Jule Klotter

Cochrane Collaboration Crisis

In 1993, Ian Chalmers and a group of 70 other international colleagues, including Danish physician-scientist Peter Gøtzsche, founded the Cochrane Collaboration to provide evidence-based reports on medical procedures. To produce these systematic reviews, Cochrane aimed to lessen bias by investigating published studies, unpublished data, and negative results as well as by evaluating the reliability of the information, giving more weight to randomized clinical trials. Cochrane Systematic Reviews have become a trusted source for health practitioners.

Peter Gøtzsche, who heads the Nordic Cochrane Centre and was voted onto the Cochrane Governing Board in 2017, was expelled from the Cochrane Collaboration in September 2018, ostensibly due to his violation of the Cochrane Spokesperson Policy and bad behavior that threatened Cochrane’s reputation. An outside law firm hired by the Board of Trustees found no evidence to support this or other charges made by CEO Mark Wilson. Wilson, whose background is in business management and journalism, came to Cochrane in 2012. The Governing Board, headed by CEO Mark Wilson, has 13 members. In addition to the five who opposed Gøtzsche’s expulsion and Gøtzsche (who was not allowed to vote), one member abstained; a “majority” of six voted for his removal from the organization. Four of the five governing board members who opposed Gøtzsche’s expulsion resigned the next day because they could not publicly defend the action, as would be expected of Governing Board members.

Gøtzsche has been a long-time advocate for transparency and scientific debate. He has authored several books and over 70 articles published in major medical journals including Cochrane reviews such as the one that reported the dangers of over-diagnosis with mammography. He has also been very critical of the pharmaceutical industry, targeting the harms and overuse of psychiatric drugs and, more recently, the serious adverse effects of the HPV vaccine. In 2016, Gøtzsche criticized the European Medicine Agency for its incomplete and inaccurate report on the safety and efficacy of the human papillomavirus (HPV) vaccine.

Throughout 2018, Gøtzsche, along with Lars Jørgensen of Nordic Cochrane Centre and Tom Jefferson at the Centre for Evidence Based Medicine in the UK, has engaged in a running debate about the quality of Cochrane’s review on the HPV vaccine that was published in May 2018. The Cochrane review by M. Arbyn et al downplayed the risk of adverse effects; its authors reported that they “did not find an increased risk of serious adverse effects” and the Cochrane press release, written by six UK experts, reported “’…the HPV vaccine is the most effect way for young girls to protect themselves against cervical cancer’ and that ‘the vaccine causes no serious side-effect.’”

In response Jørgensen et al have published critiques and responses to the review authors and Cochrane editors in the British Medical Journal and on the BMJ  blog. They report that the M. Arbyn et al review “should have included at least 35% (25,550/73,428) additional eligible females in its meta-analyses.” Moreover, the reviewers relied solely on published reports. As Jørgensen et al explain in BMJ Evidence-Based Medicine, “harms cannot be assessed reliably in published trial documents—especially in journal publications of industry-funded trials where even serious harms often are missing….As an example, the journal publication for the PATRICIA trial is 14 pages long while its publicly available corresponding clinical study report is over 7000 pages long….Clinical study reports are usually confidential documents, but they can be requested from the European Medicines Agency (EMA) and ClinicalStudyDataRequest.com (CSDR).”

In addition, Jørgensen et al point out that, throughout the review, Arbyn and colleagues use the term “placebo” when, in actuality, none of the 26 studies used a true, inert placebo (e.g. saline). All trials in their meta-analyses used active comparators: aluminum-based adjuvants or hepatitis vaccines that contain aluminum adjuvants. These adjuvants are known to have harmful effects, according to vaccine manufacturer GlaxoSmithKline. “The use of active comparators probably increased the occurrence of harms in the comparator groups and thereby masked harms caused by the HPV vaccines,” say Jørgensen et al. Moreover, the review authors did not mention that several of the studies they used only counted adverse events that occurred within 14 days of vaccination, nor did they investigate reports of postural orthostatic tachycardia syndrome (POTS) or complex regional pain syndrome. Instead, they relied on the European Medicine Agency’s conclusion that was based on “manufacturers’ own unverified assessments,” which claim no association between the vaccines and these conditions.

Jørgensen et al also point out that three of the review’s four authors had major conflicts of interest related to HPV vaccine manufacturers. Gøtzsche had been pushing for changes to Cochrane conflict-of-interest policy for over a year before his expulsion. At present, Cochrane allows up to half of a review’s authors to have financial conflicts of interest. In the case of the May 2018 HPV review, more than half of the authors had ties to vaccine manufacturers. Apparently, this very public criticism of a Cochrane review, along with previous altercations with the Cochrane CEO, led to the vote for expulsion.

In response to Gøtzsche’s removal, Cochrane Iberoamerica, consisting of 31 signatories, sent a letter to all Cochrane members requesting an ad-hoc commission to independently review the conflict as well as immediate elections to fill the vacant governing board positions. In response to this letter, David Hammerstein, one of the Governing Board members who resigned after Gøtzsche’s expulsion, responded:  “The crisis in Cochrane is about the credibility of Cochrane and not a question concerning the ‘behaviour’ by one individual.”

Hammerstein views the crisis as a conflict of competing paradigms: CEO Mark Wilson and allies, who are primarily interested in financial growth and stability rather than public health, vs. people like Peter Gøtzsche, who want “much stronger policies to avoid biases and conflicts of interest in Cochrane reviews, much greater visibility of Cochrane in policy debates on health technology evaluation, open access publishing, shared structured data and open models of biomedical innovation. What is essential for this group is where the ‘evidence’ comes from, who pays for it and if all the clinical evidence is publicly available or not.

As I write this in November 2018, the outcome is uncertain. Dr. Gøtzsche continues to post relevant documents and letters concerning the conflict at his website www.deadlymedicine.dk. After the expulsion, Cochrane Collaboration reportedly took control of the Nordic Cochrane Centre website and declared that Gøtzsche was no longer the center’s director. Dr. Gøtzsche declares this to be false. He continues to be the director of Nordic Cochrane Centre, which has withdrawn from the Cochrane Collaboration: “We are now an independent centre, no long subjected to the scientific censorship that the current Cochrane leadership favours, and we continue our work as usual.” Other centers may follow his lead.

Demasi M. Cochrane – A sinking ship? September 16, 2018. https://blogs.bmj.com.

Hammerstein D. Regenerate Cochrane to strengthen the production of trusted evidence for the common good of public health. October 8, 2018.

Jørgensen L, Gøtzsche PC, Jefferson T. The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias. BMJ Evidence-Based Medicine. October 2018;23(5):165-168.

Jørgensen L, Gøtzsche PC, Jefferson T. Response to Cochrane editors: Jørgensen, Gøtzsche Jefferson. September 23, 2018. Available at https://blogs.bmj.com.

Shah HM, Chung KC. Archie Cochrane and his vision for evidence-based medicine. Plast Reconstr Surg. September 2009;124(3):982-988.

Aluminum and Autism

In 2018, a team of British researchers reported “extraordinarily high” levels of aluminum, a known neurotoxin, in tissue from the brains of five people (4 male; 1 female) with confirmed autism diagnosis. The UK study, led by Matthew Mold and funded by the non-profit Children’s Medical Safety Research Institute, said the results showed “some of the highest values for brain aluminium content ever measured in healthy or diseased tissues in these male ASD [autism spectrum disorder] donors….” Tissue from a 15-year-old boy had a mean level of 6.02 µg/g.

In addition, the UK researchers used fluorescence microscopy to examine brain sections from 10 other donors with ASD. They found more aluminum deposits in males (129 in 7 individuals) than in females (21 in 3 individuals). The deposits were extracellular and intracellular, affecting neurons and non-neuronal cells, including microglia. Aluminum compounds (aluminium) were also found in mononuclear white blood cells in the meninges, indicating that the metal might be entering the brain via the lymphatic system. The authors conclude: “The presence of aluminium in inflammatory cells in the meninges, vasculature, grey and white matter is a standout observation and could implicate aluminium in the aetiology of ASD.” This was the first study to measure aluminum content in the brains of people with autism.

In a Letter to the Editor regarding this study, Ivan Ivanovski et al state that consumption is unlikely to be the source of the high aluminum levels, despite its widespread presence in processed foods, cooking utensils, and drinking water. They point out that only about 0.25% of ingested aluminum (Al) is absorbed into the circulation, although it may be more if the intestinal mucosa is damaged. In contrast, nearly 100% of aluminum hydroxide, commonly used as an adjuvant in vaccines, enters circulation when injected intramuscularly. Moreover, the injected Al adjuvant binds with transferrin, which allows it to cross the blood-brain and blood-cerebrospinal fluid barriers. It is unlikely to be excreted once it enters the brain.

The US vaccine schedule delivers about 4925 µg of aluminum parenterally by the age of 18 months, according to Ivanovski et al. The authors suggest postponing aluminum-containing vaccines until children lose their last primitive reflex, indicating physiological maturation, which is usually about six to seven months old. They also suggest replacing aluminum adjuvants with compounds that may be less toxic, such as squalene, calcium phosphate, or a zinc compound.

Ivanovski I, et al. Aluminium in brain tissue in autism. J Trace Elements in Medicine and Biology. 2019;51:138-140.

Mold M, et al. Aluminium in brain tissue in autism. J Trace Elements in Medicine and Biology. 2018;46:76-82.

Nanorobots in Medicine

Micro/nanorobots, measuring a few micrometers or less, offer new possibilities for medical diagnosis and treatment, according to a 2017 review from the department of nanoengineering at University of Southern California-San Diego. Nanoengineers have developed a variety of ways to power the tiny machines, many of which are made from biocompatible components that can degrade when their task ends. Some are chemically powered, using locally supplied components to fuel their activity. Others depend upon externally applied ultrasound or magnetic energies for power. Some tiny robots have also been integrated with living organisms that are capable of moving.

At this point, most research has been in vitro, with a few in vivo animal studies. Nanoengineers have shown that micro/nanorobots can make their way through complex biological media and narrow capillaries. Some have carried therapeutic compounds directly to tumors or other diseased areas. Tiny robots with microgrippers can retrieve tissues and cells from hard-to-reach locations. Eventually, the microgrippers may evolve into a tool for microsurgery, according to the authors. Micro/nanorobots can also perform ablation. Detoxification is another use; the authors envision a cohort of micro/nanorobots working together to capture and remove toxins from a body.

Of course, several hurdles need to be overcome before nanorobotics becomes part of medical practice. The authors say, “…nanorobotic scientists should work more closely with medical researchers for thorough investigations of the behavior and functionality of the robots, including studies on their biocompatibility, retention, toxicity, biodistribution, and therapeutic efficacy.”

Li J, et al. Micro/nanorobots for biomedicine: Delivery, surgery, sensing, and detoxification. Sci Robot. March 1, 2017.

Glyphosate Food Contamination

In September 2018, the Environmental Working Group (EWG), along with Stonyfield Farm, Nature’s Path, National Co-op Grocers and others, petitioned the Environmental Protection Agency (EPA) to prohibit the use of glyphosate-based herbicides as a pre-drying agent and to limit residues on oats. About three-fourths of oat-based foods, commonly eaten by children, had higher glyphosate levels (according to independent testing conducted the previous month) than EWG scientists consider advisable. Because of glyphosate’s use as a pre-drying agent immediately before harvest, even non-GMO crops (i.e., oats, wheat, and beans) may be contaminated with high levels of the herbicide—unless they are certified organic.

John Peterson Myers and a group of US colleagues published a review of the concerns and risks associated with glyphosate-based herbicides, such as Roundup, in 2016. About 240 million pounds of glyphosate was used on US farms and ranches in the year 2014, a huge increase from the 180-185 million pounds used in 2007. When it was registered for use in 1974, scientists assumed that glyphosate would have few negative effects on mammals because it targets an enzyme found only in plants. In reality, the herbicide produces multiple negative effects on mammals (and other animals).

Glyphosate disturbs mitochondrial metabolism and produces oxidative damage to the liver and kidneys in animals and humans. Glyphosate also disrupts endocrine-signaling systems, according to in vitro and animal studies. Animal studies indicate the possibilities of neurotoxicity and cancer. Severe birth defects have increased in Argentina and Paraguay where Roundup Ready crops are grown. Birth defects have also been observed among pigs and poultry that eat glyphosate-contaminated feed. Being a chelating agent, glyphosate binds to nutrient metals, including manganese, cobalt, and zinc, making these nutrients inaccessible to plants and the animals that use them for food. Myers et al say, “These micronutrient metals are enzymatic cofactors, so their loss has the potential to contribute to a number of deleterious effects, especially on kidney and liver function.” Finally, glyphosate’s antibiotic properties can have adverse effects on the GI microbiome.

Myers et al mention that US EPA was scheduled to release its risk assessment and re-registration on glyphosate-based herbicides in 2015-2016. This did not happen. A proposed interim registration review decision is expected in 2019, according to EPA’s website. The decision “will outline any proposed mitigation measures.”

The Great Plains Laboratory can test a person’s glyphosate exposure. William Shaw, PhD, and Matthew Pratt-Hyatt, PhD, wrote an article about testing for glyphosate, which appears in the January 2017 issue of Townsend Letter. Their article is also available online. In addition to testing individuals’ contamination, GlyphoCheck™ Strip Test, available at www.detoxproject.org, can detect glyphosate in food and water samples. Avoiding glyphosate as much as possible is the first step in avoiding risks.

Myers JP, et al. Concerns over use of glyphosate-based herbicides and risks associated with exposures: a consensus statement. Environmental Health. 2016:15-19.

US Food Brands Petition EPA to Ban Pre-Harvest Glyphosate Spraying. Sustainable Pulse. September 28, 2018.

This column was originally published in Townsend Letter, January 2019.

About the Author

Jule Klotter joined Townsend Letter’s staff in 1990. Over the years, she has written abstract articles for “Shorts” and many book reviews that provides information for busy practitioners. She became Townsend Letter’s editor near the end of 2016.