A talk with Santiago Elena, CSIC Research Professor at the Institute of Integrative Systems Biology (UV-CSIC). The virologist Santiago F. Elena, new member of the American Academy of Arts & Sciences, studies the mechanisms by which viruses adapt to their new hosts.

Virologist Santiago F. Elena seeks to unravel the mechanisms that govern the evolution of viruses. Their job is to understand the genetic processes that determine the appearance of new viruses. It is a work that never ends, since these microorganisms evolve constantly and at high speed. From her laboratory at the Institute of Integrative Systems Biology (I2SysBio, a joint center of the CSIC and the University of Valencia), Elena works infecting plants, which provide a safe and known environment to observe the behavior of viruses. Now, the American Academy of Arts & Sciences has recognized him as a member in the area of ​​Biology, a distinction that has only been shared by two other Spanish researchers: the biochemist Margarita Salas (1938-2019), and the biologist Antonio García Bellido. "It has been a surprise and above all an honor because it represents the recognition of all these years of work from our American colleagues," says Elena. The global COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has once again put the spotlight on the work of virologists to scrutinize the secrets of these microorganisms, which need to parasitize cells to live and which have brought the world to its knees.

What makes SARS-CoV-2 so dangerous?

That it is easily transmitted. And it has a relatively long incubation period in which it is still easily transmitted without showing symptoms. There are other viruses that have a long incubation period, but are not transmissible until the patient shows symptoms, such as sneezing. Or, as in the case of chickenpox or smallpox, through the vesicles that form on the skin. Or with Ebola, which is transmitted through the fluids, mostly blood, of those infected. But not this virus: this coronavirus, without causing symptoms that reduce people's mobility, can already be transmitted. This means that an infected person can transmit it to many people before having symptoms. And, furthermore, in most cases, the symptoms of the virus are not very severe. According to the seroprevalence data that are becoming known, only 5% of the population, on average, has been exposed to the virus and has developed antibodies. That would be about 2.4 million infected, of which only 9.7% (about 230,000) have been confirmed by PCR and just over half of these have required hospitalization. Even so, the death toll is chilling: a total of 27,321 according to data from the Ministry of Health made public yesterday Thursday.

In virology and other infectious diseases we talk about the balance that pathogens have to achieve between their level of virulence (the damage exerted on the host) and their transmissibility. If you think about evolutionary strategies for a virus, simplifying the problem, there are two opposing options: if it is very virulent and affects patients very negatively, they stop moving and, therefore, the virus will be transmitted with less probability. But this is a poor evolutionary strategy, as it limits the virus's ability to spread in a population of susceptible hosts. The other option is to be low virulent, not damaging the host, allowing its mobility, and therefore better transmission. So if a less virulent mutant of the virus appears, it will be transmitted and selected naturally. In short: the more virulence, the less transmissibility. For example, Ebola is terrible, very virulent, but it is poorly transmitted since it requires very close contact with sick patients. If Ebola were transmitted as easily as SARS-CoV-2, it would be a planetary catastrophe.

Why is it important to know how they evolve?

For various reasons. First of all, it is important to know where it comes from, to know its evolutionary origin, if it comes from a bat – which is a common reservoir for many viruses –, such as the SARS-CoV of 2002, or from a camel such as the MERS-CoV of 2012. It is essential to know what virus reservoirs exist in nature to make an assessment of their prevalence and the probability of it being transmitted directly to humans or our farm animals. If you want to prevent what is going to come, you have to evaluate what is already there. Secondly, once the virus has made the species jump from the reservoir to us or our farm animals, we must know what 3 processes make the virus adapt to the new host, what changes in the virus's genome and its behavior. Now there is a lot of talk about mutations in the S protein of SARS-CoV and whether they are involved in increasing its transmissibility, but there will be other mutations so that it replicates better in us, and if we are lucky, reduce its virulence. That may or may not happen, the evolution of a complex system is always difficult, if not impossible, to predict. We need to know how it will change when we have a vaccine and as our immune system begins to learn to handle it, to produce specific antibodies that generate a powerful immune response.

In the international race for the vaccine, what are the most promising projects?

Developing a vaccine is a lot of science, but also art. There are very standardized protocols. There is, for example, the classic method of live attenuated vaccines, such as those for Salk polio, yellow fever, measles, rubella, mumps or chickenpox. It consists of experimentally adapting the virus to an alternative host and hoping that this will reduce its virulence in us. It is a classic system for generating vaccines, which takes time and is achieved by trial and error. You attenuate the virus, but sometimes you go too far and the attenuated virus does not generate an immune response, or sometimes it reverses; In any case, many tests must be done. Once you have the candidate you have to test it on monkeys, then on people, and see if it works. There are other strategies, such as inactivated vaccines that are formed from dead viruses or fragments of these, such as flu, rabies or hepatitis A. The problem with these is that, since they are not capable of replicating, they sometimes generate little or little lasting immune response over time and it is necessary to vaccinate periodically. Another strategy, which is now being developed at the CNB-CSIC, is to generate a virus that lacks a protein, which makes it incompetent and cannot replicate on its own, but you can reproduce it in the laboratory in cells that provide it with that protein. In this way, a virus is produced that will be the one you will use in the vaccine, which you will inject into people; It will enter the cells, it will do the replication cycle, but it will not be able to leave the cells; but the important thing is that it will generate an immune response. But everything must be checked; You first have to generate the vaccine and then check that it works. If it doesn't work for you, you have to go back and start over. The process is slow. How is that achieved? Based on brute force: you have to have many laboratories attacking the problem, so that there are many errors, so that many people fail in different ways but at least one finds the optimal solution. What does brute force depend on? From the amount of money, experience, resources and equipment. And countries with a tradition of investing in science have the best resources and are the best positioned. Once the vaccine is generated and tested, comes the second part: it must be produced on an industrial scale to inoculate millions of people. That is another different problem: the industrial scale. If we want the vaccine to be public and free, a large public pharmaceutical company is required to produce it, and if I'm not mistaken, in Spain we don't have one.

Is the search for antivirals more affordable than that of a vaccine?

It is more possible to have antivirals before the vaccine. In fact, Remdesivir, which is being talked about a lot now, was originally designed to treat Ebola patients. But its mechanism of action is so basic that it can easily be adapted for use against other viruses. It belongs to a class of antivirals that are called nucleotide analogues. Nucleotides are the pieces with which the genome of viruses is built (and ours, of course). Analogs carry chemical modifications that, once incorporated into the replicating genome, prevent it from continuing. It's as if we were stacking Lego pieces and suddenly we introduced a defective one; From there we can no longer continue adding more. This does not mean that Remdesivir will work optimally with any virus, there will be some that respond better to treatment than others. It seems that tests with SARS-CoV-2 are promising. However, I recently read on the NIH website that this drug reduces the time of hospitalization of patients from 15 days to 11 days on average, something that can be beneficial for the health system because it allows beds in ICUs to be freed up sooner, but in individual terms, it does not seem like a great improvement either.

Another way to obtain antivirals is to redesign drugs that already exist and apply them to this coronavirus.

Many of the antiviral drugs that already exist undergo a redesign. You have a molecule that you know works against a virus related or not to the one you want to attack now and you do in silico studies to see what modifications you would have to make to that molecule to increase its activity against the new virus. For example, the antivirals that were developed against the 2002 SARS-CoV can be redesigned on the computer, chemically synthesized – which is relatively easy or fast – and applied to SARS-CoV-2. Testing them in cell cultures as a first phase, then in animals and then in patients. That, in principle, is faster than a vaccine, since it starts from a molecular structure that you know works against something that looks like SARS-CoV-2.

Source: Delegation of the CSIC to the Valencian Community