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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By David Tuller, DrPH

Let’s give credit where it’s due. Apparently someone with decision-making authority at the National Institute for Health and Care Excellence (NICE) has a grasp on reality and is willing to challenge the claims of the biopsychosocial ideological brigades. That’s the only logical explanation for last Wednesday’s welcome but unexpected announcement that the agency would pursue a “full update” of the guidance for the illness it calls CFS/ME. From what I gather, that means NICE will essentially start the whole guidance development process from scratch.

In announcing the decision, NICE noted the many concerns stakeholders raised about the existing guidance, which was developed in 2007 and promotes treatment with cognitive behavior therapy (CBT) and graded exercise therapy (GET). At the same time, NICE rejected the recommendation of the internal team to which it had delegated the task of reviewing the literature and producing what was called a surveillance proposal consultation document. That consultation document concluded that no changes should be made to the guidance, After NICE released the consultation document in July, it invited input from stakeholders. The agency had previously indicated that it would announce its decision in October.

I have covered the NICE issue here, here and here. I also sent an e-mail to Sir Andrew Dillon, who heads the seven-member NICE guidance executive, with my questions about the consultation document and the review process. I critiqued the topic expert reports commissioned by NICE, which I received through a freedom-of-information request. One reason I wanted to keep on top of the issue was to make sure NICE was aware that its actions were being observed, and not just in the UK.

The NICE announcement was overshadowed by the same-day release of Professor Esther Crawley’s ludicrous study of a psychobabble technique called the Lightning Process as a treatment for kids. The Lightning Process is a mish-mash of positive affirmations, neurolinguistic programming and related doggie poo. That Professor Crawley received approval for this experiment on minors is unfortunate. Despite some credulous media coverage, the results cannot be taken seriously, for reasons others have documented.

I might be too optimistic, but I think the NICE decision is a game-changer. It suggests that the PACE authors and their colleagues, despite their enormous influence, have lost control of the narrative—even on their home turf. They can no longer count on those in powerful positions to provide monolithic support for their bogus claims that CBT and GET are effective treatments. That doesn’t remotely mean that the struggle is over. There are lots of remaining hurdles—especially the central task of ensuring that any new guidance is based on sound evidence. But this is still a significant moment in the ongoing demise of the PACE/CBT/GET paradigm.

The NICE statement about the decision highlighted stakeholder concerns about the Oxford criteria and the CBT/GET evidence base, among other issues. “Key trials (particularly PACE [Pacing, graded Activity, and Cognitive behaviour therapy; a randomised Evaluation], but also Cochrane reviews of CBT and GET) have been criticised for inflating the efficacy of interventions,” declared the statement. “Issues include that some studies only require fatigue in the case definition, which may incorporate other fatiguing conditions with the potential to complicate results.”

NICE reported that 39 stakeholder organizations submitted comments. Nine of them–including professional associations like the Association of British Neurologists and the Royal College of Psychiatrists–supported the recommendation to leave the guidance as is. No patient organizations took that position. The stakeholders collectively submitted about 300 pieces of new evidence. NICE selected thirteen that met its criteria for inclusion in its surveillance review.

This group includes a study criticizing the Oxford criteria as overestimating illness prevalence and two studies about the role of postural orthostatic tachycardia syndrome, or POTS—a key symptom ignored in the 2007 guidance. Also included is Keith Geraghty’s analysis of surveys about CBT, GET and pacing. The CBT/GET cheerleaders have generally dismissed the results of such surveys because the respondents are self-selected, so the inclusion of this study of patients’ real-world experiences is welcome.

The NICE decision is a slap in the face to the PACE authors and Sir Simon Wessely, who have routinely protrayed critics as vexatious, irrational and dangerous. It is also a possible set-back for Professor Crawley, who served on the 2007 guidance committee and believes PACE is a “great, great” trial. The consultation document highlighted Professor Crawley’s ongoing FITNET-NHS study of Internet-delivered CBT as an important future source of data. (Gee, I wonder who promoted the importance of FITNET-NHS to the surveillance team?) Since last week’s decision suggests that NICE is aware of and concerned about the methodological flaws afflicting the CBT/GET research field, FITNET-NHS could turn out to be irrelevant to the new guidance.

The NICE decision occurred not long after the Medical Research Council rejected an application from Professor Crawley’s much-ballyhooed Big Data project, the ME/CFS Epidemiology and Genomics Alliance. These successive events suggest that the public controversy over PACE and related CBT/GET studies might have reached a tipping point. Perhaps the anti-scientific arguments advanced by these researchers are finally losing credibility, even among academic and medical colleagues. Maybe there’s a growing awareness that open-label trials relying on subjective outcomes cannot provide reliable evidence. I mean, maybe not, but I hope so.

The topic expert reports revealed the profound shallowness of the NICE surveillance team’s efforts. The fact that three of the seven experts were psychiatrists and four were members of the 2007 guidance committee did not inspire confidence in the panel’s objectivity. None of the experts appeared to appreciate the extent to which research on physiological dysfunctions and the PACE debunking have transformed the debate in the last two years.

In fact, Expert #6 even argued that there was “increasing acceptance” among British patients and clinicians that the illness is an “emotionally driven disorder”—a claim so stupid and ill-informed that it should immediately have disqualified this person from being deemed an “expert.” It was troubling but unsurprising that the NICE surveillance team found this narrow range of purported expertise to be sufficient input for such a critical decision.

Developing a new guidance could take quite a while. And that’s a good thing, if it means getting it right. Considering the range of issues outlined in NICE’s statement, the new guidance committee will have to include experts who can argue forcefully on behalf of basic scientific principles. These experts will have a tough job. Those who have dominated the field for years touting research riddled with flaws will obviously demand a place at the table. But I have a sense that higher-ups in the NICE hierarchy are acutely aware that stacking the committee with CBT/GET hardliners would doom the effort to irrelevance and failure, not to mention damage the agency’s international reputation.

I have not written to the PACE authors themselves in a while. Given the significance of this development, however, I decided to make another effort to extract a comment. I haven’t heard back, of course, nor do I expect to. But that’s no reason not to pose the questions.

Here’s the message I sent to Professor Chalder, Professor Sharpe and Professor White:

    I am writing a post for Virology Blog about NICE’s announcement this week that it is planning a “full update” of the guidance for the illness we have been debating. I am interested if any of you would like to make any comments about this decision. 

    Here are some of my questions: Are you surprised? Do you think this means NICE will remove CBT and GET from the updated guidance? Do you believe the CDC’s recent “dis-endorsement” of the treatments has influenced NICE’s decision-making? Do you believe the decision is an indication that the CBT/GET paradigm for treatment of the illness is collapsing, even in the UK? Do you believe the decision represents a rejection of the reported PACE trial results? 

Thanks!—David

.

Vincent travels to the University of Pennsylvania and speaks with virologists Gary Cohen, Scott Hensley, Carolina Lopez, and Susan Weiss about their careers and their research.

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Abstract readabilityThe scientists I know realize that they use jargon, both in their writing and in their seminars – but they can’t seem to stop. There is a very good reason to  stop using jargon – it has likely lead to a decrease in the readability of scientific texts for the past 100 years (link to article).

To determine if the readability of scientific writing has changed with time, over 700,000 abstracts were downloaded from PubMed, which indexes journal articles in the life sciences. These abstracts were published in 123 prominent journals (Nature, Science, PNAS, for example) in 12 selected fields of research (including microbiology, immunology, neuroscience, and more). The abstracts were subjected to two different measures of readability: the Flesch Reading Ease (FRE) and the New Dale-Chall Readability Formula (NDC).

An FRE score is calculated by considering the number of syllables in each word, and the number of words in a sentence. The NDC measures the number of words in a sentence and the percentage of difficult words – those not on a list of common words. Lower readbility is indicated by a low FRE score or a high NDC score.

When the 700,000+ abstracts were analyzed, the FRE and NDC scores showed a clear trend of decreasing readability in the biomedical science literature since 1890 (the graph shows the FRE score; image credit). To put these results in perspective, over 20% of the abstracts have a ‘readability considered beyond college graduate level English’, to quote the authors of the study.

Two sources for the trend of decreased science abstract readability were considered. An increase in the number of co-authors over time, the ‘too many cooks spoil the broth’ effect, was ruled out. But an increase in general scientific jargon correlated with the decreased readability (jargon in the abstracts was measured by using a table of 2,138 scientific jargon words, like ‘novel’, ‘robust’, ‘moreover’, ‘underlying’, and ‘therefore’.)

Why would scientists care about readability of their articles? Because lower readability impedes communicating science not only to the non-specialist, but even to people within the field!

The authors suggest several ways to reverse the trend of decreased readability, including having ‘lay summaries’ accompany articles (done by some journals). Another is to have scientists communicate via social media – I was happy that the authors believe that ‘this trend could be encouraged’.

Another suggestion is to make scientific communication part of undergraduate and graduate education. This suggestion often comes up when I speak to students about communicating science. As someone with a bit of experience in this area, I would be pleased to participate in such efforts.

Finally, I love the suggestion of determining a readability index (r-index) for scientists, analogous to the h-index for journal article citations.

By David Tuller, DrPH

In his welcome talk at last week’s annual conference of the CFS/ME Research Collaborative (CMRC), the chair, Professor Stephen Holgate, praised his colleague and second-in-command, Professor Esther Crawley, for her “stunning” and “amazing” work on the group’s main research initiative. There was just one problem: That initiative, the ME/CFS Epidemiology and Genomics Alliance (MEGA), had recently failed in its second high-profile bid for major funding.

Earlier this year, of course, MEGA announced that it had failed in its first big effort, a submission to the Wellcome Trust. This second unsuccessful bid was to the Medical Research Council (MRC). Professor Holgate tried to put a positive gloss on things by vowing that MEGA would learn from this defeat and press forward. Yet he undoubtedly knows that applicants who repeatedly get turned down for top grants can start to smell like losers. Funders prefer to shower money on those perceived as winners. Notwithstanding Professor Crawley’s stunning and amazing work, MEGA so far has proven itself more loser than winner.

Before sharing the unfortunate news about MEGA’s bid, Professor Holgate appeared to be trying to soften the blow and rationalize the rejection by praising proposals in this emerging research field that get “to the edge of being funded,” even if they ultimately fail.

“As we start to ramp up the quality of research, you won’t just see a switch and suddenly money pouring in,” Professor Holgate explained to those assembled for the two-day conference. “You see people almost getting there but not quite, reconfiguring their applications and then coming back in again and getting it right. So this is the right direction of travel and I think it’s absolutely wonderful that we’re seeing this happening now.”

As I interpret his remarks, Professor Holgate’s optimistic view is that MEGA, after two failed bids, is now traveling in the “right direction” on its “wonderful” journey. As he explained, the MEGA proposal survived the first round at the MRC and made it to the interview stage, along with several other candidates. Then the bid lost momentum, for reasons he did not share.

“We got down to the short list, which was great,” said Professor Holgate. “We were interviewed but at the interview we didn’t quite make the cut. That doesn’t mean this whole thing is just going to wither on the vine, it means we need to take the feedback from the Medical Research Council committee, sit down, get serious about what they said, and think about where we’re going next with this. But I can tell you this is not the end by any means, we are definitely going to move forward. We just have to make sure that when we do move forward we learn from the experience and then we look for opportunities for funding elsewhere.”

Whatever. Perhaps this is not the end for MEGA, and next year will be more productive. But apparently the reviewers for two major funders have not agreed with Professor Holgate’s assessment of Professor Crawley’s work. I presume she and her team put great effort into pulling together the proposal rejected by Wellcome. Putting on a brave front after that failure, MEGA appeared determined to regroup for the MRC bid. Now the MRC has also turned thumbs down on whatever it was that MEGA proposed. Hm. Professor Crawley must feel deeply disappointed and even embarrassed—an understandable reaction, of course, after such a humiliating public defeat.

It’s no secret that Professor Crawley and I are not the best of friends. I have accused her of problematic research practices, and she has accused me of writing “libellous blogs.” I have documented my charges and backed up every claim. Professor Crawley has failed to respond to my repeated requests for evidence that anything I’ve written about her work is inaccurate. I take her silence as acknowledgement that her libel claim is false.

I wrote several blog posts about this situation. I sent an open letter to the CMRC board, chastising Professor Holgate and the other members for failing to address their colleague’s unprofessional behavior. I complained to Bristol University, since Professor Crawley made her defamatory statement about my work at her inaugural lecture there this past spring. And I recently wrote about her curious failure to seek ethical review for a 2011 study of children, using the questionable claim that it was a “service evaluation” project and therefore exempt from such a review.

Have these and other developments begun to be noticed by the kinds of people who would serve on MRC and Wellcome review committees? Would these reviewers have heard by now of the mushrooming scandal around the conduct and findings of PACE, which Professor Crawley has declared to be a “great, great” trial? Would these reviewers know that large segments of the international scientific and public health communities, including the U.S. Centers for Disease Control, have rejected the GET/CBT ideological movement, for which Professor Crawley is an ardent advocate?

It is certainly possible that awareness of these developments is slowly spreading beyond the narrow confines of those actively engaged in the debate—that is, beyond the communities of patients, advocates and ME/CFS investigators. It is even possible that these developments are starting to impact Professor Crawley’s prospects for obtaining research funding. These two recent rejections suggest that could be the case. On the other hand, she has received support for her problematic FITNET-NHS trial, so perhaps the rejections had nothing to do with the debate around PACE/CBT/GET.

In any event, the issues are not going away. Given Professor Crawley’s apparent inability or unwillingness to provide satisfactory answers to legitimate concerns raised about some of her ethical and methodological choices, she is likely to face continued scrutiny.

As I have previously pointed out, Professor Holgate and the CMRC have enabled Professor Crawley’s bad behavior by endorsing her leadership despite her high-profile public campaign to discredit critics as vexatious and libelous. However, no matter what the CMRC does or does not do at this point, the CBT/GET approach to ME/CFS is collapsing under the weight of its own absurdity and the accumulating scientific evidence. In the face of this ongoing paradigm shift, Professor Holgate’s fulsome praise of Professor Crawley’s unsuccessful efforts to seek support for MEGA seemed like a desperate effort to forestall the inevitable reckoning.

On Saturday morning, I wrote to Professor Holgate and others on the CMRC leadership team, seeking comment about MEGA. I haven’t heard back—not that I expected to. Here’s what I wrote:

“I’m writing a post for Virology Blog about some of the news coming out of the conference. So I am wondering if you [i.e Professor Holgate]–or any other members of the CMRC executive committee–want to comment on the failure of MEGA at the interview stage in the MRC funding cycle. My blog will be posted on Monday or Tuesday, so please send me back any comments by Sunday evening, California time.

Here are my questions: Are there specific shortcomings in the proposal that the MRC reviewers highlighted? Or was the interview itself problematic, in terms of how the MEGA team presented its ideas? Given that the MEGA team presumably gave this proposal its all, especially after the previous rejection from Wellcome, what grounds do you have to expect better results in the future? Do you think other funders will perceive similar issues to those that apparently proved to be a stumbling block for the Wellcome and MRC reviewers?

Do you think it is possible that Wellcome and MRC reviewers have started to notice the mushrooming international concerns around the conduct and reporting of the PACE trial? Do you think there might be growing reluctance to fund people and projects perceived to be associated with the PACE/GET/CBT school, including investigators who have declared this self-evidently flawed piece of research to be a “great, great trial”? 

I have not included Professor Crawley on this e-mail; it is my understanding that she considers contact from me to be unwelcome. But I of course would include a statement from her about MEGA in my post. I am also still interested in a statement from her about her false accusation that I have written “libelous blogs,” since she has never bothered to clear up that issue or explain her charge. So please feel free to forward this e-mail to her!”