virology blog

Trial By Error: PACE Authors Now Blame “Misunderstandings” for GET/CBT Criticisms

23 October 2021 by David Tuller 18 Comments

By David Tuller, DrPH

It is hard to know what to make of the news that a peer-reviewed journal has actually accepted a PACE-reunion paper from the three lead investigators—Professors Michael Sharpe, Trudie Chalder, and Peter White. Even more so for a paper titled–without irony, it seems–“Evidence based care for people with chronic fatigue syndrome and myalgic encephalomyelitis.” This surprising event occurred on October 1st, according to a notice on the website of King’s College London, Professor Chalder’s home base.

The full text has not yet been made available by the professors, as far as I can tell, and the Journal of General Internal Medicine hasn’t formally published the article yet.* {I have removed a sentence here. Details below.] So I can’t yet comment on the substance of the arguments they present to persuade readers at this late date that graded exercise therapy and their specialized version of cognitive behavior therapy are in fact “evidence based.” They definitely confront a tough challenge, since the UK’s most recent official assessment of PACE and related research has found the quality of the evidence for the main claims of effectiveness is either “very low” or merely “low.” *[I added UK to this sentence. Explanation below.] This scathing assessment emerged from an authoritative source—the National Institute for Health and Care Excellence, the agency charged with developing clinical guidelines.

In their new paper, do the professors attempt to refute these NICE findings, and if so, how? Just by insisting that the assessment is wrong and re-affirming the soundness of their own research? Given their long-standing prominence, that strategy worked for many years to deflect, discredit and/or squelching legitimate criticism, most of it from patients. Perhaps this time the professors will provide a robust case—but judging from the abstract, they won’t.

Here’s the abstract:

Chronic fatigue syndrome (CFS), sometimes referred to as myalgic encephalomyelitis (ME) and often as CFS/ME, is an illness characterized by disabling fatigue and other symptoms, typically worsened by activity. The main evidence-based treatments are rehabilitative in nature and include specific types of cognitive behavior therapy (CBT), and graded exercise therapy (GET). In this article we briefly review the evidence for their safety and effectiveness and propose that much of the controversy about them arises from misunderstandings about their nature and delivery. In particular, we emphasize that successful rehabilitation from CFS/ME does not indicate that the illness is not real. We recommend that rehabilitative treatment always be preceded by a thorough clinical assessment and delivered by appropriately trained therapists working in close collaboration with the patient. We conclude that properly applied rehabilitative treatments offer the best hope of safely improving fatigue and function for patients with CFS/ME. However, we also recognize the need for more research into the treatment of this neglected condition, especially for those most severely disabled by it.

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The abstract is revealing. First of all, note the decision to use CFS/ME throughout rather than acknowledge the term ME/CFS, which has been adopted by NICE and US agencies as well. This contrarian choice strikes me as petulant, defensive and unneccessary. Perhaps it represents the professors’ refusal to acknowledge that they have lost all control of the narrative–even naming rights to the disease. (To be clear, many patients dislike the composite names ME/CFS and CFS/ME, believe their continued use is harmful, and strongly prefer ME.)

Furthermore, it is inaccurate and unwarranted at this juncture to call GET and CBT “evidence-based.” It is true that there is more evidence about these treatments than any others. But the evidence does not demonstrates what the professors claim, as has been documented most recently by NICE. The Journal of General Internal Medicine should know better than to allow self-interested parties to mis-characterize the current status and stature of critical evidence in an article’s title and abstract.

It is also not the case that “the controversy about them [the interventions] arises from misunderstandings about their nature and delivery.” The controversy revolves around the fact that, for decades, the highest levels of the academic and medical establishments accepted nonsense as if it were impeccable research—even though first-year epidemiology students at Berkeley have no trouble identifying disqualifying flaws. To pretend this is all due to some unfortunate miscommunications is ridiculous—a desperation move.

In another problematic statement, the professors note: “In particular, we emphasize that successful rehabilitation from CFS/ME does not indicate that the illness is not real.” This declaration demonstrates their inability to respond to the actual objections about the methodological and ethical lapses that mar their research. They haven’t provided credible evidence that their interventions lead to “successful rehabilitation,” so this statement is essentially meaningless. Moreover, the assurance that the condition is “real” indicates that they continue to think patients object to the treatments mainly because of a prejudice against mental illness rather than because the research is bogus.

In short, this article appears to be an effort to massage the past and salvage reputations. The interventions were developed and presented as curative in nature based on the presumption that patients had no underlying pathology causing the prolonged symptoms. Instead, they were declared to be severely out of shape due to their unhelpful beliefs of having an organic disease that caused them to deteriorate after exertion.

Are these investigators still promoting this theory, which provided the rationale for their therapeutic approach? It doesn’t sound like it, although it’s hard to know from the abstract. Instead of acknowledging that clinical trials have failed to provide high-quality evidence supporting the theory and the interventions, they seem to be blaming other people for some “misunderstandings.” It is painful and sad to watch anyone engage in fruitless attempts to save face and escape public humiliation, much less eminent professors accustomed to being treated with deference and respect.

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*I deleted the following sentence, which was obviously unnecessary: “(Perhaps more renowned journals were not interested?)”

*I added UK to the sentence to distinguish the NICE document from the recent draft of another evidence review commissioned by the US Centers for Disease Control and Prevention.

Trial By Error: NICE Announces Upcoming Release of ME/CFS Guideline After Prolonged Hostage Drama

20 October 2021 by David Tuller 10 Comments

By David Tuller, DrPH

Two days following a high-profile meeting with opponents and supporters of its new-but-still-unpublished ME/CFS guideline, the UK’s National Institute for Health and Care Excellence announced on Wednesday that it plans to release the document next week. The decision comes after a powerful cabal of medical practitioners held the process hostage for two months with unwarranted criticisms and bogus claims.

(Yes, I’m referring to Professor Michael Sharpe and others of his ilk, whose unfortunate delusions about the quality of their research persist. Sad! I advise these self-regarding experts to discuss their inevitable feelings of rejection, loss and public humiliation with their therapists and stop inflicting their anti-scientific notions on unsuspecting patients.)

The ongoing drama has inflicted serious harm on the patient community–a continuation of decades of abuse from the medical establishment in UK and elsewhere. And certainly publication won’t end the suffering, as patients have properly noted. One regular and valued Virology Blog commenter, who goes by Lady Shambles, wrote the following sharp critique:

“Pardon me if I don’t get too excited by the reports which have come from yesterday’s Roundtable meeting.

i) it should never have taken place at all

ii) given it did take place the lack of transparency does not please most (probably all?) people with ME

iii) I’ll only ‘believe it when I see it’ wrt the embargoed Final Guideline being published without change

iv) even if it is published it’s still worse than the Draft [published in November last year] and the Draft was unfit for purpose (no matter how valiantly our representatives tried to make it better .. this is not a criticism about them). This is not what a Guideline for a severe neuroimmune disease should look like in the C21st

v) it will make absolutely zero difference to my own experience of this disease unless I’m abused and gaslighted less when I meet medics: what an indictment that is.

vi) I, like many other people with ME, am at a point with my disease presentation where I’m looking down the barrel of a gun. Life is ticking louder for some of us than others and those with presentations where this is true have NO chance of any useful, ameliorative help at all.

vii) thus if the Guideline is published as per the 18th August document then it not a day for celebration but one in which the medical profession, the medical sciences, Establishment Quangos and Luddite Royal Colleges should hang their heads in shame that *this* is all we’re worth. There is no good result here. There are just 50 shades of grim.”

I can’t really refute these views. I obviously can’t speak from the devastating perspective of having been a patient with this terrible disease for years, if not decades. I believe publication of the guideline will represent a key step in the process of change–but without continued advocacy and pressure it will not amount to much on its own. And as indicated in Lady Shambles’ comment, many patients argue that changes from last November’s draft to the final version have weakened the document.

In my non-patient view, both the draft and final version are clear and explicit that graded exercise therapy, or any therapy based on fixed incremental increases in activity, is not recommended. And any form of cognitive behavior therapy based on the notion of abnormal illness believes and/or deconditioning is also not recommended. Does the guideline leave room for supportive exercise regimens and psychological interventions, should patients desire them? Yes. Does it leave an opening for continued abuse of patients? Of course. Any clinical guideline can be misinterpreted or misapplied by those delivering care.

Here is a comment I wrote on Facebook in response to some of the issues noted by patients.

“I understand and sympathize with all the concerns expressed here. Nothing is going to turn things around immediately. Every positive development is just a step and will need to be built on, and will not undo any of the harm caused in decades past and the harm that continues to be done. A new guideline will not solve the problem of lack of proper funding, ongoing bad research into bogus interventions (FITNET, for example), poor understanding among doctors, lack of proper services, etc. A huge amount obviously remains to be done. But it will still be a big deal if the likes of Sharpe, Chalder, etc., can no longer cite NICE’s 2007 guideline as evidence that supports their shenanigans. It will have an impact in other countries, where they were waiting for this new guideline to make their own determinations. It is a big deal to be able to say that NICE does not support GET and “curative” CBT, but of course the process of change in medical thinking and practice is a long-term project. And even when the guideline is published, as it hopefully will be, it will require lots of pressure and public attention to force changes in the approach to so-called “medically unexplained symptoms,” Long Covid, and other complex illnesses. That is mainly why I’m continuing my work and not just hanging it up right now.”

Jonathan Edwards, an emeritus professor of medicine from University College London, attended the Monday meeting hosted by NICE as a representative of the Science For ME forum. (I participate in the forum.) In a comment under my last Virology Blog post, he offered the following thoughts on the current moment:

“I have sympathy with a lot of the cautious comments. In terms of building adequate ME/CFS services I think this is much more the end of the beginning than the beginning of the end. But for reasons not necessarily related to this meeting I think that NICE and most of the organisations present at RT [roundtable–that is, Monday’s meeting] see things the same way. There is a huge amount of work to do in educating health care professionals in a more sensible approach. There is also work that needs to get started on gathering reliable evidence for exactly what factors in such an approach are most important, so that next time there is a guideline committee there will be some evidence of a reasonable standard based policy on. And there is a need for adequate funding of service provision and research.”

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In any event, here is the statement that NICE posted today:

“NICE will publish the guideline following a meeting of its Guidance Executive next week.

Today’s announcement follows a roundtable meeting held earlier this week involving representatives from a range of patient and professional organisations, to discuss concerns raised about some aspects of the guideline that had led to the publication of the guideline being paused.

Professor Gillian Leng, NICE chief executive, said: ‘We would like to thank all those who took part in the meeting earlier this week for their contributions to what was an extremely open and positive discussion. During the meeting we had a constructive conversation about all the key issues that had been raised – those concerning the criteria for diagnosing ME/CFS, the decision not to recommend graded exercise therapy, the role of CBT, and the particular challenges of treating children and young people with the condition, as well as the approach taken to identifying and considering the evidence.

‘We are now confident that the guideline can be effectively implemented across the system and we will discuss the input from the meeting at our Guidance Executive next week with a view to publication of the guideline.’”

Trial By Error: Advocates Issue Hopeful Comments After NICE Pow-Wow on ME/CFS Guideline

18 October 2021 by David Tuller 20 Comments

By David Tuller, DrPH

Two months ago, the UK’s National Institute for Health and Care Excellence (NICE) abruptly delayed publication of its new ME/CFS clinical guideline under fierce objections from the GET/CBT ideological brigades and their minions. Today (Monday, October 18^th), the agency hosted a meeting to allow these powerful dissenters from some of the British medical associations grandly known as “royal colleges” to present their case, however stupid and unwarranted that case might be.

These esteemed parties apparently found it inconceivable and unacceptable that the main evidence for their purportedly “evidence-based” interventions was dismissed by NICE as being of “very low” or, in some cases, merely of “low” quality–an assessment reflected in the guideline’s rejection of the long-standing standard-of-care. Some GET/CBT brigadiers accused the guideline development committee of being over-influenced by irrational patients—even though only five patient representatives sat on the 21-person body. Some news organizations, even at this late date, accepted this sort of nonsense as legitimate scientific argumentation.

Professor Michael Sharpe, eminent PACE author and one-time Trial By Error commenter (!!!), publicly projected confidence that the delay would lead to a reconsideration of the evidence. It is of course understandable that Professor Sharpe has remained firm in his conviction that the evidence from PACE was not of appallingly poor quality–in other words, that the trial was not the piece of crap I have always called it. I empathize with his need to protect his ego, but not with his doing so at the expense of logic and patients’ well-being.

For patients, the last two months have been hellish. This community has been badly served by the medical establishment for decades. It should not be surprising that the NICE delay struck many as a continuation of that abuse. The unexpected decision furthered a widespread conviction that the guideline would never be published in the form endorsed by the guideline committee.

And the events alarmed others not explicitly covered by the guideline. A host of organizations representing Long Covid patients recently weighed in, sending NICE an open letter that noted the overlaps between the two illnesses and urged immediate publication of the guideline. (The letter expressed agreement with the similar appeal I organized and sent to NICE last month, which was signed by more than 150 experts and 120 patient groups.)

The Monday meeting was attended not just by those representing the dissatisfied parties but also by representatives from patient and advocacy organizations. It was conducted under a widely known framework called the Chatham House Rule, under which “participants are free to use the information received, but neither the identity nor the affiliation of the speaker(s), nor that of any other participant, may be revealed.” Given that, the public reports later Monday from some meeting participants have been limited but positive.

Extremely positive, in fact.

Assuming these early reports are borne out by swift publication of the version of the guideline endorsed by the NICE committee, today will prove to be a tipping point in this debate—with long-term implications for the future. More on that another time. For now, suffice it to say that Professor Sharpe and his main PACE colleagues—Professors Peter White and Trudie Chalder—are unlikely to be pleased by the reports from today’s event.

So, who said what?

Janet Sylvester, who represented #MEAction UK, tweeted this:

“I felt this was a positive meeting. There were large areas of agreement from all attendees, including all acknowledging the terrible experiences people with ME have had to endure. Together, the representatives from ME patient organisations were able to strongly get across the reality for people living with ME. I’m optimistic for a swift decision from NICE to publish the guideline.”

Here’s part of what Dr Charles Shepherd, who participated in his capacity as medical director of the ME Association, wrote in a Facebook post:

“What I can say is that it was a well managed and constructive meeting which covered all the objections from the Royal Colleges and I hope that this will now lead to publication and implementation of the new guideline…I assume that NICE will produce some sort of statement on the next steps forward fairly shortly.”

Jonathan Edwards, emeritus professor of medicine at University College London, provide a bit more information in several posts on the Science For ME forum:

“The meeting went much better than most people expected.”

“There were no substantive objections that were not handled simply and effectively by Peter Barry and Ilora Finlay [the guideline committee chair and vice chair], at least as it appeared to me…“

“There appeared to be an overwhelming majority view that the term GET should go. It was described as toxic. Similarly for ‘curative’ CBT…There was also complete agreement that GET should not continue under some other name. The inappropriateness of GET as defined in PACE was agreed by all.”

“I think it [the meeting] may have achieved exactly what its purpose was…to make people all stop and think what it is they are really arguing about and see what matters to the patients. More than one person present made strong comments about the importance of listening to patients – and not just for the sake of saying it.”

Trial By Error: North Bristol NHS Trust’s Biased Survey of Patients Attending “CFS/ME Specialist Services”

15 October 2021 by David Tuller 11 Comments

By David Tuller, DrPH

*October is crowdfunding month at Berkeley. I conduct this project as a senior fellow in public health and journalism at the university’s Center for Global Public Health. If you would like to support the project with a donation to Berkeley (tax-deductible for US taxpayers), here’s the place: https://crowdfund.berkeley.edu/project/27513

Two years ago, the North Bristol NHS Trust conducted a survey among current and recent attendees of clinical services for patients with CFS/ME (as the illness was then being called). The survey included one key question: Did respondents believe that specialist care should be available for CFS/ME patients?

Molnupiravir, a SARS-CoV-2 antiviral drug, is mutagenic in cells

14 October 2021 by Vincent Racaniello 4 Comments

Molnupiravir might be the first highly effective antiviral drug given emergency use authorization for treatment of COVID-19. Should we be concerned about the results of a recent study which show that the drug is mutagenic in cells?

Molnupiravir is an orally available pro-drug of the nucleoside analog N4-hydroxycytidine (NHC). The latter is a nucleoside analogue which is incorporated into RNA by the viral RNA-dependent RNA polymerase (pictured above). Once incorporated into RNA, NHC is recognized as either C or U by the RNA polymerase. As a consequence, many mutations are introduced into the viral genome, causing lethal mutagenesis and inhibition of infectivity. NHC has been previously shown to have broad-spectrum anti-RNA virus activity and blocks transmission of influenza virus in a guinea pig model of infection. It has been shown to block SARS-CoV-2 transmission in ferrets and results of a phase 2/3 clinical trial look promising, leading to a request for emergency use authorization.

N4-hydroxycytidine could be metabolized by the host to produce the 2’-deoxyribonucleotide form, which could be incorporated into cellular DNA and lead to mutagenesis. To test this hypothesis, a mutagenesis assay was used in Chinese hamster ovary cells (CHO-K1). These cells have one copy of the gene encoding the enzyme hypoxanthine phosphoribosyltransferase (HPRT), which makes the cells sensitive to the base analog 6-thioguanine (6-TG). If NHC were mutagenic, changes in the HPRT gene would allow cells to survive in the presence of 6-TG.

Cells were exposed to NHC for 32 days and assayed for sensitivity to 6-TG. The drug conferred 6-TG resistance in a dose-dependent manner. Two other antivirals that are base analogs, ribavirin and favipiravir, displayed either no or modest mutagenic activity in this assay. Sequence analysis of HPRT mRNA revealed the presence of base changes.

Molnupiravir is a far more active coronavirus antiviral than favipiravir and ribavirin, yet NHC has the distinct ability of causing mutations in cell DNA. The concern is that such mutations could lead to cancer or birth defects in a developing fetus. Whether or not Molnupiravir might cause cancer in humans is not known. However Merck, the developer of Molnupiravir, is required to carry out a series of gene toxicity studies before phase I testing of the compound in humans. Included is the Ames test, which uses bacteria to assess mutagenic activity of a compound. Bacteria do have the enzyme which can convert NHC to the DNA form. The results of these safety studies will not be published until after the drug receives EUA, but presumably nothing was observed that would preclude clinical trials.

Consequently until we have further information about preclinical studies on NHC, we should be cautious in our interpretation of the results of mutagenesis assays in CHO cells.

Trial By Error: Professor Lubet’s Take on The New Yorker’s Long Covid Article

8 October 2021 by David Tuller 5 Comments

By David Tuller, DrPH

I wrote a post last month about the recent wave of Long Covid coverage—some of it excellent (The Atlantic) and some way over the edge in its assertions of psychogenic causation of symptoms (The American Spectator, Spiked). Then there was the seemingly sympathetic New Yorker article by a physician, with its more subtle form of patient-bashing—portraying adherents of a pathophysiological perspective on Long Covid as irrational, anti-science zealots even as the author expressed compassion for their plight.

This New Yorker piece generated a wave of criticism and push-back from many of those experiencing Long Covid—not to mention ME/CFS patients, who have confronted similar attitudes for years. Among those troubled by it was my friend and sometime co-author Steven Lubet, a professor of law at Northwestern University, who wrote the following commentary for Social Science Space, an academic site. I am reposting the essay here with Professor Lubet’s permission.

Trial By Error: UC Berkeley’s October Crowdfunding Campaign

7 October 2021 by David Tuller 1 Comment

By David Tuller, DrPH

When I launched the Trial By Error project in 2015 with a 15,000-word investigation of the piece of crap known more formally as the PACE trial, I had no idea I was launching anything. I figured it was a one-off. After all, could such a disaster of a study really survive the sort of in-depth scrutiny to which I had just subjected PACE? I assumed a retraction would be forthcoming. (In truth, 15,000 words was not nearly enough to cover all the methodological and ethical flaws that marred this awful trial.)

Boy, was I stupid, or at least unbelievably naïve. Lancet editor Richard Horton ignored my investigation, ignored the open letters from distinguised experts condemning the trial, ignored the fact that PACE represented a possible case of serious research misconduct, if not worse. Six years later, PACE remains in the literature—a potent symbol of the many failings of the peer-review system that science has long relied on for quality assurance.

An Appreciation for Viruses

7 October 2021 by Gertrud U. Rey 1 Comment

by Gertrud U. Rey

Most people associate viruses with illness and suffering. After all, the word “virus” is derived from the Latin word for “poison.” However, considering that the vast majority of viruses cause no illness and are actually beneficial to humans and the planet as a whole, this sentiment is largely misplaced. Let me explain.

The ability of viruses to enter cells by attaching to host cell receptors and releasing their genome into the cell can be exploited for various purposes. For example, viruses can be used as vectors for delivering vaccines, healthy copies of defective genes (i.e., for “gene therapy”), and therapeutic drugs to specific cells.

Several SARS-CoV-2 vaccines, including those made by AstraZeneca and Johnson & Johnson, consist of a “vector virus” (an adenovirus) that contains a gene for the SARS-CoV-2 spike protein. Upon injection into a vaccine recipient, the vector virus should enter cells and serve as a code for host proteins to synthesize the encoded spike protein. Genes that regulate replication of the vector virus are removed to ensure that the vector itself cannot cause an infection in human cells. Other genes not needed for purposes of vaccine delivery are also typically removed to create more room inside the vector for the inserted antigen gene. Adenoviruses are particularly suitable for delivering foreign genes into cells because they have a double-stranded DNA genome that can accommodate segments of foreign DNA and because they infect most cell types without integrating into the host genome. However, poxviruses, retroviruses, vesicular stomatitis virus, and other viruses can also be used for vaccine delivery. As of today, six viral-vectored vaccines have been authorized for use in humans: four SARS-CoV-2 vaccines (two of which were previously described here and here) and two Ebola virus vaccines.

Viruses may also serve as vectors for targeted gene therapy to treat genetic disorders caused by mutations in the sequence of a person’s DNA. By replacing the mutated, non-functional portion of DNA with its healthy counterpart, the function of the defective gene could potentially be restored. Some viruses, like retroviruses, already insert their genetic material into the host genome as part of their replication cycle, making them suitable for delivering such functional genes to target cells. Recent advances in technology may even allow for the delivery of CRISPR-mediated gene editing tools to edit the target genome in the cell by excising the defective gene and replacing it with a functional version. One such targeted therapy aimed at treating genetic muscle disease by specifically targeting muscle cells was recently discussed on TWiV 812. Another exemplary gene therapy method for potentially deleting integrated HIV-1 from the genomes of infected individuals using CRISPR technology was described in a previous post.

A similar vector approach can also be used for cell-specific delivery of therapeutic drugs. For example, replication-incompetent viruses (viruses that have been engineered so they can’t replicate) can be further modified. These modifications may allow the viruses to specifically target dividing tumor cells or cells that display surface proteins that are unique to cancer cells, and deliver chemotherapeutic drugs only to those cells. Alternatively, replication-competent viruses can be manipulated to directly target and kill cancer cells in a mechanism known as oncolytic virotherapy. An example of this mechanism described previously involves a herpes simplex virus engineered to target a receptor that is practically absent in healthy brain cells, but is specifically expressed on glioblastoma multiforme tumor cells. The engineered virus also encodes a gene for a cytokine that increases the effectiveness of oncolytic viruses by recruiting cytotoxic T lymphocytes, which cause the tumor cells to burst. An accumulating body of evidence suggests that the cancer-specific antigens that emerge from burst cancer cells may also trigger additional downstream immune responses, further enhancing the potency of oncolytic viruses.

Considering that we are on the brink of a major antibiotic resistance crisis, viruses may just come to our rescue in this regard as well. Bacteriophages (“phages” for short) are viruses that only infect bacteria, and as it turns out, they can be used to treat pathogenic bacterial infections. There are numerous potential advantages to phage therapy compared to traditional antibiotic therapy. Phages are equally effective against antibiotic-sensitive and antibiotic-resistant bacteria. They are also more specific than antibiotics, and this specificity leads to reduced impact on commensal bacteria, which are typically obliterated by conventional antibiotics. Unlike most antibiotics, phages are capable of disrupting bacterial biofilms, and their use would lead to reduced incidence of opportunistic infections and reduced toxic effects of bacterial infection. Although bacteria can become resistant to phages, phages can likewise evolve to overcome this resistance, making bacterial resistance to phages less of a challenge than their resistance to antibiotics. Furthermore, scientists have found that the efficacy of phage therapy can be improved by combining phages with an antibiotic treatment regimen, or by combining several phages in a “phage cocktail.” In a highly publicized phage therapy success story, infectious disease epidemiologist Steffanie Strathdee describes how she recruited the help of an international team of physicians to cure her husband of a life-threatening multi-drug-resistant Acinetobacter baumanii infection using an intravenous phage therapy cocktail.

Phages can also be used as an alternative energy source by powering the electrodes in batteries. As repeatedly demonstrated by materials scientist Angela Belcher at MIT, biological scaffolds composed of M13 phages that display the negatively charged peptide sequence glutamate-glutamate-alanine-glutamate (E-E-A-E) inevitably attract nickel phosphide molecules, and the resulting nanostructures can be used directly as freestanding negative electrodes in batteries. These “virus batteries” have multiple advantages over traditional batteries. They are more environmentally friendly because they’re made from non-toxic materials. Their synthesis requires relatively little equipment, so they are inexpensive to produce. They are lightweight and flexible and can thus be woven into fabrics, which makes them suitable for military clothing. They also have higher conductivity than conventional lithium-ion batteries, making them extremely useful for portable electronics, medical implants, and various aerospace applications. It is even possible that they could one day be used to power electric cars.

The examples described so far are ones in which people have capitalized on virus functions for the benefit of humans. However, viruses have other benefits that just relate to their natural functions. For instance, phages are also an essential component of our environment, where they help control pests and recycle nutrients. If phages didn’t exist, some bacterial populations would explode and outcompete other populations, causing them to disappear completely. This imbalance would be especially disastrous in the oceans, where microbes make up more than 70% of the total biomass. Phages kill a large portion of oceanic bacteria every day, allowing the organic molecules released from the dead bacterial cells to be recycled as nutrients for other organisms. Perhaps the most important organisms to benefit from these recycled nutrients are microscopic plants called phytoplankton, which produce oxygen by removing carbon dioxide from the atmosphere. In fact, phytoplankton are a crucial element of the global carbon cycle and one of the largest contributors to our atmospheric oxygen. This means that without viruses, we would not have air to breathe.

Viruses are deeply integrated in life on earth, and their functions in sustaining environmental equilibrium and our ongoing survival are too numerous to describe in a single blog post. Moreover, our current appreciation of what can be accomplished using viruses is cursory, at best. Future research will lead to a deeper understanding of how viruses can be utilized to do more good.

[This post was written in honor of Virus Appreciation Day, which occurs annually on October 3]

Trial By Error: BBC’s Problematic Coverage of New Long COVID Study

3 October 2021 by David Tuller 6 Comments

By David Tuller, DrPH

Since the start of the coronavirus pandemic, suggesting an equivalence between COVID-19 and influenza has been a consistent approach among those seeking to downplay the current situation. So it’s not surprising to see something similar happen with comparisons between Long COVID and the delayed recovery some people experience after an acute bout of the flu. The BBC has just provided an excellent example of how this framing can appear to minimize the significance of Long COVID.

An article in PLoS Medicine, published on September 28^th, offered a look at Long COVID symptoms based on data from US electronic health records. The study, called “Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19,” tracked nine key symptom clusters: “breathing difficulties/breathlessness, fatigue/malaise, chest/throat pain, headache, abdominal symptoms, myalgia, other pain, cognitive symptoms, and anxiety/depression.”

Gain of function to build therapeutically useful viral vectors

30 September 2021 by Vincent Racaniello 3 Comments

Another excellent example of gain of function research is modification of a viral vector to make it more useful for human gene therapy.

Adenovirus associated virus (AAV) is the most commonly used vector for a variety of gene therapy applications, including gene replacement and gene editing. These small viruses, which comprise a single-stranded DNA genome surrounded by an icosahedral protein shell (illustrated), have a number of features that make them useful for gene therapy, including easy manipulation and growth in large quantities, and induction of persistent gene expression for long periods of time. An example is the drug Luxturna which is an AAV vector containing a retinal pigment gene that is used to treat some forms of blindness.

Naturally occurring AAV vectors have some limitations, including the propensity to become sequestered in the liver after systemic injection. Consequently reaching other organs with AAV vectors requires injection of large amounts of recombinant virus, which may be accompanied by toxicity.

A number of approaches have therefore been developed to modify AAV vectors so they preferentially infect other tissues. A number of muscle diseases would benefit from gene therapy and therefore AAV vectors have been developed to target that tissue. In one approach that I described before, ancestral AAV viruses were recovered and shown to efficiently infect muscle cell types.

A more recent approach involved modifying the AAV genome by inserting random stretches of 7 amino acids into the viral capsid protein, infecting mice with large libraries of these variants, and identifying those that best infect muscle. In addition, muscle-specific promoter sequences were also incorporated in the viral genome. After multiple rounds of infection of mice, recovery of viruses from muscle and reinfection, capsids were identified that more efficiently infect muscle tissue and less efficiently infect liver, in multiple mouse strains and in nonhuman primates. The new AAV capsids can rescue two different types of muscle disease in mice: Duchenne muscular dystrophy and X-linked myotubular myopathy after intramuscular inoculation.

The ability of these new AAV vectors to preferentially infect muscle cells depends on the presence of three added amino acids in the viral capsid, RGD. This three amino acid motif is known to bind cell surface proteins called integrins. Indeed, the increased efficiency of these engineered vectors depends on the presence of integrins on target cells.

These findings not only have produced better AAV vectors for targeting muscle tissue, but establish a strategy to engineer viruses to preferentially infect any tissue. The new vectors are the product of gain of function research: the original AAV has been given new properties. This work constitutes another example of the broad potential benefits of gain of function research in virology.