institutions here and abroad look to the CDC for guidance in public health matters.

“So many patients have been made worse by the treatments,” said Dimmock, who became an advocate after her son became seriously ill several years ago. “While there is more to be done, removing these recommendations is a significant step forward in protecting ME patients from harm.”

In the revision, the CDC website has dropped the agency’s 1994 definition of the illness. The new definition, based on the one proposed in a 2015 report from the Institute of Medicine (now the Academy of Medicine), requires the presence of “post-exertional malaise.” In the 1994 definition, that was only one of eight optional symptoms. The immediate implication of the shift is that GET should likely be considered contraindicated, given the premium this intervention places on steadily boosting activity levels. The form of CBT prescribed in PACE could also be contraindicated, since the ultimate goal of that intervention is likewise to increase activity. (The CDC has not adopted the name proposed by the IOM report, “systemic exertion intolerance disease.”)

In addition to symptomatic relief, the revised CDC website suggests such management strategies as a balanced diet, nutritional supplements and complementary medicine. Here’s some of the new language on managing the illness that has displaced the previous sections on GET and CBT:

*Avoiding ‘push-and-crash’ cycles through carefully managing activity. “Push-and-crash” cycles are when someone with ME/CFS is having a good day and tries to push to do more than they would normally attempt (do too much, crash, rest, start to feel a little better, do too much once again). This can then lead to a “crash” (worsening of ME/CFS symptoms). Finding ways to make activities easier may be helpful, like sitting while doing the laundry or showering, taking frequent breaks, and dividing large tasks into smaller steps.

*Talking with a therapist to help find strategies to cope with the illness and its impact on daily life and relationships.

Of course, avoiding “push-and-crash” is what patients already do when they practice pacing. The “push-and-crash” language itself appears to be closely aligned with the arguments provided by the PACE investigators and their colleagues; many patients might describe their experiences differently. Nevertheless, removing the CBT/GET recommendations is a welcome step, if overdue. For years, patients and advocates pointed out the problems with PACE and related research, and also cited the evidence that too much exertion caused harm because of physiological abnormalities, not the deconditioning presumed by CBT and GET. But until now, the agency refused to make the necessary changes.

The CDC’s longtime promotion of these therapies has had a widespread negative impact, as I reported at length last fall in the MIT-based online magazine Undark. So it is not enough now to merely tweak the website quietly. The agency should publicly announce the changes and explain the reasons for making them. By removing CBT and GET, the CDC is conceding the truth of what patients and advocates have repeatedly told them—the evidence does not support recommending these therapies for this illness, either as treatments or as generic management strategies. Agency officials should now apologize for having gotten it so wrong and for having failed to address these legitimate and often-expressed concerns.

Many U.S. health care organizations continue to recommend CBT and graded exercise for ME/CFS, in part or in whole because of the CDC’s guidance. This approach still causes many patients to suffer serious and permanent deterioration along with the stigma and blame that come with the illness, said Mary Dimmock. She hopes CDC officials will now strongly promote awareness of the changed recommendations not just among the public but specifically among medical societies, medical education providers, state health commissioners and others involved in health care delivery.

“I want them to take a leadership position to disseminate this information proactively,” said Dimmock. “They have a responsibility to reach out and fix this problem.”

The CDC has another urgent obligation: To communicate with the U.K.’s National Institute for Health and Care Excellence, which develops clinical guidelines for various medical conditions. NICE is currently debating whether or not its recommendations for the illness—which it calls CFS/ME–need to be reviewed; of course, these recommendations include CBT and GET as indicated treatments. NICE is soliciting input this month from stakeholders, but the expert panel assessing the situation has apparently made a provisional decision that no review is required.

The CDC has a long history of collaborating with key members of the PACE team and others in the U.K. medical and public health establishments; it is not surprising that prescribing CBT and/or GET should have become standards of care in both countries. It is now incumbent on U.S. public health officials to alert their British colleagues, including those at NICE, that they have just abandoned these longstanding recommendations. They should also explain why they have taken that major step, and why NICE should consider doing the same. (More on the NICE guidelines later this week.)

The TWiV Council explores the finding that facial appearance affects science communication, and evidence that RNA interference confers antiviral immunity in mammalian cells.

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Wired Magazine recently published an article with a headline distinctly opposite of mine, which claims that the traditional lecture is dead. I disagree, and here is why.

The thesis of the article, by Rhett Allain, is that modern technologies have made the traditional lecture obsolete. The traditional lecture is one during which a teacher stands at the front of the room and ‘disseminates knowledge to students’. Allain claims – rightly so – that animated videos like The Mechanical Universe are far more engaging. He suggests that, to teach physics, just show the students episodes from this show. If they have questions, just pause the show.

He claims that showing these videos – or equivalents for other subjects – beats most lectures. Lectures in which teachers drone on and on.

Well guess what – I teach a virology course at Columbia University, and at the end of the year, most of the students say its one of the best, or the best class they have taken in their college years. I don’t show The Viral Universe or any other videos during my class. I talk to the students about my knowledge of viruses, gained from researching them for over 30 years.

Not every virology lecturer has my experience in the field. Many of them learn virology from a book. I agree that lectures given by those individuals are dead.

I do record each lecture and post them at YouTube, so that the students in the class, or anyone in the world for that matter, can watch them. It’s a new technology that Allain likes. I like allowing the students to time-shift their learning: some never come to class. But it’s still me making the videos and sharing my knowledge via a traditional lecture format.

Allain is also fond of the flipped classroom – assign a video for students to watch before class, and then use class time to discuss it. I love this idea. But I still think that for my introductory virology class, it’s better for me to talk to them. To walk around the room, without notes, look them in the eye, and muster all my passion and love for the field and send it their way. And don’t think that doesn’t matter – many of my students tell me that my passion for the subject is what makes them interested in viruses.

Research says that most students learn better by doing. I do pause a few times during each lecture to have students complete an online quiz – something Allain also likes. It gives me time to see if what I’m saying is sinking in, and to clarify complex material.

When I lecture, students come to me afterwards with questions, and some even walk with me to the subway, to talk about viruses. How can a video provide that experience?

Allain’s response might be that if anyone wants to teach a virology course, just play my lectures and discuss them in class. I’m all for that. But every spring semester, I’ll be in front of the class, talking about viruses, and making new videos. There is no substitute for a expert who is passionate about their subject. I realize that every physics course can’t be taught by Einstein, but he can teach at least one, and the students at his university will love it.

Not every passionate researcher will make a great lecturer, and for them,  videos and flipped classrooms are a great way to teach. But for those passionate researchers who can teach – why not put them in front of a class and inspire the next generation? I do it every year.

by Steven Lubet

On 1 June 2017, Professor Michael Sharpe presented the “Special Ethics Seminar” at Oxford University’s St Cross College. In his posted abstract, he asserted that “some areas of scholarship are politicised (U.K. spelling in original),” including “the role of psychiatric or psychological approaches in the treatment” of ME/CFS patients. Sharpe also likened ME/CFS patients to climate change deniers, claiming:

The use of such co-ordinated pressure group action against science was prominently seen in the field of climate change research but is now emerging in other areas. 

Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME for short) is one of these. 

The analogy is obviously aimed at critics of the PACE trial, of which Professor Sharpe was a principal investigator, but it is inaccurate, unfair, and insulting.  First, of course, there is a nearly universal consensus among scientists about the reality of climate change, supported by many decades’ worth of objective data, which places deniers among extreme outliers who are impervious to evidence. Sharpe’s theory that ME/CFS can be reversed through Cognitive Behavior Therapy and graded exercise, on the other hand, is shared within his own working group and accepted by many in the U.K. medical establishment, but it has been rejected or disregarded by highly credentialed researchers and scientists at major universities in the U.S., including Columbia, Stanford, and the University of California at Berkeley, among others.

More significantly, climate change denial has been backed by powerful political and economic forces – including oil companies and their allies – that have ulterior financial interests in preventing government environmental regulation. Criticism of the PACE trial, for the most part, has originated among patients whose life experience has caused them to question the validity of Sharpe’s approach, but who otherwise have no interest other than the search for an effective treatment. 

To put it starkly, President Donald Trump and the Koch brothers are climate change deniers, who in combination bring both a vast fortune and the power of the entire U.S. government to bear on their side of the issue.  PACE critics are simply sick people, with almost no political clout, who have only logic and experience available to make their case. If not quite a smear, Sharpe’s comparison of the two groups is a prime example of attempted guilt by association, which has no place in a scholarly discussion.

According to Sharpe’s abstract, however, there is nothing less at stake in the PACE controversy than “the future of science” itself. While he allows the possible value of “openness, interconnectedness and the patient voice the internet offers,” he is far more concerned by the threat of “the coordinated harassment of researchers by email, the issuing of repeated and co-ordinated (sic) freedom of information requests and the publication of comment on numerous blogs.”

Here again, Sharpe conflates obviously different phenomena for the apparent purpose of discrediting his critics.  I recognize that some British ME/CFS researchers have been harassed in the past, by email and otherwise, although I have seen no evidence that it was “coordinated” (sinister as the implication may be). Moreover, claims of harassment were evaluated in a U.K. judicial proceeding in which they were found to be “grossly exaggerated.”

In any case, the “repeated” use of freedom of information requests is clearly distinct from harassing emails.  Like it or not, the law in the U.K., and in most democratic countries, requires public access to government documents, including the data underlying publicly funded research studies.  Regarding the PACE trial, this principle was affirmed by decisions from both the Information Commissioner’s Office, which adjudicates freedom-of-information requests, and an appellate tribunal. These decisions forced the release of key PACE trial data, which led to the discovery that the results were overstated and ultimately unreliable. Sharpe may well feel aggrieved by this decision, but his position is not bolstered by associating the information-seekers with “harassment,” accusing them of coordination, or tarring them with the same brush as climate change deniers.

Perhaps Sharpe’s actual presentation explained these points more reasonably than appears from his abstract.  For that reason, I wrote to Sharpe and requested the text of his lecture. Recognizing his concern about email harassment, I assured him that my proposed commentary would be “measured and respectful,” in keeping with my firm commitment to “an academic discourse that maintains standards of civility.” Nonetheless, he did not reply.  Nor have I been able to locate anyone who attended the event, which, unlike previous iterations of the St Cross Special Ethics Seminar, was closed to the public.
 
I attempted to obtain further information about the seminar series – which is sponsored by the philosophy department at St Cross College – and especially the reason for barring the public from Sharpe’s presentation.  I wrote to both a departmental administrator and a professor who is identified on the St Cross website as specializing in “practical ethics,” but I got no answers.

Reading Sharpe’s abstract, it is impossible to miss the irony in a psychiatrist’s concern about the implications of patient protests “for the future of science.” Protesting patients, after all, greatly improved psychiatry when, in 1973, they finally obtained the removal of homosexuality as an officially designated “mental disorder” to be treated with psychotherapy. It took years of sometimes disruptive activism to get mainstream psychiatrists to recognize the tremendous harm they had caused to the gay community, and even then the Diagnostic and Statistical Manual (DSM) continued to include “sexual orientation disturbance” until 1987. Many leading psychiatrists no doubt regarded the protests as harassment or even anti-science, but in fact they were simply pro-humanity.

Having specialized for many years in the study of professional ethics, I would very much like to know how Sharpe characterized the relationship between ethics and the criticism of his work.  As to the future of science, however, I am certain of one thing:  it will not thrive in secrecy.

Steven Lubet is the Williams Memorial Professor at Northwestern University Pritzker School of Law, where he specializes in professional responsibility and ethics. He has previously written about issues related to PACE and ME/CFS at The Faculty Lounge, including here, here, and here.

From ASV 2017 in Madison, Wisconsin, the complete TWiV team speaks with Mavis Agbandje-McKenna about her career and her work solving virus structures by x-ray crystallography and cryo-electron microscopy.

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