For a few months in early 2020, hydroxychloroquine was touted as a promising treatment for SARS-CoV-2, the virus that causes COVID-19. After months of testing and trials, there’s little doubt that it’s not effective.
What went wrong? Scientists who ran the lab experiments — which yielding promising data — used the wrong type of cells. Instead of using human cells, they used a supply of mass-produced, standardized cells made from a monkey’s kidney. This decision to test hydroxychloroquine on monkey cells made the test results irrelevant to human health. Now, it’s possible that further research into novel coronavirus treatments or cures will be jeopardized by the same mistake.
Initial Studies on Using Vero Cells
In early February, Cell Research published a data set from the Wuhan Institute of Virology. This data suggested that a pharmaceutical compound related to hydroxychloroquine was highly effective in controlling infections of SARS-CoV-2. A second study from a different Chinese group that appeared in Clinical Infectious Diseases in March 2020 showed that hydroxychloroquine had an even more potent effect, and has since been cited hundreds of times. Also in March 2020, Cell Discovery published the results from yet another research study by the same group of Wuhan scientists, stating that hydroxychloroquine has a “good potential to combat the disease.” All of these studies — which received lots of attention — started with a set of kidney cells, called Vero cells, from an African green monkey, that was dissected in 1962.
It is possible for scientists — or entire scientific fields — to waste time in this way. They choose the most familiar animal model as the basis for their work, even though it’s not well-suited to the scientific question. Different cell lines (cultures of animal cells that can be propagated repeatedly and sometimes indefinitely for use in scientific research) can sometimes be misapplied in scientific research out of convenience.
These Vero cells, derived from that single African green monkey decades ago, are popular among virologists. This is partially because they contain fewer interferons, or antiviral proteins. This makes the Vero cells a perfect breeding ground for quick growth of viruses that may ordinarily take a long time to grow and replicate in a lab. Vero cells have long been very helpful in studying coronaviruses — including during the SARS outbreak in 2005. But whereas hydroxychloroquine does stop SARS-CoV-2 from infecting Vero cells, it does not protect human lung cells when studied in the lab.
According to Stefan Pöhlmann, head of the Infection Biology Unit at the German Primate Center in Göttingen, that had to do with how the cells interact with SARS-CoV-2’s spike protein. Human lung cells contain two different enzymes that can help SARS-CoV-2 break through their membranes. But Vero cells only have one of those enzymes, and it happens to be the one enzyme that is inhibited by hydroxychloroquine, thus making it effective in Vero cells. Pöhlmann and his team of researchers published these findings in July 2020’s Nature, citing the misleading hydroxychloroquine results as a clear example of why human lung cells need to be used to study treatments during this pandemic. “It is true that Vero cells are very popular. But unfortunately for this particular aspect of COVID-19 research, they are absolutely not useful. I think this is now clear to the field,” says Pöhlmann.
Future Use of Vero Cells in Coronavirus Research
It is worrisome to consider that physicians and scientists might forge ahead with treatment plans based only on Vero cell research. These cells may be fine for investigating drugs that could slow the virus or stop it from replicating once it’s inside a human cell — but not all scientists currently studying COVID-19 are aware of those nuances.
Many scientists who have never worked in virology before are abandoning their traditional fields of study to work on COVID-19. Madhu Pai, an epidemiologist and direct of the Global Health Program and TB Centre at Canada’s McGill University, describes this trend as the “Covidization of research.”
“Well-intentioned scientists with real expertise in one field intrude into another, passing judgment where they lack expert-level training and insight,” says Pai. The results of research by these scientists can be misleading and can waste valuable time and funding. Additional areas of concern with regard to Vero-based COVID-19 research include findings on how the novel coronavirus infects its hosts and whether COVID-19 positive patients are contagious after their first week of infection.
Learning from Mistakes
As the use of Vero cells in research and their inherent limitations become more widely known, academic journals will look at Vero-based research with more scrutiny. But prior to any peer-reviewed publication, preprints will be available to journalists and the public. Those parties must be aware of the potentially significant research flaws before accepting or disseminating any information from those preprints.
Massive amounts of time and money were spent on clinical trials of hydroxychloroquine during the nearly six months it took until scientists discovered it was not effective and why. The U.S. scrambled to secure a stockpile of the drug and distributed more than 31 million pills to state and local health departments. During that time, patients who take the drug to combat diseases against which is proven — lupus, malaria, and rheumatoid arthritis — were having trouble getting their regular supply. This all could have been avoided if scientists and researchers had checked their Vero cell findings in human lung cells. Time is of the essence in a pandemic, but the case of hydroxychloroquine goes to show that a small, incorrect choice in the beginning can have outsize consequences.
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