A team of prominent scientists is on the hunt for a better COVID-19 test. Sometimes, people who have had COVID-19 in the past will still test positive using the most reliable test, a polymerase chain reaction (PCR) test, even though they show no evidence of COVID-19 replication in their systems.
These scientists have a hypothesis that COVID-19 can reverse-integrate into human chromosomes (insert pieces of its genetic code into the human genome), a process that isn’t unusual for viruses and might explain these rare cases of false positives on the PCR test.
Some recent experiments have strengthened the case for reverse-integration of COVID-19 RNA genes into human DNA, but critics of the research aren’t so sure, saying the results could be an artifact of lab preparation. They have also raised concerns that the work could be misconstrued and lead to public safety issues.
The goal of the research
Accurate and abundant testing is important to help control the spread of any disease. The PCR test has long been the gold standard for COVID-19 testing. We have used PCR testing very successfully and have learned different limitations of the test. In the pursuit of having a more reliable test, these scientists set out to explain why some patients continue to test positive for COVID-19 even though they don’t have an active COVID-19 infection.
Richard Young, a gene regulation specialist, and Rudolf Jaenisch, a stem cell biologist from the Massachusetts Institute of Technology, led a team of researchers to investigate this anomaly. Because SARS-CoV-2, the virus responsible for the COVID-19 infection, has genes made from RNA, this team of researchers focused on the idea that infrequently a human enzyme may copy viral sequences into our DNA and insert them into our chromosomes.
Reverse transcriptase (RT) is an enzyme that is used by LINE-1 (Long Interspersed Nuclear Element) to generate complementary DNA from an RNA template; this is called reverse transcription. LINE-1 encoded sequences, by far the most abundant LINE in humans, are scattered across 17 percent of our genome and are filled with the genetic remnants of ancient retroviral infections. In total, LINE elements make up about 21 percent of the human genome.
In their newest paper published by the Proceedings of the National Academy of Sciences (PNAS), Jaenisch claimed his team has found “ambiguous evidence that coronavirus sequences can integrate into the genome.” The researchers found a relationship between LINE-1 elements and integrated viral genetic sequences that supported their hypothesis of reverse transcription. Additionally, they worked with Stephen Hughes, a skeptic of their work from the National Cancer Institute, to help clarify whether the viral integration was actually happening or if it was just noise in the experiment. This work supported the original hypothesis and was both helpful and insightful to the experiment.
Another critic of the work, Cedric Feschotte from Cornell University, who is an expert on endogenous retrovirus sequences in humans, considers the May 25th paper much more convincing and now considers this hypothesis “plausible,” although he isn’t totally convinced that this data has any relevance to the question being asked. He states “In the absence of evidence of integration in patients, the most I can take away from these data is that it is possible to detect SARS-CoV-2 RNA retroposition events in infected cell lines where L1 is overexpressed. The clinical or biological significance of these observations, if any, is a matter of pure speculation.” Young believes that they have found RNA markers that are indicative of the integrating process but does acknowledge they haven’t found direct evidence of viral RNA integration.
Though the case has been strengthened for the idea that COVID-19 can be reverse transcribed into human DNA, the jury is still out. Researchers haven’t yet determined if this process is indeed happening or if the information from this research is going to be useful for scientists as we continue to fight against the COVID-19 pandemic.
Criticisms and misinformation
This research traces back to December 2020 when Jaenisch and Young first published this work in a preprint on bioRxiv and the team has since received a great deal of criticism over their work. Some, like Feschotte, criticized the science in the original publication, believing that the data was too thin to support the hypothesis of reverse transcription. Anastasiya Kazachenka from the Francis Crick Institute and George Kassiotis, from the department of infectious disease at St. Mary’s Hospital at Imperial College London, published a paper on bioRxiv which pushed back on the claims made by Jaenisch and Young. Their paper claimed the original data, “are more likely to be a methodological product, [sic] than the result of genuine reverse transcription, integration, and expression.”
The team has been open to scientific criticisms of their work. Jaenisch acknowledged that Kazachenka and Kassiotis might be right and that the technique they used probably created human-viral chimeras. The researchers also know that their data was incomplete and weak when they first published it on bioRxiv.
Like most journals, PNAS requires authors to immediately post all COVID-19 related studies to a preprint server. Rather than waiting months for potentially informative studies to make it through a peer review process, immediately posting results to a preprint allows scientists to get early access to information that might prove useful to COVID-19 studies.
Despite this system, which is intended for use only by scientists, some critics have accused Jaenisch and Young of stoking unfounded fears that COVID-19 vaccines, which are based on messenger RNA (mRNA), could somehow alter human DNA. Importantly, mRNA vaccines do not alter human DNA. Janesich and Young have also repeatedly stressed in each of their publications that they do not imply that mRNA vaccines can integrate into human DNA. They have also received unfair criticism over the idea that people who have integrated COVID-19 genes are contagious, a claim they disavow in their thesis.
Even though this controversy has calmed down since December, both Jaenisch and Young say this is the most criticism they’ve ever received for a preprint. So much so, when Jaenisch was asked about the decision to release the preprint in December ahead of the original journal submission (which was rejected), he said, “I probably should have said screw you, I won’t put it on bioRxiv. It was a misjudgment.” Jaenisch has also pointed out that the journal where he was initially seeking publication required all coronavirus papers to be posted on the preprint server on submission.
To capture that same sentiment from the other side, a microbiologist on bioRxiv posted a comment saying “If there ever was a preprint that should be deleted, it is this one! It was irresponsible to even put it up as a preprint, considering the complete lack of relevant evidence. This is now being used by some to spread doubts about the new vaccines.”
This case points up the importance of being intentional and careful as we gather information in science, especially as it relates to health and a novel virus. Should we encourage scientists to share information rapidly through preprint servers to help “get information out there”, even if the information is flawed? Should we suppress some kinds of research in less developed stages to fight back against dishonest actors who would use the information inappropriately? How do we maximize our ability to share useful information while minimizing bad studies and misappropriation of research? These are the kinds of questions the scientific community will need to answer as we come out of this pandemic and continue to progress into the 21st century.