By David Tuller, DrPH

Last week I sent an e-mail with some questions to Sir Andrew Dillon, the chief executive of the National Institute for Health and Care Excellence (NICE). In particular, the questions involved the status of the ten-year-old guidance for CFS/ME, CG53, and of references to the illness elsewhere within the NICE system.

A few days ago, I received Sir Andrew’s response. He indicated that the current guidance remains in effect while NICE undergoes the process of developing the updated version. Whether and how much the NICE recommendations actually change in the updated version is apparently up to the new guideline committee.

Here’s what Sir Andrew wrote:

“The current guideline remains in force until it is replaced by the next version. The decision to update was based on the potential for the evidence published since the guideline was introduced, together with the views put forward by stakeholders to change the current recommendations. Whether that potential is realised is a matter for the new guideline committee to decide, as they apply our guideline development methods and undertake consultation with stakeholders. Other NICE guidance which refers to our CFS/ME recommendations will reviewed [sic] and amended if necessary once the new guideline has been published.”

This was the response I expected, more or less, but it was still disappointing. NICE was remiss in the first place to accept Oxford-criteria studies, including the PACE trial, as legitimate science, given their obvious flaws. The agency has since outlined the reasons why the current guidance is not fit for purpose and needs a full update. Now it has an opportunity—and a moral obligation, really–to take a more proactive stance and alert patients to the concerns raised about these potentially harmful treatments.

If these concerns are truly being taken seriously by NICE, how can the agency stand fully behind CG53 in the interim? Can it really be ethical for NHS clinics and doctors to continue to prescribe CBT and GET based on the current guidance without mentioning that these treatments are up for review and have already been dis-endorsed by the U.S. Centers for Disease Control? Who will be liable for any harms arising from the recommendations going forward, now that NICE has acknowledged the problems?

Whether NICE recognizes it or not, the current guidance has already acquired something of a lame-duck status, especially given widespread international rejection of CBT and GET. Any further argument from the CBT/GET ideological brigades that their approach remains the accepted standard of care can now be readily refuted. And that’s bad news for the public and private disability insurance agencies that have long relied on the CBT/GET paradigm to reject legitimate claims for ME/CFS-related benefits.

At Tufts University Dental School in Boston, Vincent speaks with Katya Heldwein and Sean Whelan about their careers and their work on herpesvirus structure and replication of vesicular stomatitis virus.

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Origin of virusesWe have previously discussed the idea that viruses originated from selfish genetic elements such as plasmids and transposons when these nucleic acids acquired structural proteins (see A plasmid on the road to becoming a virus). I want to explore in more detail the idea that the structural proteins of  viruses likely originated from cell proteins (link to paper).

Three ideas have emerged to explain the origin of viruses: 1. viruses evolved first on Earth, before cells, and when cells evolved, the viruses became their genetic parasites; 2. viruses are cells that lost many genes and became intracellular parasites; 3. viruses are collections of genes that escaped from cells. Missing from these hypothesis is how nucleic acids became virus particles – that is, how they acquired structural proteins. It seems likely that viral structural proteins originated from cellular genes.

An analysis of the sequence an structure of major virion proteins has identified likely ancestors in cellular proteins. Following are some examples to illustrate this conclusion.

A very common motif among viral capsid proteins is called the single jelly roll, made up of eight beta strands in two four-stranded sheets. Many cell proteins have jelly role motifs, and some form 60-subunit virus-like particles in cells. The extra sequences at the N-termini of viral jelly roll capsid proteins, involved in recognizing the viral genome, likely evolved after the capture of these proteins from cells.

The core proteins of alphaviruses (think Semliki Forest virus) has structural similarity with chymotrypsin-like serine proteases. The viral core protein retains protease activity, needed for cleavage from a protein precursor.

Retroviral structural proteins also appear to have originated from cell proteins, with clear homologies with matrix, capsid, and nucleocapsid proteins. The matrix Z proteins of arenaviruses are related to cellular RING domain proteins, and the matrix proteins of some negative strand RNA viruses are related to cellular cyclophilin. There are many more examples, providing support for the hypothesis that viruses evolved on multiple instances by recruiting different cell proteins.

Given this information on the origin of viral capsid proteins, we can modify the three hypotheses for the origin of viruses into one. Self-replicating, virus like nucleic acids emerged in the pre-cellular world and from the emerged the first cells. The replicating nucleic acids entered the cells, where they replicated and became genetic parasites. At some point these genetic elements acquired structural proteins from the cells and became bona fide virus particles. As cells evolved, new viruses emerged from them.

It is important to point out that the genes do not always flow from cells to viruses. We know that viral proteins can be returned to cells, where they serve useful functions. One example is syncytin, a retroviral protein used for the construction of the mammalian placenta.

By David Tuller, DrPH

First, for those who might have missed it, here’s a conversation from This Week in Virology (TWiV), posted a few days ago. Dr. Racaniello and I discuss the CDC, NICE, Esther Crawley’s ethically challenged behavior, the CMRC, and other stuff.

Second, earlier today, I sent the following e-mail to Sir Andrew Dillon, the NICE chief executive:

Dear Sir Andrew:

I would like to congratulate NICE on its decision to pursue a full update of CG53, the CFS/ME guidance, rather than accept the surveillance report’s recommendation to leave it as is. The Guidance Executive made the right call, based on the current science—and given the international controversy over PACE trial and other CBT/GET trials. In NICE’s announcement, the list of concerns about the 2007 guidance was a fair accounting of what has troubled people for years and led to the outpouring of stakeholder comments opposed to the initial recommendation.

The decision to pursue a full update leaves some unanswered questions. Given that the new guidance might not be available until 2020, I am hoping you or someone else at NICE can shed light on these issues. The first involves the official status of the current guidance. The second involves references to CFS/ME elsewhere within NICE that do not appear to be aligned with the decision to fully update the guidance.

1) What is the official status now of CG53? Is it considered “provisional” or on stand-by in some way? Or does it remain fully in force? In other words, if National Health Service clinics and doctors claim to be following the “NICE guidance” for CFS/ME, do they also have an obligation to inform patients that the current version has been deemed no longer fit for purpose and is undergoing a “full update”? If these clinics and doctors prescribe CBT and/or GET, citing NICE as evidence and support, do they now have an obligation to explain that the effectiveness of these two treatments is under serious question?

2) The decision to pursue a “full update” suggests that NICE has joined the international scientific community in questioning whether psychological and behavioral approaches are appropriate for this illness—especially given the extensive evidence of physiological dysfunction. Does that mean NICE will reconsider other references to CFS/ME in agency documents? So far, patients and advocates have noted two sets of references to CFS/ME that do not appear to reflect the updated NICE position on CG53 and the illness itself.

One involves a NICE initiative called Improving Access to Psychological Therapies. According to the IAPT site, NICE is working with NHS England on the program. IAPT is designed to “assess digitally enabled therapies for anxiety, depression and medically unexplained symptoms which offer the potential to expand these services further.”

Chronic fatigue syndrome is included in the list of thirteen conditions identified by “the NICE expert IAPT panel” as appropriate targets for interventions developed through this program. The IAPT site indicates that these interventions need to be consistent with NICE guidance. The site then refers readers to CG53 but makes no mention that this guidance is undergoing a full update.

Why is chronic fatigue syndrome still listed under the IAPT program? Does the Guidance Executive agree that it should be removed, since it is not a psychological or psychiatric disorder and the use of CBT and GET is very much under question? If it is not removed from under the auspices of IAPT, does that mean NICE intends to encourage the development of digital methods of delivering CBT and GET to people with CFS/ME, even as the guidance itself undergoes a full update?

Is the Guidance Executive aware that inclusion of CFS/ME in the IAPT program creates enormous concern among patients and advocates specifically because it suggests NICE might adopt or endorse some version of FITNET-NHS? That is the trial in which Professor Esther Crawley is examining the delivery of online CBT to children, based on the purported success of earlier Dutch research. Is the Guidance Executive aware that, as with the PACE trial, critics (including me) have documented serious methodological flaws in both the Dutch FITNET study and Professor Crawley’s own work in this field?

A second set of references to chronic fatigue syndrome is in a recent draft guideline on “suspected neurological conditions”—essentially, a primer on the symptoms and signs that might indicate a neurological condition and trigger a referral to specialist care. NICE published the draft in August and sought stakeholder comments. In its stakeholder submission, Forward ME noted that the draft guideline includes several unfortunate references to chronic fatigue syndrome as being a “functional” symptom or disorder.

As the draft guideline itself explains: “Functional symptoms are complaints that are not primarily explained based on physical or physiological abnormalities. They are likely to have an emotional basis. They may mimic neurological disorders.” The draft guideline suggests, for example, that “concentration difficulties” do not warrant referral to a neurologist if these difficulties are “associated with chronic fatigue syndrome or fibromyalgia.”

Psychiatrists and other adherents of the biopsychosocial field have long classified chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and other conditions involving so-called “medically unexplained symptoms” as functional somatic syndromes or disorders. Given the current effort to revamp the CFS/ME guidance and the significant evidence of actual physiological dysfunctions, does NICE feel comfortable at this point describing the illness elsewhere as a “functional” symptom that is “not primarily” organic in nature but is “likely to have an emotional basis”?

Thank you, Sir Andrew. I look forward to your response. –

Best–David

Truth WinsJonathan Yewdell, Chief of the Cellular Biology Section at the National Institute of Allergy and Infectious Diseases, has written a book entitled Truth Wins: A Practical Guide to Succeeding in Biomedical Research. 

Dr. Yewdell is well known for his presentations about the problems with biomedical science, a subject we discussed on TWiV 208: The Biomedical Research Crisis.

Here are two excerpts from the book:

The joy of making discoveries is the beating heart of a successful scientific career. The power of the scientific method to reveal truths about nature through iterative rational experimentation and interpretation inspired the title of the book.

The book is mostly intended for young people either contemplating a career in biomedical research or those who have already embarked on the journey. I hope that others might find it interesting and useful in understanding how scientists tick and what they do all day.

Truth Wins is free to download in either epub or mobi format.

The TWiViridae review the 2017 Nobel Prizes for cryoEM and circadian rhythms, and discuss modulation of plant virus replication by RNA methylation.

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N6-MethyladenosineChemical modification of RNA by the addition of methyl groups is known to alter gene expression without changing the nucleotide sequence. The addition of a methyl group to adenosine has been found to regulate gene expression of animal viruses, and most recently of plant viruses.

The illustration shows a methyl (CH3-) group added to the nitrogen  that is attached to the #6 carbon of the purine base adenine. The entire molecule, with the ribose, is called N6-methyladenosine (m6A). Methylation of adenosine is carried out by enzymes that bind the RNA in the cell cytoplasm.

The m6A modification is found in multiple RNAs of most eukaryotes. It has also been found in the genome of RNA animal viruses. The modification is added to RNAs by a multi-protein enzyme complex, and is removed by demethylases. Silencing of the methylases decreases HIV-1 replication, while depletion of demethylases has the opposite effect. The replication of other viruses, including hepatitis C virus and Zika virus, is also regulated by m6A modification, but the details differ. For example, m6A negatively affects the replication of the flaviviruses hepatitis C virus and Zika virus.

Methylation of adenosine has been recently shown to modulate the replication of plant viruses. The RNA genomes of alfalfa mosaic virus (AMV) and cucumber mosaic virus (CMV) were found to contain m6A. An m6A demethylase was identified in Arabidopsis thaliana, a small flowering plant commonly used in research. This demethylase protein bound the capsid protein of AMV but not of CMV. Elimination of the demethylase from Arabidopsis reduced the replication of AMV but not CMV. These results show that m6A methylation negatively regulates the replication of AMV. Binding of the AMV capsid protein to the m6A demethylase might be a mechanism for ensuring that the enzyme demethylates viral RNA, allowing for efficient viral replication.

While it is clear that m6A regulates the replication of RNA viruses, the mechanisms involved are not well understood. Methylation of adenosine is likely to affect multiple functions, including the structure, celllular localization, splicing, stability, and translation of viral RNA (link to review). As m6A is also found in cellular RNAs, studies of its effect on viral processes is likely to provide insight into its role in cellular biology.

Vincent speaks with 1993 Nobel Laureate Phillip A. Sharp about his career and his seminal discovery of RNA splicing in mammalian cells, which changed our understanding of gene structure.

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By David Tuller, DrPH

The National Institutes of Health is making a $2.1 million grant to the UK ME/CFS Biobank–a huge endorsement of this important project run by CureME and housed at the London School of Hygiene and Tropical Medicine. Here’s what the ME Association wrote on its website:

“The funding represents the biggest ever single investment in biomedical research to happen in the UK and it will enable a current project, that is searching for disease biomarkers, to be extended for another 4 years – until 2021.

The project is a longitudinal study that is measuring changes in the immune system and genetic profile of individuals in a disease whose symptoms are known to fluctuate over time. The initial £1 million project, which began in 2013, was over 3 years and had also been made possible by funding from NIH.”

The announcement comes a few weeks after the annual conference of the CFS/ME Research Collaborative, which has backed a parallel project called the ME/CFS Epidemiology and Genomics Alliance (MEGA). At the CMRC gathering, the organization’s chair, Professor Stephen Holgate, extolled his colleague, Professor Esther Crawley, for her “amazing” and “stunning” work on MEGA–even as he announced that the project had failed its recent bid for funding from the Medical Research Council.

The MRC rejection followed Wellcome Trust’s rejection of an earlier MEGA application. But this second decision was particularly surprising, given that Professor Holgate himself has longstanding ties with the MRC. An MRC representative also sat on the CMRC’s executive committee. That the agency chose not to fund MEGA was clearly an unwelcome public embarrassment for the CMRC, Professor Holgate and Professor Crawley.

In his remarks, Professor Holgate tried to mitigate the negative impact by promising that MEGA would regroup, learn from the MRC’s comments, and pursue other funding opportunities. In particular, he highlighted the organization’s upcoming meeting with Vicky* [corrected from Vicki] Whittemore of the NIH as an exciting opportunity–raising the expectation that this event might lead to positive developments for the CMRC and its pet project.

Vicky* [corrected from Vicki] Whittemore “has taken a great interest in what this collaborative is doing, and wants to talk to us about how we can…form collaborative initiatives between the National Institutes of Health and the researchers here in UK,” Professor Holgate noted in his remarks. “What shape that might look like and where it goes I don’t know because we haven’t had the conversation yet, but the mere fact that she’s giving up a whole morning to meet with us…is incredibly encouraging, and we’ll let you know how it all goes.”

Now we know how it all went. The NIH is funding the UK ME/CFS Biobank.

Earlier today, I sent the following e-mail to Professor Holgate (and other members of the CMRC executive committee), seeking comment on this exciting new funding development:

“At your opening remarks at the CMRC conference, you mentioned that the group would be meeting soon with Vicki [sic] Whittemore of the National Institutes of Health. You called the prospect of having the meeting and exploring collaborative initiatives ‘incredibly encouraging.’ 

You presumably hoped, when you announced the upcoming meeting, that the NIH would take an interest in the CMRC and MEGA. Since MEGA’s grant applications to two major UK funders–the Wellcome Trust and the Medical Research Council–were both turned down, it makes sense to regroup and seek links with a large overseas funding agency like the NIH. 
 
Given that context, I wonder if you (or anyone on the executive committee) would like to comment on the announcement that the NIH is providing $2.1 million to the UK ME/CFS Biobank, at the London School of Hygiene and Tropical Medicine. That is obviously a huge investment in biomedical research and a major endorsement of the UK ME/CFS Biobank’s vision and leadership. So:
 
Why do you think the NIH chose to provide such substantial support to the UK ME/CFS Biobank? Are you surprised at the NIH decision, or did you learn about it in the meeting that took place after the CMRC conference? Has the NIH given any indication that it might offer CMRC and MEGA similar support in the future? 

And a few more questions: Given the CDC’s recent “dis-endorsement” of the CBT/GET treatment approach to ME/CFS, do you think NIH officials are likely aware of the international uproar over the conduct and findings of the PACE trial and related biopsychosocial research? Do you think US public health officials might be reluctant at this point to fund investigators who are firmly associated with the CBT/GET camp and who declare PACE to be a “great, great” trial? 

Furthermore, do you think US public health officials might be reluctant to fund investigators who believe patients seeking access to public information are “vexatious,” or who publicly advise other researchers how to avoid their obligations under British freedom of information laws? Do you think US public health officials might be reluctant to fund investigators who make false accusations of “libellous blogging,” and then refuse to either provide evidence for the charge or apologize? Do you think they might be reluctant to fund organizations that affirm “full support” for investigators who engage in such behavior? 
          
As before, I have not included Professor Crawley in this e-mail, since I am aware that she considers messages from me unwelcome. However, I would of course be pleased to post any comment from her about this issue. It goes without saying that I would also still welcome any explanation or documentation of her accusation of “libellous blogging.” So please feel free to forward this e-mail to her!”

The TWiVers discuss the declining readability of scientific texts, and review the use of self-inactivating rabies virus for tracing neural circuits.

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