The mysterious loss of smell due to COVID-19 begins to clarify

We begin to have molecular explanations for this irritating but common symptom.

On a Saturday in early April last year, while sipping an infusion of fresh mint leaves, Eian Kantor realized that he had lost his sense of smell. She suspected it when she noticed that the tea didn’t smell of anything, so she rummaged in the fridge to sniff out a pot of pickles, a chili pepper sauce, and some garlic. But nothing.

Since New York State was confined in late March, 30-year-old Kantor and his girlfriend have been isolated in their Queens, New York apartment. So I did not even suspect that I could have COVID-19 despite a mild fever that he attributed to seasonal allergies. When she got tested weeks after her loss of smell (anosmia), she was negative. Months later, other tests indicated that he had antibodies against the new coronavirus “wildly high, confirming that he had passed the disease.”

It is estimated that 80 percent of people with COVID-19 have abnormalities in smell, and that many also have dysgeusia or ageusia (alteration or loss of taste, respectively), or changes in chemoesthesia (the ability to perceive irritating substances , like chillies). Loss of smell is so common in people with COVID-19 that some researchers have recommended using it as a diagnostic test, as it could be a more reliable marker than fever or other symptoms.

How the new coronavirus deprives its victims of these senses remains a mystery. At the beginning of the pandemic, doctors and researchers were concerned because they thought that COVID-19 anosmia indicated that the virus was making its way into the brain through the nose, where it would cause serious and lasting damage. It was suspected that the path would pass through olfactory neurons, which perceive odors in the air and transmit the signal to the brain. But the studies indicate that this is probably not the case, says Sandeep Robert Datta, a neuroscientist at Harvard Medical School. “All the data to date makes me think that the invasion really begins in the nose, in the nasal epithelium”, a layer of cells similar to the skin that is responsible for detecting odors. “It seems that the virus prefers to attack support cells and stem cells, but not neurons directly,” says Datta, and points out that this does not mean that neurons are not affected.

The surface of the olfactory neurons does not have the ACE2 receptor (angiotensin converting enzyme 2) that the virus uses to enter, while the support cells, which provide important support for the olfactory neurons in different ways, are dotted with them. These are the cells that maintain the delicate balance of saline ions in the mucus that neurons depend on to send signals to the brain. Any alteration of this balance would turn off neural signaling and with it smell.

Sustainability cells also provide the metabolic and physical support necessary to sustain the cilia emitted by olfactory neurons, where the receptors that detect odors are concentrated. According to Datta, “the physical alteration of these cilia causes loss of smell.”

Available tests

In a study by Nicolas Meunier, a neuroscientist at the University of Paris-Saclay, published in the journal Brain, Behavior and Immunity , the snouts of Syrian golden hamsters were infected with SARS-CoV-2. In two days, almost half of the support cells were infected, but not the olfactory neurons, even if two weeks had elapsed. What surprised Meunier was that the olfactory epithelium was completely detached, like the skin that peels off after a sunburn. Although the olfactory neurons were not infected, the cilia had completely disappeared. “The absence of cilia leads to the loss of olfactory receptors and the ability to detect aromas.”

The destruction of the olfactory epithelium could explain the loss of smell. It remains unclear whether the damage is done by the virus itself or by the invasion of immune cells that Meunier observed after infection. The abundance of reports of anosmia due to COVID-19 does not occur in other viral diseases. “We think it is very specific to SARS-CoV-2,” says Meunier. In a previous study of their laboratory with other respiratory viruses, they found that sustainable cells were not usually infected, while with SARS-CoV-2, almost half contained the pathogen. With other viruses, smell is often compromised by nasal congestion, but COVID-19 does not usually cause it. For Meunier, “it is very different.”

The researchers came up with a few clues to the loss of smell, but the mechanism by which the virus causes loss of taste is fraught with uncertainties. Flavor receptor cells detect chemicals in saliva and send the signal to the brain, but, according to a paper published last July, they do not contain ACE2, so they are unlikely to be infected with SARS-CoV- two. In contrast, other support cells in the tongue do carry the receptor, which may provide some clue to the disappearance of taste. Although the taste may seem to disappear with anosmia because odors are a key component of taste, many people with COVID-19 develop true ageusia and do not taste even sweet or salty.

Nor do we have an explanation, yet, for the loss of perception of other characters, such as the itchiness of chilli peppers or the refreshing sensation of mint. These sensations are not flavors, but their detection is transmitted through the body (including the mouth) by nerves that detect pain, some of which express ACE2.

Those recovering from anosmia are another source of explanations for the loss of smell due to the virus. According to Datta, “most patients lose their sense of smell as if a switch were turned off, and they regain it just as quickly. When the anosmia is much more persistent, recovery takes longer. The olfactory epithelium regenerates regularly. Meunier explains that “in this way the body is protected against the continuous avalanche of toxins that reach it from the environment.”

Even today, more than seven months after he first experienced anosmia, Kantor is one of the group of patients who still cannot smell anything at all. «It costs a lot, because you are not aware of how much you need smell until you lose it. If there was a fire in the house, I wouldn’t know about it. It worries me a lot. ” And, furthermore, anosmia takes away pleasure from food: “My favorite foods now don’t taste like anything to me.”

Carol Yan, a rhinologist at the University of California, San Diego, says that anosmia poses a real health risk. “It really increases mortality because if you don’t smell or taste food, you are exposed to harm, for example rotten food or a gas leak. It can also lead to social isolation or nutritional deficiencies. “

Sensory disturbances extend to another symptom called parosmia, a possible sign of recovery in people with long-lasting anosmia. This is the case of Freya Sawbridge, a 27-year-old New Zealander who fell ill with COVID-19 in March last year. After several weeks with anosmia and ageusia, when everything tasted like “ice cubes and cardboard”, Sawbridge began to recover the most basic flavors (sweet, salty and bitter), but no taste nuances from the aroma of food. “Chocolate tastes like sweet gum to me,” he says.

After about five months he recovered some smells, but not as expected: for a while, all the foods smelled like artificial raspberries and now “everything has a terrible and distorted smell. Nothing smells like it should and I find the aromas unpleasant. ” For Sawbridge, the smell of onions is unbearable, and a strange, artificial scent permeates everything. “All foods taste like they’ve been sprayed with glass cleaner to me.”

Parosmia may occur when newly generated stem cells that differentiate into neurons in the nose try to extend their long fibers, called axons, through tiny holes at the base of the skull to connect with the brain structure called the olfactory bulb. Sometimes axons connect to the wrong place and cause an erratic odor, although these misconnections usually self-correct after a sufficient time.

Recovery of smell

This news is great for people like Sawbridge. But the question you want an answer to is about how long your anosmia will last. According to Yan, “we do not know how long it will take for people with anosmia to recover,” but the normal is between six months and a year. “With long-term postviral anosmia due to the flu, the chance of spontaneous recovery after six months is between 30 and 50 percent” without any treatment. And he continues: «Cases have been described that recover after two years. After this period, we believe that the regenerative capacity could be inhibited, so, unfortunately, the possibility of recovery would be very remote ”.

Kantor has tried everything imaginable to regain his sense of smell: high-dose corticosteroid treatment to reduce inflammation; a smell training program with essential oils; b-carotene supplements for nerve regeneration; acupuncture … Nothing has made any difference. Yan recommends “flushing” the sinuses with budesonide, a topically administered corticosteroid shown to improve outcomes in a Stanford University study of patients who lost their sense of smell for more than six months after the flu . Other treatment Promising that Yan and his colleagues are investigating is platelet-rich plasma, an anti-inflammatory preparation isolated from blood that has been used to treat some types of nerve damage. But Yan says that regardless of treatment, the results “are not sensational. No one is going to get up noticing that they smell again. But if you smell soap again or enjoy the taste of some foods, you have gained a lot. “

And one final worrying note about anosmia: It has been determined to be a risk factor for some neurodegenerative diseases. Meunier informs us that “after the pandemic flu of 1919 we saw an increase in the prevalence of Parkinson’s disease. It would be really disturbing if something similar happened now.

But Yan thinks this fear is exaggerated: “There is certainly a connection between anosmia and disease, but we believe that virus-induced anosmia occurs by a very different mechanism. That we have postviral anosmia does not imply that the risk for other diseases is greater, because they are two completely independent phenomena. This should reassure Sawbridge and Kantor, as well as the millions of people around the world affected by COVID-19-related anosmia.

The immune ravages of COVID-19

The virus sabotages the body’s chemical defense system.


The design of treatments against SARS-CoV-2 depends on a thorough understanding of its interaction with the cells of the body and the immune response displayed against it.

The virus unleashes a hyper-inflammatory response by the immune system that causes severe damage throughout the body. The ins and outs of this process continue to be elucidated.

In addition to the rapid cell spread facilitated by its route of entry, and its rapid multiplication, the virus causes changes in the ranks of white blood cells to its advantage.

All these aspects are being investigated at a forced pace and with an unprecedented investment of resources that has changed the rules of basic research.

We will surely remember the 21st century divided in two: before and after SARS-CoV-2. Despite decades of warnings about the risk of a deadly global pandemic, health systems have been completely overwhelmed. The first COVID-19 patients were admitted to a hospital from Wuhan on December 16, 2019. Many citizens around the world felt safe because of the great distances, even though China was not able to contain the virus within its borders. This complacent viewpoint ignored that previous coronavirus outbreaks, such as SARS-CoV (causing severe acute respiratory syndrome) and MERS-CoV (causing Middle East respiratory syndrome), spread across multiple continents and that this The latter has not yet been eradicated. The fact is that SARS-CoV-2 spread across the globe in early 2020 and the health response was chaotic and motley. Some governments issued home confinement orders and the requirement to wear a mask, while others simply hoped that everything went well. At the time of writing this article,

Despite the disorganization, health professionals and researchers prepared to combat the new threat in a coordinated manner before its arrival. Less than a year has passed, but thanks to global collaboration we already know quite a bit about the new coronavirus and its impact on the human body. We are beginning to understand why SARS-CoV-2 causes very different diseases: some people show no symptoms, while others cough or have a fever. Most seriously, some people suffer from life-threatening pneumonia and a condition called acute respiratory distress syndrome (ARDS). Today we already know that this virus, like SARS-CoV and MERS-CoV, causes the immune system to become disoriented and causes inflammation that will lead to ARDS and a range of dangerous symptoms. The most handy clinical tests clearly show a very high concentration of immune proteins (IL-6, TNF-a and CRP) in the blood of critically ill patients. A few months after the start of the pandemic, the promising Broad spectrum immunosuppressants , such as the corticosteroids prednisone and dexamethasone , which would end up giving unsatisfactory results. At least this served to confirm the suspicions that, in the sickest patients, the immune system was running rampant and causing hyperinflammation. They were the same anti-inflammatory treatments adopted against severe infections during previous coronavirus outbreaks.

Today we know that in a fraction of patients with COVID-19 an excessive immune response is unleashed that causes damage throughout the body, with blood clots, heart damage and even organ failure. The most serious cases require admission to intensive care units (ICU). The usual cocktail of steroids is not enough to treat them: they need more targeted treatments. We also urgently need rapid tests to examine tissue samples for biological indicators (biomarkers) that predict the course of the disease, such as the likelihood that a mild case will worsen.

Immune disorientation

The development of biomarkers and pharmacological treatments is based on a thorough understanding of the interaction between SARS-CoV-2 and the cells of the body, as well as the immune response to the arrival of the virus. Last spring, in collaboration with many laboratories, we began to explore the immune dysregulation that occurs in severe cases of COVID-19. From the beginning we knew that the immune system orchestrates an intricate chain of mechanisms to repel invading pathogens. Also that if any of the stages of this response begins at the wrong time, it can trigger an exaggerated inflammation that damages the tissues. There is a quick emergency response and a slower but more durable response to viruses, bacteria, fungi, and more. The first is the “innate” response, in which some receptors on the surface and inside the immune cells detect intruders and activate an elaborate signaling cascade involving proteins called cytokines. These alert neighboring cells to prepare their defenses, initiate the death of infected cells or amplify the alarm with the synthesis of other types of cytokines. The cells responsible for the innate response also attract certain leukocytes from the blood so that they mount a more lasting immunity against the pathogen. Within a week or two, these members of the “adaptive” immune system are activated, reinforcing the amount of antibodies and specific T lymphocytes that will eventually neutralize or kill the invader.

In most COVID-19 patients, the innate immune system does its job as it learns to neutralize and destroy SARS-CoV-2. But in almost 5 percent of cases, the counterattack does not go as planned: When the carefully programmed cascade of signals is twisted, the cells of the innate response react by making too many cytokines, an overproduction reminiscent of the “cytokine storm.” »That appears in other clinical pictures and was thought to contribute to COVID-19 aggravation. The most recent research suggests that, in most cases, inflammation is not the typical storm, although it also poses a threat to the patient’s health. If you cause ARDS, the lung and other tissues will suffer lasting damage. It also involves the synthesis of fibrin, a protein that encourages clot formation. And if all this was not enough, the liquid fraction of the blood begins to leak out of the blood vessels (extravasation), which triggers respiratory failure.

All viruses manipulate cellular machinery to their advantage to reproduce. One strategy of the innate immune system is to sabotage that ability, but it appears to fail against SARS-CoV-2. In recent months, interferons, a type of cytokine that act as the first line of defense, blocking the replication of the virus within the cell, have received a great deal of attention. In theory, the rapid production of type I interferon (IFN-I) would make it possible to contain the virus and not exceed the limits of a mild infection, but some studies indicate that it would continue to reproduce due to the delay in the immune response in the elderly or in patients exposed to large amounts of the virus. What’s more, the entry into the scene of interferons would end up unleashing a hyperreaction that would stimulate the massive manufacture of other cytokines, which would lead to severe inflammation and symptoms. Measuring the response to interferons would provide vital insight into the progression of COVID-19 into a life-threatening disease, as well as some keys to treating the infection.

However, there are so many ways to put sticks in the wheels of the immune response that we learn as we go. For example, the virus could make it difficult for the patient to synthesize interferon. Another possibility is that certain patients produce less IFN-I for genetic reasons. It is even possible that the individual’s immune response is so erratic that it ends up making antibodies against IFN-I. There are several scientists who are investigating whether the presence of these “autoantibodies” would eventually cause COVID-19 symptoms, in which case it would serve as a biomarker to predict worsening. Some patients would also benefit from infusion of laboratory-made interferon. Clinical trials of such treatments have already begun, but the results are still unclear.

Many laboratories around the world have reoriented their line of research to focus on the fight against COVID-19.  In Siena (Italy) a biosafety laboratory develops an antibody test.  [PAOLO LAZZERONI, GETTY IMAGES]

Many laboratories around the world have reoriented their line of research to focus on the fight against COVID-19. In Siena (Italy) a biosafety laboratory develops an antibody test. [PAOLO LAZZERONI, GETTY IMAGES]

An inflammatory rash

The cytokine storm was news in the severe cases of the preceding coronaviruses (SARS-CoV and MERS-CoV), so when SARS-CoV-2 appeared, the intervention of a similar mechanism was naturally seen. From the beginning of the pandemic, doctors detected a high concentration of cytokines in patients, but their quantity and the subsequent inflammatory state they caused differed from the typical storm.

These patients were shaken from within by the high concentration of cytokines that, depending on the cell that received them, had disparate consequences, some very harmful. Cytokines such as IL-6, TNF-a, IL-1b, and IL-12 amplify inflammation and tissue damage. Diane Marie Del Valle of the Icahn Mount Sinai School of Medicine in New York and her colleagues described a  remarkably high concentration  of some in the blood of about 1,500 New York patients. This indicated that an abnormal elevation of IL-6 and TNF-a could serve as a reliable predictor of severity and risk of death.

We observed the same changes in the patients whose evolution we followed closely. Furthermore, we weren’t the only ones to begin to recognize some unusual extreme values ​​in patients’ cytokine profiles relative to a typical cytokine storm. We observed an increase in  IL-5  and  IL-17 , which are not usually associated with antiviral activity, since they usually appear as a response against parasites and fungi. We still do not know if this causes tissue damage or if it only diverts resources that would otherwise be used to fight the virus.



In some patients we also find a high concentration of chemokines, a subclass of cytokines that guide immune cells to where they are needed. The accumulation of the chemokines CCL2, CCL7, CXCL9 and IL-8 generated in the infection foci would serve as a kick-off. Not only was there local damage caused by cytokines and other immune messengers, chemokines also recruited cells from throughout the body to join the battle.

Numerous research groups have decided to look at blood and lung cells in order to discover the origin of tissue lesions. In the field of immunology, flow cytometry is widely used, as this technique allows the various types of blood cells to be labeled with fluorescent antibodies. Thanks to these markers, our group has been able to detect a large change in the composition of the circulating immune cells of patients, in contrast to that of healthy donors. Two types of innate immunity cells stand out for their abundance: monocytes and neutrophils. Let’s look at an example: in healthy donors, monocytes make up 10 to 20 percent of peripheral blood mononuclear cells, a well-studied set of white blood cells. Instead,

As an integral component of the innate immune system, monocytes patrol the blood and are the first to initiate the elimination or isolation of pathogens. When they perceive a microbial threat, they respond by transforming into two types of white blood cells: macrophages, which engulf pathogens and cell debris, and dendritic cells, which recognize and mark pathogens for target recognition by other defensive cells. The number of monocytes is strictly regulated so that the immune system does not overreact, but this control is lost in severe cases of COVID-19. In the  worst cases, monocytes and macrophages infiltrate the lungs. When the team led by Mingfeng Liao of the Chinese Center for Clinical Research of Infectious Diseases in Shenzen, analyzed the interior of these  organs  in critically ill patients using cell samples obtained from the fluid of the lower respiratory tract with the technique of bronchoalveolar lavage (BAL). ), found  monocytes and macrophages  in abundance. In line with  other findings , both cells expressed an amount of cytokines comparable to that of severe inflammation. As cytokines, synthesized primarily by monocytes and macrophages, are supposed to worsen all these damages, anything that blocks their inflammatory activity would prevent the infection from worsening.

If cytokines turn out to be the main drivers of severe COVID-19, it would make sense for us to try to reduce them in patients. This is achieved with certain drugs, such as tocilizumab, which blocks the receptor to which an important cytokine, IL-6, binds. Unfortunately, this drug  does not appear to improve  disease outcome in clinical trials. More and more scientists and clinicians are looking beyond the cytokine storm for a more satisfying explanation for the damage caused by the hyperinflammatory response to COVID-19.

A peptide or small protein called bradykinin also appears to contribute to the immune disorder of COVID-19. When they re-analyzed the lung fluid data from the patients, Michael R. Garvin of Oak Ridge National Laboratory in Tennessee and his colleagues  hypothesized  that bradykinin would induce an inflammatory response, like cytokines. And the latter would make those “bradykinin storms” worse. Too much of it would cause massive dilation of blood vessels and many of the surprising symptoms that COVID-19 patients display, such as arrhythmias and sudden cardiac arrests. A notable increase in hyaluronic acid synthesis has also been observed in severely ill patients. , whose aggregates retain a large amount of water. The flooding of the lungs that is discovered in the autopsies makes clear the dire consequences that for some patients the confluence of this affectation with extravasation from the blood vessels has.

The implication of bradykinin in COVID-19 has not yet been confirmed, but although its direct measurement remains difficult, the incipient successes of an   exploratory study with icatibant, a bradykinin receptor inhibitor, support the hypothesis. that lowering the concentration of this peptide would alleviate severe cases.

Defective microbial traps

Bradykinin also appears in another inflammatory pathway in the blood of patients, since its synthesis would be activated by  neutrophils , responsible for phagocytosis of pathogens. Different laboratories, including ours, have found a  huge accumulation  of neutrophils in the blood of some patients. The large amount of IL-8 cytokine that circulates in the blood with COVID-19 attracts these cells to the sources of infection, such as the lungs, and contributes to their abundance. The detection of this elevation of neutrophils on the first day of hospitalization is key, since it reliably predicts transfer to the ICU. Some  articles Recent ones point to them as one of the possible culprits of the COVID-19 picture, for emitting the so-called extracellular traps set by neutrophils (TEN). These are meshes of DNA, antimicrobial proteins, and enzymes that isolate and destroy pathogens, but would unfortunately also damage tissue.

In lung autopsy specimens, Moritz Leppkes and his colleagues at the Friedrich-Alexander University in Germany have discovered   striking blockages in blood capillaries from TEN aggregation. They have also observed TEN in the vessels of liver and kidney samples. In addition to obstruction, TEN degrade anticoagulant proteins, contributing to clot multiplication   in severe cases. Recognizing the possible implication of these aggregates, McGill University has announced a  pilot study  of a cystic fibrosis drug that sheds DNA from TENs.

All of these studies have shown that SARS-CoV-2 directs the immune system against itself. But it is not only innate defenses that circulate uncontrollably; the adaptive immune system is also impaired. One of the most obvious differences between the blood of some COVID-19 patients and healthy people is the marked lymphocytopenia, specifically the shortage of T lymphocytes, key components of long-term adaptive immunity. It has been seen that the behavior of T lymphocytes in moderate patients differs from that in severe patients: lymphocytes that are specific for an invader, or antigen, normally accumulate as a protective measure, but this is not the case in the sickest.

There are two types of T lymphocytes: some kill virus-infected cells without delay and others only act against any invader once they receive the signal from cytokines. As in other  respiratory infections , it has been  observed that those hospitalized with COVID-19 lose both, although a small remnant persists for a long time, up to weeks in some cases. Thanks to the study of other respiratory viruses, we know that T lymphocytes leave the blood to settle in infected tissues. Those infected with these viruses raise the levels of chemokines that guide T lymphocytes to infectious foci, such as CXCL9 and CXCL10. On the other hand, although the blood of patients with COVID-19 contains a multitude of chemokines, we did not observe a similar abundance of T lymphocytes. Several studies have focused on the lungs of patients with severe COVID-19 symptoms because that is where they are hosts the virus. A nucleotide sequencing method called scRNA-seq (single cell RNA sequencing) has identified several subsets of immune cells, including a sizable conglomerate of T lymphocytes. But this finding did not provide a complete explanation. . Neither these experiments with lungs nor Autopsy studies of  numerous organs explained the shortage of T lymphocytes in the blood. The absence is likely due simply to his death, and in fact  data  from many research groups support this conclusion.

How then do T lymphocytes disappear? Many of them have a  receptor  that indicates their propensity for early disappearance in COVID-19 patients. Another possibility is that the bone marrow cannot make enough precursor cells to differentiate into T lymphocytes, so they would be in short supply among mature cells. Studies on aging and other diseases have clearly shown that cytokines modulate the production of T lymphocytes in the bone marrow. But even though the same inflammatory cytokines appear in COVID-19, a similar connection remains to be confirmed. Finally, it could happen that it is the virus itself that kills them. Contrasting these hypotheses would indicate us with what treatments would increase their effectiveness.

Many of the serious immune manifestations of COVID-19 appear in other viral respiratory infections (drastic elevation of cytokines, infiltration of inflammatory cells in the lungs, TEN, and a decrease in white blood cells). SARS-CoV-2 brings with it its own challenges, especially a spread never seen before during the presymptomatic phase and among people who do not have any symptoms.

SARS-CoV, responsible for the 2003 epidemic, reaches its maximum multiplication relatively late, 10 days after the onset of symptoms. MERS-CoV reaches that point between 7 or  and 10 or  day. SARS-CoV-2 only takes  3-5 days . This precocity of the peak means that before symptoms appear, which in most people happens four or five days after infection, the infected person already releases a large amount of viral particles. That is, you spread the virus everywhere before you feel the slightest itchy throat.

The involvement of so many organs in the symptoms of COVID-19 also seems a unique trait among respiratory viruses. The  SARS-CoV-2  anosmia causes, obtundation, digestive problems, blood clots, cardiovascular disease and even covídicos chilblains. It also infects neurons in the brain. In the recovered, the tissue lesions persist for  months . All this is not so surprising if we realize that the three types of cells that make up blood vessels (endothelial, pericytes and vascular smooth myocytes) surround all tissues and are  dotted  with ACE2 receptors. And since this receptor is the gateway of SARS-CoV-2 to the cell, these tissues would constitute a kind of  red carpet. To make matters worse, cytokine and bradykinin storms damage the tissues these cells form.

Despite the fact that its predecessor, SARS-CoV, uses the same receptor and causes cytokine storms and ARDS, severe extrapulmonary lesions, similar to those of COVID-19, appear to be rare. 80 percent of the genome of both viruses is almost  identical , so it is possible to suspect that the remaining 20 percent is responsible for the differences. Another simpler explanation would be that SARS-CoV-2 has infected many more people than its predecessor (6,700 times more, so far), and it has done so in the eyes of the scientific community.

The past nine months of discoveries and innovation testify to the commitment and dedication of scientists and healthcare professionals. They have never been more united by a common purpose, and never before has the translation from the laboratory to the patient been so rapid as today. This legacy will endure despite the successes or failures of the hundreds of trials seeking treatment for COVID-19. Innovations will remain to fight future pandemics.

Keep calm in times of uncertainty

When will the COVID-19 pandemic end? What havoc will the economic crisis wreak? Can we save the planet? Uncertainty makes us anxious. However, there are ways to overcome our fears and regain serenity.


Faced with the unknown and unpredictable, such as the COVID-19 pandemic, we imagine the worst. It is a cognitive bias that leads us to overestimate the impact of tragic events.

Uncertainty acts as a magnifying glass directed at our mental contents that cause us anxiety and negatively influence our mood.

Acceptance and commitment therapy offers numerous tools to alleviate the negative thoughts that cause us anxiety. Among these, cognitive defusion.

A pandemic that affects the health of millions of people, an economic crisis that destabilizes the labor market, an increasingly exploited planet … Uncertainty has been installed as a guest of honor at this beginning of the 21st century. Undoubtedly, we had ignored their presence under the sweet purr of a consumer society that promised to immediately satisfy all our desires and, logically, we were distressed by this unforeseen and this new dose of ignorance.

How do we react to uncertainty? Why do we feel so puzzled sometimes? Are there means to better manage this situation? As we will see below, uncertainty is most destabilizing when we assume that the uncontrollable and the unknown are fraught with potential evils. We often fear the unknown because we do not know what it will bring us and because in the face of that blind spot we tend to assume that disasters are coming.

This bias that leads us to overestimate the impact of tragic events on life has been studied in depth by psychologist Daniel Kahneman of Princeton University. His work won him the 2002 Nobel Prize in economics, along with Amos Tversky, from the universities of Jerusalem and Stanford. In his book Think Fast, Think Slow , Kahneman highlights the human inclination to overestimate the impact of life’s tragic events; not because of the possibility that they affect us, but because of the damages that they could cause. However, we are likely to adapt to them much better than we anticipate.

A big trap: the focal illusion

To get an idea of ​​the gap between our expectations and reality, let us be guided through harrowing scenarios by those who have actually been through them. Sometimes, from the mouths of friends or even our own, we hear phrases like: “If my son died, I would not bear it”, “If my husband left me, I would be devastated and could never get over it”, “If I lost mobility of the legs after an accident, I would rather die ”, etcetera. However, these hypothetical future concerns respond to what researchers call “the focal illusion”: we place too much importance on what we fear and instead ignore other factors that would have a real impact on our well-being in the case. of them happening.

In a longitudinal study published in 2003, married people who had to cope with the death of their spouse were followed for several years. The interest of this type of study lies in being able to compare the well-being and satisfaction of the same people before, during and after the trance. In this way, the method avoids the methodological bias that occurs when different people are compared at different stages of the separation process. It was clearly demonstrated that widowhood is a painful event and that well-being plummets. But it was also shown that the perception of well-being improves progressively over time: five years later, the life satisfaction of the participants had recovered to almost its initial level, and it is possible to suppose that the happiness in the day to day did not present any difference any. The person then begins a new life.

A magnifying glass that amplifies the evils

The loss of a spouse is burdensome, but as painful as it may be, it can at least lead to new encounters that help to get out of loneliness and rebuild life. But what about irreversible tragedies with permanent results? What to do when an accident causes a lifelong disability? If participants without disabilities and without any contact with paraplegic people are asked to estimate the percentage of sad feelings that the latter experience on a daily basis, their assessment is close to 70 percent.In other words, for them, a person with paraplegia mainly experiences negative emotions. They tend to think that disability undermines everyday life and, of course, they consider that, if the same happened to them, it would greatly overshadow their own existence.

It is interesting to analyze the reasons that contribute to this perception bias. The analyzes reveal that the respondents only imagine the difficulties that paraplegic people face on a daily basis, and ignore the sweeter aspects of existence that are also present: spending time with family, going to the movies, seeing friends or eat in a restaurant, among many others. Pleasant activities are just as enjoyable for people with paraplegia, but our brain gives more importance to what we lose (being able to use our legs) than to everything else. This phenomenon, known as “loss aversion”, was one of the pillars of Kahneman and Tversky’s Nobel Prize [ see “Preference Psychology”, by Daniel Kahneman and Amos Tversky; Research and Science, March 1982].

Influenced by the focal illusion, we focus our attention on certain parameters to the detriment of other more pleasant ones.

But when such a question is posed to those affected by disability, they respond that, in general, they do not experience more bitter feelings or a worse mood than those of healthy people, once they accept their new condition. This led Kahneman to state: ‘Various detailed observations show that paraplegics are in a good mood more than half the time from the beginning of the second month after the accident, although their mood is obviously gloomier when they think about it. your situation”. This echoes a famous study carried out by the social psychologist Philip Brickman (1943-1982), in which he compared the degree of well-being of people with paraplegia with that of lottery winners. According to their results, the former took almost as much pleasure in their daily lives as the control group and more than the lottery winners! While it is true that people with paralysis lead a more complicated existence in some practical ways, their life is just as satisfying as for others. Especially when there is a phenomenon of post-traumatic growth (positive psychological change as a result of adversity to achieve higher vital functioning).

When we do not know what the future will bring, and we see other people sick with a virus, affected by an attack or who have lost their jobs, the uncertainty about what awaits us often makes us imagine the worst. This is the source of our anxiety. Influenced by the focal illusion, we focus our attention on certain parameters to the detriment of other more pleasant ones. And hence Kahneman’s “antidote phrase”: “Nothing in life is as important as what you think and when you think about it.” This helps us to remember that in our inner theater, the projector of attention pays an inordinate importance to what it illuminates to the detriment of what it leaves in the shadow. And that it is in our hands to restore that balance by modifying the way of thinking. Let’s not forget that formidable coping mechanisms work in the brain to build our resilience and help us overcome and recover from adversity. In all certainty, no experience we have will affect our happiness as much as we fear.

Avoid the rebound effect

Uncertainty acts as a magnifying glass directed at our mental contents that cause anxiety and negatively affect our mood. Professor Mihaly Csikszentmihalyi, considered one of the fathers of positive psychology, puts it this way: ‘The mood of chronically depressed or anorexic people is indistinguishable from that of healthy people while they are accompanied and busy doing something that requires concentration. But as soon as they are alone and with nothing to do, their mind is invaded again by depressing thoughts and entropy settles in their consciousness. The sabotage of our care networks by our concerns would be, therefore, the main responsible for the difficulty we have to face uncertainty with serenity.

Once the evil is known, what could be the remedy? Each of us has suffered the painful experience of having inopportune thoughts that invade our consciousness despite our attempts to ignore them. We all know the rebound effect very well, which makes us think more about what we are trying to get out of our minds, like the white bear in which the social psychologist Daniel Wegner (1948-2013) asked the participants of his experiments that they will not think. Unfortunately, we are familiar with those endless mental ping-pong games in which each argument generates a counterargument that immediately sweeps away the first. No, it wouldn’t be the end of the world if I lose my job. Well, if you look at the unemployment rates … Yes, but I am qualified and I can demonstrate a solid professional experience. Yes,

Respondents only imagine the difficulties that people with paraplegia face on a daily basis and neglect the sweeter aspects of life.  Precisely those who usually value people with disabilities.  [Getty Images / dmphoto / iStock]

Respondents only imagine the difficulties that people with paraplegia face on a daily basis and neglect the sweeter aspects of life. Precisely those who usually value people with disabilities. 

Acceptance and commitment therapy

Thinking about not thinking about something is certainly not a successful strategy, and neither is countering yourself. A more promising avenue that we can all use to calm uncertainty, even when it does not reach “pathological” levels, comes from the work carried out by the third generation of cognitive and behavioral therapies, whose central idea lies in weakening the thoughts that provoke anxiety rather than fighting them in vain. These works, validated by various studies, are the origin of the so-called acceptance and commitment therapy (TAC). CT provides multiple tools to mitigate anxiety-causing thoughts beyond psychotherapies. In this regard, it is advisable to read the book  The Happiness Trap, from TAC expert psychotherapist Russ Harris.

We learn that anxiety-provoking thoughts are not, in themselves, the problem, but the credit we give them. To weaken a thought means to let it exist in consciousness, but without giving it importance. In other words, observing it as it is, as an autonomous production of our mind, and letting it go as it came. This approach is directly inspired by  mindfulness meditation.: we let thoughts flow like clouds in the sky of our mind without clinging to them. For example, we can “show gratitude” to the mind for the ideas it generates, even the most anxious ones, while it produces new ones and reminds us that, after all, a thought is nothing more than a thought. a succession of silent sounds in our consciousness. And nothing more. In the same way that an image is never reality, a thought is not reality, but only a mental representation of it, which, moreover, is often biased. The TAC speaks of cognitive defusion: we must distance ourselves from our thoughts instead of trying to modify them.

Happy Birthday! I’m going to lose my job!

CT has developed even more sophisticated techniques to weaken intrusive thoughts. One of them is to mentally express the idea that causes anxiety with a funny voice. Try repeating “It’s terrible, I’m going to get sick and lose my job” with the nervous tone of the comedian Louis de Funès playing the Saint-Tropez gendarme. You will see how everything suddenly sounds less dramatic. Another way to proceed is to tune the problematic thought to a familiar melody (e.g.  Happy Birthday). For the thoughts that arise in the form of images you can represent them on a movie screen, where you are a spectator. Beyond their apparent simplicity (mastering such strategies requires training), these tools are designed to create a distance between the thinker and the thought, to become aware that an idea is nothing more than a mental process with which we should not identify us.

In TAC therapy, the weakening of the thoughts refers to the term of acceptance. What does the second axis, that of commitment, propose to us? Changes in the world do not occur only through thoughts, but through the actions that these make possible. We always have the opportunity to act, even in situations of great uncertainty. In that case, we can identify our values ​​and take action, no matter how small, to head in that direction. It is about asking ourselves what is the smallest step we can take at that moment to move forward in the sense of what is important to us. If, for example, we are suffering from the social distancing imposed by health measures to fight the new coronavirus pandemic, it is we who must take small actions to strengthen ties with others. They can be, among others, contacting friends and family by phone or videoconference, staying in small groups of people respecting safety regulations, collaborating with a non-profit association and for social purposes, and so on. Action is always an antidote to depression: on the one hand, it mobilizes attention by diverting it from our concerns; on the other, and above all, making a concrete contribution to the world around us. Action is always an antidote to depression: on the one hand, it mobilizes attention by diverting it from our concerns; on the other, and above all, making a concrete contribution to the world around us. Action is always an antidote to depression: on the one hand, it mobilizes attention by diverting it from our concerns; on the other, and above all, making a concrete contribution to the world around us.

We are not helpless in the face of uncertainty and the anxiety that this entails. Psychology offers a multitude of tools to deal with it constructively. Being aware of the cognitive biases that aggravate our distress can help to make the trials we go through more relative. One of them is the aforementioned tendency to overestimate the setbacks that the future may bring us compared to happy events. There is also the inclination, in situations of uncertainty, to delight in information that generates anxiety and that, in some way, embodies said anguish. Above all, the tumult of our anxiety-provoking thoughts can be soothed and calmed so that we can act, even if our actions seem insignificant to us. in the direction of what we consider important. Therefore, our core values ​​are like the reassuring beacon that guides disoriented sailors in the fog.

Act with certainty in uncertainty. This phrase uttered by Conrad Lecomte, who was my clinical psychology professor at the University of Montreal twenty years ago, comes to mind frequently. The uncertainty, on which it is worth reflecting, is typical of our human condition. Faced with the destabilizing awareness, rather than being carried away by the vortices of anxiety, we can oppose it with an action of commitment dictated by our values. Action as an antidote to crisis: this is, without a doubt, how we can face the traps of our brain in the face of the challenges that await us.

What we know about nervous system disorders due to COVID-19

Neurological symptoms can have many causes, but is it possible for the new coronavirus to penetrate neurons?

Many of the symptoms seen in people infected with SARS-CoV-2 reside in the nervous system. Weeks and even months after infection, they experience headaches, muscle and joint pain, fatigue, drowsiness, or loss of taste (ageusia) and smell (anosmia). In severe cases, COVID-19 also causes encephalitis or stroke. Although the virus has undeniable neurological effects, how it affects neurons remains a mystery. Are symptoms caused by the mere activation of the immune system? Or does the new coronavirus directly attack the nervous system?

Some studies, including a recent prepublication studying mouse and human brain tissue, offer evidence that SARS-CoV-2 manages to enter neurons and the brain. We still do not know if it always does it or only in the most serious cases. Once the immune system is put into overdrive, the effects can be far-reaching, even with an invasion of immune cells into the brain, where they wreak havoc.

Some neurological symptoms are less severe than they appear, but perhaps more disconcerting. One symptom (or a set of them) that illustrates this puzzle, and which is receiving increasing attention, is the imprecise diagnosis called “clouding.” Even after the main symptoms disappear, it is not uncommon for COVID-19 patients to have a poor memory, feel confused, and do not reason clearly. The fundamentals of these sensations remain surrounded by uncertainty, although they could be due to the generalized inflammation that usually accompanies this disease. However, many people feel tired and clouded for months, even after a mild case in which the immune system has not gone haywire.

Another common symptom is anosmia, which could also be due to changes not directly related to infection of the nerves. The olfactory neurons, which transmit odors to the brain, do not have the main receptor where SARS-CoV-2 attaches, so they appear to be immune to it. It is still being studied whether loss of smell could be caused by an interaction between the virus and another receptor on olfactory neurons, or by contact with the non-neural cells that line the nasal cavity.

Experts say it is not necessary for the virus to enter neurons to cause some of the mysterious neurological symptoms that surface in some cases. Many pain-related effects could arise from attack on sensory neurons, the nerves that extend from the spinal cord throughout the body to gather information from outside or from internal processes in the body. Researchers are now focusing on how SARS-CoV-2 appropriates pain-sensing neurons, classified as nociceptors, to produce some symptoms of COVID-19.

Chronic pain from nerve injuries

Neuroscientist Theodore Price, who studies pain at the University of Texas at Dallas, took note of the symptoms described in the first articles and those explained by the patients of his wife, a telecare nurse for people with COVID-19. He found a sore throat, headaches, general muscle pain, and a severe cough (the cough is triggered, in part, by sensory neurons in the lungs).

Interestingly, some patients report that they lose a specific sense, the so-called chemosesthesia, which prevents them from detecting hot peppers or mint, perceptions that are transmitted by nociceptor neurons, not taste cells. Although many of these effects are typical of viral infections, the prevalence and persistence of pain-related symptoms, as well as their presence even in mild cases of COVID-19, suggest that sensory neurons could be affected by something more than the normal inflammatory response against infection. In other words, the effects would be directly linked to the virus itself. Price notes: “It is surprising, affected patients suffer from headaches and some appear to have pain problems similar to neuropathies.” That is, chronic pain due to nerve injuries.

The main criterion used to determine whether SARS-CoV-2 will infect a cell in the body is the presence of angiotensin-converting enzyme type 2 (ACE2) that is embedded in the surface of cells. ACE2 acts as a receptor that transmits signals into the cell to regulate blood pressure, but it is also an entry point for SARS-CoV-2. That is why Price set out to look for it in human neurons, as reported in a study published in the journal PAIN .

Nociceptor neurons and other sensory neurons are found outside the spinal cord, in distinct clusters called dorsal root ganglia (DRG). Price and his team obtained the nerve cells from post-mortem donations and cancer surgeries. They sequenced the RNA to determine which proteins were about to be synthesized in a cell; they also used antibodies against ACE2. They found that a subset of neurons in the DRGs contained ACE2, which would allow the virus to access them.

Sensory neurons send long extensions (axons), the ends of which perceive specific stimuli from the organism that they transmit to the brain in the form of electrochemical signals. The ACE2 neurons in the DRGs also had the genetic instructions, the mRNA, for a sensitive protein called MRGPRD. Their presence defines a subset of neurons whose endings are concentrated on the surfaces of the body (skin and internal organs, such as the lungs) where they would be ready to “grab” the virus.

Price argues that the acute symptoms, as well as the long-lasting ones, of COVID-19 could be due to infection of the nerves. As he explains: “In the most likely scenario, the autonomic and sensory nerves would be affected by the virus. We know that viral infection of sensory neurons has long-term consequences, ‘even if the virus is no longer in cells. And he adds: “It is not necessary for neurons to be infected.” In another study compared nucleotide sequence data from lung cells from COVID-19 patients and healthy participants (control group) to look for interactions with neurons from non-infected DRGs. His team found many cytokines (immune system signaling molecules) in infected patients that could interact with receptors on the surface of neurons. “It’s basically a lot of things that we know are involved in neuropathic pain.” This observation suggests that nerves, without being directly infected by the virus, suffered lasting damage from immune molecules.

Neurologist Anne Louise Oaklander of Massachusetts General Hospital wrote a commentary accompanying Price’s PAIN article, arguing that the study “was exceptionally good,” in a way, for using human cells. Although he adds that while “there is no evidence that the main mechanism of [neuronal] damage is direct entry of the virus into these [nerve] cells,” the new findings do not rule out such a possibility. For Oaklander, it is “very possible” that the inflammatory conditions surrounding neurons alter their activity or cause permanent damage to them. Another possibility would be that viral particles that interact with neurons promote an autoimmune attack against nerves.

It is widely accepted that ACE2 is the main entry point for the new coronavirus. But neuroscientist Rajesh Khanna, who researches pain at the University of Arizona, emphasizes: “ACE2 is not the only route of entry for SARS-CoV-2 into cells.” Another protein, neuropilin-1 (NRP1), “could serve as an alternative gateway” for the virus to enter. NRP1 plays an important role in angiogenesis (the formation of new blood vessels) and in the growth of the long axons of neurons.

The idea comes from cell and mouse studies where NRP1 was found to interact with the notorious spike protein of the virus, which helps it enter cells. “We showed that it binds to neuropilin, which could act as a receptor for infection,” explains virologist Giuseppe Balistreri, from the University of Helsinki, co-author of the mouse study that was published in Science along with another study with cells. It seems more likely that NRP1 acts as a cofactor with ACE2 rather than that it alone is sufficient for the virus to enter. “We know that there is more infection when the two receptors are present: together they are more powerful,” adds Balistreri.

Possible anesthetic effect?

These findings piqued the interest of Khanna, who was studying vascular endothelial growth factor (VEGF), a very important molecule for pain signaling that also binds to NRP1. He wondered if the virus would disturb the pain signal through NRP1, so he investigated it with rats in a study that was also published in PAIN.. Khanna explains: “We put the VEGF into the animal [in its paw] and, look where, we observed powerful pain for 24 hours. Then came the really amazing experiment, in which we introduced VEGF and spicule at the same time. The result was incredible: the pain was gone. The study showed “what happens to the signaling of neurons when the virus plays with the NRP1 receptor. The results are firm ”, says Balistreri. As he adds, they show that neuronal activity was altered “by the contact of the virus spike with NRP1.”

In an experiment with rats that were damaged a nerve to use as a model of chronic pain, it was enough to administer spike protein to attenuate the animals’ pain behavior. This finding suggests that we would be facing a possible new anesthetic: a drug that simulates the spicule and that binds to NRP1. Such molecules are already in development against cancer.

Khanna offers us a more provocative hypothesis yet to be tested: the spicule could act on NRP1 to silence people’s nociceptive neurons, perhaps masking pain-related symptoms from the onset of infection. The idea is that the protein provides an anesthetic effect as the SARS-CoV-2 infection begins, making the virus more easily spread. Balistreri does not rule it out: “It is possible that viruses have an arsenal of tools never seen before. What they do best is to silence our defenses.

It remains to be determined whether a SARS-CoV-2 infection would produce analgesia in people. Balistreri notes: ‘High doses of a piece of the virus have been used in a laboratory system with rats, but not in a human. The magnitude of the effects that are being seen [could be due to] the large amount of viral protein that he used. We will have to see if the virus by itself can [dull the pain] of a person.

The experience of patient Rave Pretorius, a 49-year-old South African, suggests that this line of research is worth pursuing. In a car accident in 2011, Pretorius fractured several vertebrae in his neck and suffered numerous nerve injuries. As he explains, he lives with a constant burning in his limbs that wakes him up every night at three or four in the morning: “I feel like someone is pouring hot water over my legs non-stop.” But this changed dramatically in July 2020, when he contracted COVID-19 at his workplace. “I was very surprised that the pain was bearable when I had COVID-19. At times, it felt like he was gone. I could’nt believe it.” He was able to sleep soundly for the first time since the accident: “My quality of life improved when I was ill, because the pain had disappeared. This, despite feeling tired and disabling headaches. Once recovered from COVID-19, he suffered neuropathic pain again.

For better or for worse, it appears that COVID-19 affects the nervous system. It is still unknown if the nerves are infected, like many other things that are not known about SARS-CoV-2. Although the virus seems, in principle, capable of infecting some neurons, this does not seem necessary, because it can cause a lot of damage from outside them.

Readers’ Letters: Vaccines and Transmission of COVID-19

The article « Will Covid-19 stop being transmitted thanks to vaccines? »[Smriti Mallapaty; Research and Science , April 2021] addresses the question of the extent to which vaccination will prevent the spread of SARS-CoV-2. It states that “preliminary analyzes suggest that some vaccines are likely to be able to stop the transmission of the virus. But it is not easy to confirm this effect or its forcefulness, because a fall in infections in a given region could be explained by other factors, such as confinements and changes in customs. Furthermore, as asymptomatic carriers also spread the virus, the detection of such infections is very difficult. ‘

The author includes the opinion of several experts and mentions the clinical trials carried out to evaluate the vaccines, as well as the intention of Pfizer to start doing swabs to see if their injections can block the infection. Studies are also pointed out that suggest that the viral load after vaccination “is a good indication of contagiousness” and two bibliographic citations are included, one from February 2 and another from February 8, 2021, which reinforce the opinions expressed in Article.

In this regard, it is interesting to note that, a few days after the original version of Mallapaty’s article appeared in the journal Nature , Noa Dagan, of the Clalit Research Institute, and her collaborators published in The New England Journal of Medicine a study evaluating the results of the vaccination campaign in Israel. This study included some 1,200,000 people separated into two groups, one of 600,000 unvaccinated individuals and another of 600,000 people who had received the two doses of the vaccine. From the results it can be inferred that those vaccinated with Pfizer’s mRNA vaccine would reduce their contagion capacity by 92 percent.

Of course, it is a single study, so we will have to wait for its results to be confirmed by other studies. However, it is a very robust trial and possibly the largest and best planned to date.

Justo Aznar
Bioethics Observatory
Catholic University of Valencia

Find  here  all the
 Research and Science content   on the COVID-19 pandemic. You can also access the articles published by  Scientific American  and other of its international editions through  this website .

Uncertainty invites wisdom

Accustomed to a welfare society based on the concept of security, current crises generate anxiety. We need to get out of our bubble and assume that life has uncontrollable and unpredictable parts.


The human brain tries to anticipate events to increase the chances of survival. When situations become unpredictable, anxiety ensues.

For half a century, we have managed to control almost everything through an excessive supply of technical means. The health and environmental crisis has cast doubt on that dream.

To confront this destabilization, we must once again trust not only ourselves, but also the bonds that bind us to our fellow human beings.

Uncertainty is, of all torments, the most difficult to bear, and in various circumstances of life, I have exposed myself to great misfortunes, for not knowing how to wait patiently. The writer and playwright Alfred de Musset (1810-1857) wrote these lines in his 1836 novel Confessions of a Century Child . How would you have felt in 2021? How would you live the second year of the COVID-19 pandemic, with more contagious strains of the virus, stuck economies, confined countries and citizens who, despite the arrival of vaccines, face a more uncertain future than ever?

Without a doubt, there have been worse times in the past: with wars, crises and even pandemics more serious than the current one, which have been much more terrible tests for humanity. But the uncertainty generated by the COVID-19 pandemic has two interesting characteristics: on the one hand, it affects populations that have become accustomed to the comfort of certainty, driven by progress that offers solutions for everything. On the other hand, it seems to be the emerging face of a much greater future catastrophe, even peremptory, since it is possible, even probable, that it constitutes the expression of a massive ecological alteration that would have facilitated the transmission of the virus from animals to humans.

An unpleasant feeling

Living things seem to spontaneously dislike uncertainty: to survive they need to clearly and quickly distinguish between good and bad, friend and foe, danger and safety. Hence the existence in the mammalian brain of structures, such as the cingulate cortex, which act as rapid detectors of inconsistencies in relation to what is known and predictable. Therefore, uncertainties are perceived as a potential risk and trigger stress alerts.

Humans like uncertainty so little because we are the anticipating animals par excellence. The need to control the environment, predictability and security is not only applied to the present, but also to the future. “I’m fine today, but tomorrow?” However, life is made up of fragile and transitory certainties. So how did our ancestors survive to bring us back to the present day?

Since time immemorial, in the face of the precarious nature of all human life, people and societies have followed a type of natural movement, namely, to minimize the uncertainties susceptible to control and effort, and to tolerate the remaining uncertainties.

In traditional societies, people stored food, saved, struggled not to be left alone, and grouped into vast family or tribal groups to cope with the unpredictability of material adversity. In the collective and cultural aspect, prudence was often encouraged through social stories, stories and proverbs (“A cautious person is worth two”), as well as a certain fatalism, a form of acceptance of adversity (“It is destiny”) . Also, there was great hope for tomorrow or a better future. Religion promised to reward the virtuous and anxious for the present (“Help yourself and heaven will help”), and the virtuous unhappy for the hereafter (“Blessed are the afflicted, for they will be comforted”).

Our contemporary societies have evolved towards different options, guaranteeing their material security, on the one hand, through more individualistic choices and limited to the nuclear family (parents and children), not to the great clans; on the other, through a collective system of insurance and guarantees, be it social laws (professional adversities), the welfare state (natural disasters) or private insurance (health adversities or destruction of material goods). The hopes for a better tomorrow, offered by religion and belief, seemed less and less necessary, as material uncertainties seemed to recede, until they were supposed to disappear (fantasies of prosperity and immortality).

Short-sighted and sleepy, satiated by our material certainties, we had come to forget the obvious: adversity is part of life, and accepting unpredictability is part of wisdom. Let’s remember the Jewish proverb: “If you want to make God laugh, tell him about your plans.” A maxim that, in 2021, seems more true than ever.

Spoiled children of safety

Many Westerners had become spoiled children of security and certainties so that, faced with the turbulence of COVID-19, they are prey to an emotional upheaval: great fears about the virus and the future, and great fury, especially towards the leaders and the experts, whom they believe incapable of protecting them and giving them their dose of certainties. When is this going to end? When will we go to restaurants again? When will we have effective drugs and vaccines?

Short-sighted and sleepy, satiated by our material certainties, we had come to forget the obvious: adversity is part of life, and accepting unpredictability is part of wisdom

Adversity always returns, uncertainty always returns. To do? Wait patiently as Musset suggested? Maybe not, but we can take advantage of the current crisis and those to come to rethink our lifestyle. First, by accepting the uncertainty and adversity inherent in all human life. It is not about holding on, but about getting stronger. Adversity and uncertainty are the norm, therefore, it is convenient to accept them and prepare without giving up savoring life. Contradictory? The ancient Romans adopted this precept: Si vis pacem, para bellum (“If you want peace, prepare for war”). In these times, we should be inspired by it and adapt it: “If you want serenity, accept adversity.”

However, it will not be easy to move from declaration of intent to behavior changes. We will have to fight against two of our contemporary poisons (in addition to addiction to security and certainties): individualism and materialism.

The fight against individualism will require a reconstruction of what we call “confidence,” which we lack. It is no longer about having confidence in oneself (personal resources), but also in others (interdependence and relational resources) and in society (collective resources). This tripod will offer us a better balance than just individual confidence.

Prepare for the unexpected

The fight against materialism will lead us to stop confusing happiness with comfort, and to accept diminishing a certainly comfortable, but ecologically destructive lifestyle. This entails many “fewer”: less meat and fish on our plates, less shopping, less travel, less consuming, and more savoring. All studies show that this is possible and that it will not affect our happiness.

We have begun our reflection with the lines of a poet. Let’s conclude it with the verses of another. All these resignations, which seem more and more necessary, perhaps offer a contemporary perspective to the magnificent and enigmatic verses that Guillaume Apollinaire (1880-1918) wrote in 1911, at the dawn of the Great War that would end the Belle Époque: «Uncertainty We will go far and happy, never returning, as crabs go, backwards, backwards ». Thus, we leave behind our time and its mirages; we abandon our toxic pleasures under the pressure of a microscopic coronavirus. What if we turned around to take a better look at what awaits us and what remains to be done? See you in 2022, to see if we’ve learned our lesson.

Persistent COVID-19, an inexplicable tiredness

Months after SARS-CoV-2 infection, many people still have symptoms. The most frequent is a constant exhaustion that makes it difficult to return to daily life.


Some of the people who become infected with SARS-CoV-2 later develop profound exhaustion. Sometimes this prevents them from going about their daily routine.

The virus causes various neuropsychiatric manifestations. These not only affect seriously ill people with COVID-19, but also people with asymptomatic or mild symptoms.

There is not enough data yet on whether medications can relieve fatigue. A combination of targeted training and psychotherapy can help you cope.

In November 2020, a young man of athletic bearing came to my office. He was 28 years old, slim and, at first glance, in good health. In February of that same year, he had gone skiing and in March, he had felt ill. He developed a slight cough and had some fever. He also suddenly lost his senses of smell and taste. But her discomfort subsided within two weeks. In addition, his sense of smell gradually improved, until it recovered completely after four weeks. However, he was unable to return to his demanding IT job. He was constantly feeling tired and down. He lacked the concentration to work for an hour or more in front of the computer screen. In addition, he had headaches and muscle aches. Before the first confinement, I trained every week in the gym, he played tennis regularly and jogged frequently. Now he complained that he was not able to participate in any sporting activities.

About four weeks after the first symptoms, a blood test revealed the presence of antibodies against SARS-CoV-2, which showed that he had been infected with the new coronavirus and his immune system had developed defenses against this pathogen. Since he was no longer suffering from the acute phase of COVID-19, a nasopharyngeal PCR could no longer detect the virus. More than half a year later, he was still on leave and was unable to return to work. How could you help him? What was behind the abnormal exhaustion that kept him out of the game?

In 2019, no one knew that one of the greatest pandemics in history threatened the world. By the end of 2020, more than 84 million people had been infected with the SARS-CoV-2 virus, which claimed the lives of more than 1.8 million of them. In record time, researchers around the world studied the virus and its symptoms. They found that it is not a simple lung disease, but that the new coronavirus can affect a large number of organs, including the brain.

In the acute phase of the disease, neurological symptoms can be seen mainly in people in intensive care units. Sudden onset of confusion, or delirium, is one of the most common complications. According to a 2021 study carried out by the international team for the investigation of COVID-19 in intensive care, this symptom affected more than half of the 2,088 patients studied. In addition, critically ill people sometimes develop memory and orientation problems, seizures, or a stroke.

Persistent COVID-19 symptoms

Many of those affected who have presented a mild picture of the disease complain of alterations of smell and taste, headaches and muscles and abnormal fatigue. Many others have not even realized that they had been infected. An analysis published in September 2020 by the team of Nicola Low, from the University of Bern, estimates that this was the case for one in five infected. The researchers reviewed 79 previously published studies with data from 6,616 people who tested positive for SARS-CoV-2; of these, 1278 had had an asymptomatic infection.

In general, a large part of patients continue to have long-term discomfort after the disease has passed. It is what is known as persistent COVID-19. Among those with mild symptoms, about one in three complain of persistent problems; among severe cases, four out of five are affected. Late neurological consequences are increasingly seen in hitherto healthy young people. Often, a strong fatigue appears that persists even after having had enough sleep. Those affected perceive it as unbearable. This syndrome, called “fatigue,” makes tasks that require concentration, sports, and even reading almost impossible. Frequently,

Several studies provide preliminary data on the onset of fatigue after COVID-19. In the Faroe Islands in Norway, a team led by Maria Skaalum Petersen asked patients about persistent symptoms 125 days after disease onset. More than 50 percent said they had at least one of them; one in three, two of the symptoms, and almost one in five interviewed, three of them. The most common long-term symptoms were fatigue, taste and smell disturbances, and joint pain. A study conducted in Israel by Barak Mizrahi and his collaborators showed similar results. The team analyzed the symptoms of nearly 2,500 people before, during and after COVID-19. In many cases they detected fatigue, muscle pain and respiratory problems,

In England, David Arnold’s team examined 110 COVID-19 patients treated at Bristol City hospital three months earlier. According to their  study , fatigue and respiratory problems (39 percent in both cases) were the most frequent symptoms. Also, sleep disorders (more than 24 percent) and muscle pain (20 percent) appeared often. A group led by Mayssam Mehne and Olivia Braillard, from the Geneva University Hospital, studied mildly ill patients with SARS-CoV-2. As they found in their  research , a third of the 669 people with an average age of about 43 years had persistent symptoms after the disease. The most frequent complaint was fatigue.

Thus, the appearance of fatigue does not appear to depend on the severity of the disease. The tendency to exhaustion can persist for weeks or even months after infection and significantly affect quality of life. In this context, doctors already speak of a “post-COVID-19 syndrome.” In addition to fatigue, other discomforts may occur, such as pain, breathing problems or mental disorders.

The many causes of fatigue

In general, fatigue is a typical side effect of debilitating illnesses. These include, for example, cancer and other chronic infections, such as tuberculosis. Sometimes it is even the first sign of a serious health problem. In addition, it is often accompanied by loss of appetite and weight and a general feeling of malaise. In some mental disorders, including depression, exhaustion is also a central symptom. During the COVID-19 pandemic, psychiatrists have observed an increase in cases of anxiety disorders, sleep disorders, depression, and post-traumatic stress disorder.

The cause could depend on different factors. The conditions of the pandemic reinforce the fears of some people. The social pressures and economic effects of confinement, as well as isolation, can also have a negative impact on mental health. Despite the many people suffering from the pandemic and its consequences, post-COVID-19 fatigue is unlikely to be a purely psychological problem. Many patients develop extreme fatigue, but do not meet the clinical criteria for depression. After a SARS-CoV-2 infection, along with exhaustion, concomitant cognitive problems sometimes appear. Those affected often complain of forgetfulness, difficulty concentrating, and loss of attention.

Some research has concluded that SARS-CoV-2 can penetrate directly from the nasal mucosa to the brain and there trigger inflammation. However, according to current data, this only happens rarely. In severely ill people, most neurological problems are likely to arise for other reasons. The body of some affected reacts to the virus with strong inflammation or by over-activating the blood clotting system. Lung damage can also have effects on the brain, since it makes it difficult for oxygen to reach the brain. By means of resonance images, diffuse lesions in the white matter, related to inflammation or circulation problems, have been observed in seriously ill patients. A team led by Avindra Nath, from the Bethesda National Institute of Neurological Disorders and Stroke, used a particularly powerful MRI scanner to examine the brains of 13 people who had died from COVID-19. In ten of them, they found small brain lesions. However, in most patients, standard MRI scans are normal.

The fact that fatigue appears even after mild COVID-19 symptoms and is not clearly correlated with severe cases, suggests that it is not a direct effect of the disease. On the other hand, many indications suggest that immune system disorders due to SARS-CoV-2 could cause neurological symptoms. Thus, as a defense against the virus, antibodies are formed that can cause inflammation in the brain, spinal cord, and peripheral nerves.

Some of the problems that remain after the acute phase could be due to these processes. In many infections, the body’s defenses produce proteins that promote the inflammatory process. The release of these cytokines is associated with fatigue and low mood. In severe COVID-19 cases, an excess of such molecules is sometimes generated and what is known as a ‘cytokine storm’ forms. This leads to many, sometimes life-threatening problems. In moderate conditions, fewer cytokines are secreted. But there are also clinically important effects.

What role does the immune system play?

Multiple teams have detected antibodies in the cerebrospinal fluid of people with severe COVID-19. These immune system molecules target structures in the body itself. They may interfere with brain function, causing extreme fatigue and cognitive problems. To date, such data is scarce in people with post-COVID-19 syndrome, and autoantibodies have not been shown to be present in the blood of those affected. However, from a neuroimmune point of view, it seems plausible that they play a role in fatigue. If this theory is confirmed, it could become the basis for future therapies. Perhaps exhaustion could be controlled with medications that influence the immune system.

Until the relevant data are available, the source of exhaustion cannot be tackled, but some drugs could alleviate it. Drugs such as modafinil (used to treat narcolepsy) or amantadine (used for Parkinson’s and fatigue in people with multiple sclerosis) would be possible candidates. However, controlled studies are required to show whether they are adequate.

In the coming months, more systematic studies will have to be carried out in people who have suffered from COVID-19 and continue to suffer its consequences. Magnetic resonance neuroimaging, as well as the analysis of antibodies in blood and cerebrospinal fluid, could shed light on the deterioration of bodily functions. They would have to be supplemented by clinical drug trials.

Last November I decided to pursue a combination treatment with my young and athletic patient. Thus, I prescribed specific physical and cognitive training, guided and accompanied by experts. I also prescribed a performance-enhancing drug used to treat people with depression. Thanks to the support of professionals for occupational reintegration, little by little he is returning to working life.

SARS-CoV-2: attack on neurons

Apparently, the new coronavirus moves from one neuron to another, although how is not yet known.

COVID-19 is more than a disease of the respiratory tract: in addition to the heart and lungs, it affects the central nervous system. Frank Heppner, from the Charité Hospital in Berlin, and his team analyzed different tissue samples from 33 patients, with an average age of 72 years, who had died from the new coronavirus. Using an electron microscope and special staining, they visualized intact SARS-CoV-2 virus particles inside the nerve cells of the olfactory mucosa, as well as in the processes of the lining cells present there.

In addition, the researchers found the coronavirus in different regions of the brain, for example, those that regulate respiratory activity. It is still unknown how the virus passes from the olfactory mucosa to the brain [ see ” What we know about changes in the nervous system due to COVID-19 “; by Stephani Sutherland; Mind and Brain , n. or 108, 2021]. Still, they suspect that it moves from neuron to neuron. It could also be carried by blood vessels to the brain. In addition, it is unknown if this process occurs the same in people who do not have any serious disease.

The image on the left shows a nerve cell infected by SARS-CoV-2 ( pink ) and stained by immunofluorescence within the olfactory mucosa. The coronavirus particles appear in yellow and the lining cells in blue. The electron microscope image to the side is of a cell from the olfactory mucosa. Intact virus particles appear red and cilia appear brown.

Organ regeneration with drugs

A drug that had been discarded reveals its ability to rebuild organs damaged by disease or injury.


Stem cell treatments make headlines about healing and regeneration of various parts of the body, but they have had little success.

The compound MSI-1436 appears more promising, as indicated by animal experiments. It removes the brake on the body’s natural ability to regenerate cells.

The molecule, originally intended for the treatment of diabetes and obesity, successfully passed safety tests in people, a huge advantage in drug development.


Regenerative medicine

An account of shark bites in a Scottish tavern opened us up to new ideas about rebuilding damaged organisms. At the beginning of this century, Georgetown University geneticist Michael Zasloff gave a lecture at the University of St. Andrews on various natural antibiotics found in animal skins. After the talk, he went to have a drink with other academics, and a marine biologist commented that dolphins were frequently attacked by sharks, causing huge injuries, 45 centimeters long and 12 centimeters deep. Surprisingly, the dolphins were cured within weeks, with no signs of infection.

Amazed by such speed to recover from excruciating injuries, Zasloff couldn’t stop thinking about that conversation. In the years that followed, he read reports on bitten dolphins and spoke with marine biologists who studied these animals. In 2011 he published a letter in the Journal of Investigative Dermatologyentitled “Observations on the extraordinary (and mysterious) wound healing of the bottlenose dolphin.” In it, he pointed out that the dolphins did not seem to just mend the tear with a scar, which produces other types of cells, but actually regenerated the damaged tissue. Soon after, he called one of us. Strange, then president of the Mount Desert Island Biology Laboratory (MDIBL) in Maine, was pushing for research into natural and synthetic compounds that stimulate regeneration, and Zasloff thought that some of the antibiotics he had discovered in animal skin also could encourage this kind of recovery. Anything that contributes to replenishing or restoring cells destroyed by disease or injury would be a medical breakthrough.


  • Limb regeneration
  • Challenges of regenerative medicine
  • Advances in regenerative medicine

Six years after that call, the three of us (Yin, Strange and Zasloff) have shown that the natural antibiotic MSI-1436, discovered by Zasloff in a small shark, intensely stimulates the regeneration of various damaged organs in zebrafish and the heart muscle. on the mouse. The compound releases certain molecular “brakes” that suppress the natural ability of tissue to regenerate after injury. In mice affected by the equivalent of muscular dystrophy in humans, it slows down the degeneration of the muscles. We are still experimenting with animals and have not demonstrated these effects in humans, but MSI-1436 has a significant advantage over the myriad compounds that show promise in the lab and then fail in people – it has already proven its safety.

Brain waves detected in mini-brains

A new method of stem cell culture has resulted in a network of neurons complex enough to produce electrical activity.

  • Sean Bailly

Section of a cerebral organoid. Each color corresponds to a different type of brain cell. [Muotri Lab / UCTV]

With some 86 billion neurons, the brain is a particularly difficult organ to study. One solution is to investigate a simplified system with fewer neurons. In 2013, Madeline Lancaster’s team from the Vienna Institute for Molecular Biotechnology created miniature brains, also known as brain organoids, from human stem cells in the laboratory.

Although these mini-brains are very useful to researchers, until now they have never observed electrical activity in them. Now they have. Alysson Muotri of the University of California, San Diego, and her team have improved organoid harvesting techniques and discovered that, after a period of development, brain waves similar to those seen in the brains of babies appear spontaneously premature

It was known that in the brains of these babies the electrical activity shows chaotic patterns. But what happened before, that is, how complex neural activity arises and develops, was completely unknown. Furthermore, although the work with rodents had made it possible to observe the activity of immature brains, the question arose as to whether this could be extrapolated to the human brain.


  • Brains created in the laboratory
  • Organoids: The Body Builders
  • Small artificial brains to investigate

Brain organoids offer an opportunity to study such questions. About the size of a pea, they are obtained from pluripotent human stem cells. If placed in an environment that reproduces the conditions in which the brain develops, these cells differentiate and form neurons that organize themselves in a three-dimensional structure. This results in a reduced and simplified version of the human cortex (brain region involved in the cognition and interpretation of sensory information). Building on previous work that had produced mini-brains without electrical activity, Muotri’s team refined the technique, allowing them to track hundreds of organoids for ten months.

The researchers first showed that organoids harbor the same cell types and proportions as human brains at the same stage of development. They also recorded the electrical activity of the organoids using multiple electrode arrays. Within a few months, the mini-brains produced activity never before seen in these systems. They were chaotic single-frequency electrical patterns, signals that are also detected in the immature brains of premature babies. Over time, the signals became more regular and more diverse in terms of frequency, a transition that indicates that mini-brains continue to develop as the number of neural connections increases.

Next, the authors created a deep learning program to study the formation of mini-brains. They used the brain wave recording of 39 babies born six to nine months after conception as a reference. By analyzing the signals from the organoids in different phases, the algorithm was able to predict the level of maturity of the minibrains. This confirms that human brains and organoids have comparable development. Therefore, the latter could be a model of great interest to study the development of the brain, but also diseases such as Alzheimer’s, epilepsy or autism, or to test drugs.

Despite this breakthrough, organoids remain rudimentary models and are a long way from representing the complexity of the human brain. The current work also raises ethical questions: from what moment can a miniature brain with brain activity be considered conscious? We still lack much knowledge about the brain to answer this thorny question.