13 Apr What the Red Queen hypothesis and gene noise tell us about coronavirus
“Now, here, you see, it takes all the running you can do, to keep in the same place”
“Through the Looking-Glass” by Lewis Carroll
While the world is racing to find drugs and vaccine against the coronavirus, we propose to focus on treatments that lessen the severity of the disease in order to improve the survivorship. Thus, managing pneumonia and sepsis, the most common cause of death from the coronavirus, becomes the priority. We propose an effective tool to predict clinical outcome and demonstrate that mitochondrial and peroxisomes dysfunctions implicated in the pathogenesis of pneumonia and sepsis can be effectively treated by methylene blue and phenylbutyrate, cheap and safe drugs.
In the past several months the global spread of the novel coronavirus has caused an upheaval not seen since the 1918 Spanish flu pandemic. This newly emerged virus, SARS-CoV-2, is characterised by a rapid spread and high mortality rate. There is currently no treatment for the coronavirus, and companies and scientists around the world are racing to find the best drugs to treat COVID-19 and to develop an effective vaccine. But this race is endless, and next time we will have to search again for new wonder drugs and vaccines.
It is a close reminder of the Red Queen and Alice race, where they have to run just to stay in the same place in the looking-glass world. In biology, this metaphor led to the Red Queen hypothesis, which describes the evolutionary race between host (human) and parasite (virus, bacteria) species, who constantly adapt and evolve side by side in response to each other in order to survive. In other words, we must always “run” in this arms race, otherwise we may go extinct.
There is a global hunt for a coronavirus drug and a vaccine. In the meantime, the numbers of infected and dead pile up. As the Red Queen says: “If you want to get somewhere else, you must run at least twice as fast.” We cannot afford to wait for months it might take to find wonder drugs. In a fight against time we propose to focus on treatments that would lessen the impact of the coronavirus and for this matter other infections by reducing disease severity and thereby saving lives.
Scientific data show that coronavirus causes pneumonia of varying severity as well as sepsis, a life-threatening condition when the immune system overreacts to infection leading to death. About 15% of severely ill COVID-19 patients develop acute respiratory failure requiring intubation and artificial ventilation, which also increases the risk of the sepsis. Unfortunately, sepsis is often detected too late, treatment is challenging and mortality rate is high. According to The Lancet, nearly a quarter of all deaths worldwide are caused by sepsis.
As there is no treatment proved to be effective against the virus, the sepsis management becomes the priority. It includes finding novel drugs to treat sepsis and predicting clinical outcome, namely mortality.
Sepsis is highly heterogenous in nature, which makes treatment very challenging. We took a novel approach to tackle this question. Given the heterogenous response of individuals to the disease, we reasoned that the solution might lie in gene noise. Our analysis revealed that gene noise in immune and other pathways allow prediction of patients’ mortality with high accuracy. We also found that gene noise in genes encoding mitochondrial and peroxisome proteins represent potential targets for adjuvant treatment of sepsis by methylene blue and phenylbutyrate respectively.
Methylene blue, first prepared in 1876, has a long history of utilisation. It is a safe, cheap and effective drug listed on WHO’s List of Essential Medicines, with the main side effect being blue staining of urine. Methylene blue does two things. It restores mitochondrial respiration, and thus cellular bioenergetics. It also inhibits nitric oxide (NO) production, a product which associates with poor prognosis in sepsis patients. In addition to its benefits for treating respiratory failure, methylene blue is equally effective for treating sepsis.
Phenylbutyrate is an orphan drug, which is converted to a substance that helps eliminate extra ammonia. But phenylbutyrate also restores peroxisome biogenesis. Similar to mitochondrial respiration, peroxisomes play an important role in the pathology of sepsis as their dysfunction results in oxidative stress, a potential life-threatening condition. Likewise, pathological accumulation of ammonia may lead to death of sepsis patients. As such, phenylbutyrate appears to be promising in the sepsis management.
Methylene blue and phenylbutyrate, cheap and safe drugs, offer a great potential asadjuvant treatment of pneumonia and sepsis, the most common cause of death from COVID-19.