A talk with Santiago Elena, CSIC Research Professor at the Institute for Integrative Systems Biology (UV-CSIC) Virologist Santiago F. Elena, a 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. His work is to know the genetic processes that determine the appearance of new viruses. This is a never-ending task since these microorganisms are constantly evolving at great speed. From his laboratory at the Institute for Integrative Systems Biology (I2SysBio, a joint centre of the CSIC and the Universitat de València), Elena works on infecting plants, which provide a safe and familiar environment for observing the behaviour of viruses. Now, the American Academy of Arts & Sciences has recognised him as a member in Biology, a distinction only shared by two other Spanish researchers: biochemist Margarita Salas (1938-2019), and biologist Antonio García Bellido. "It has been a surprise and above all an honour because it means the recognition of our American colleagues for all these years of work", says Elena. The global pandemic of COVID-19, caused by the coronavirus SARS-CoV-2, has once again put the spotlight on the work of virologists to probe 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 that it has a relatively long incubation period in which without showing symptoms it is still easily transmitted. 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 spread by the fluids, mostly blood, of those infected. But not this virus: this coronavirus, without causing symptoms that reduce the mobility of people, can already be transmitted. This means that an infected person can transmit it to quite a few people before having symptoms. Moreover, in most cases, the symptoms of the virus are not very severe. According to the seroprevention data that is 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 people infected, of which only 9.7% (about 230,000) have been confirmed by PCR and a little more than half of these have required hospitalization. Even so, the number of deaths is chilling: a total of 27,321 according to the data from the Spanish Ministry of Health made public yesterday, Thursday.
Virology and other infectious diseases talk about the balance pathogens have to achieve between their level of virulence (the damage done to the host) and their transmissibility. If you think of evolutionary strategies for a virus, simplifying the problem, there are two opposite 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 ability of the virus to spread in a susceptible host population. The other option is to be less virulent, not to harm the host, allowing for mobility, and therefore better transmission. So, if a less virulent mutant of the virus appears, it will be spread and selected naturally. In short: the more virulent, the less transmissible. For example, Ebola is terrible, very virulent, but it is badly spread because it requires very close contact with sick patients. If Ebola were to be as easily transmitted as SARS-CoV-2, it would be a planetary catastrophe.
Why is it important to know how they evolve?
For various reasons. Firstly, it is important to know where it comes from, to know its evolutionary origin, whether it comes from a bat -which is a usual reservoir for many viruses-, like the SARS-CoV of 2002, or from a camel like the MERS-CoV of 2012. It is essential to know which virus reservoirs exist in nature to assess their prevalence and the probability of their direct transmission to humans or our farm animals. If you want to prevent what is coming, you have to assess what is already there. Secondly, once the virus has made the jump from the reservoir species to us or our farm animals, we need to know what 3 processes are making the virus adapt to the new host, what is changing in the genome of the virus and its behaviour. Now there is a lot of talk about mutations in the SARS-CoV S protein and whether they are involved in increasing its transmissibility, but there are going to be other mutations to make it replicate better in us, and if we are lucky to decrease 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 how to handle it, to produce specific antibodies that generate a strong immune response.
In the international race for a vaccine, what are the most promising projects?
Developing a vaccine is a lot of science, but it is also an art. There are very standardised protocols. There is, for example, the classic approach of live attenuated vaccines, such as those for Salk's 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 of vaccine generation, 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 reverts; in any case, many tests must be done. Once you have the candidate you must 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 able to replicate, they sometimes generate little immune response or do not last long, 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. This produces a virus that you will use in the vaccine, that you will inject into people; it will enter the cells, it will do the cycle of replication, 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; first you have to generate the vaccine and then check that it works. If it does not work, you have to go back and start again. The process is slow. How do you do that? By brute force: you have to have many laboratories attacking the problem, so that there are many mistakes, so that many people fail by different routes but at least one finds the optimal solution. What does brute force depend on? On the amount of money, experience, resources, and equipment. And countries with a tradition of investment in science have the best resources and are the best positioned. Once the vaccine is generated and tested, the second part comes: it has to be produced on an industrial scale to inoculate millions of people. That is a 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 am not mistaken, in Spain we do not have one.
Is the search for antivirals more affordable than a vaccine?
It is more possible to have antivirals earlier than a vaccine. In fact, Remdesivir, which is much talked about 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 so-called nucleotide analogues. Nucleotides are the building blocks of the virus genome (and ours, of course). Analogues carry chemical modifications that once incorporated into the replicating genome prevent it from continuing. It is as if we were piling up pieces of Lego and suddenly, we introduce a defective one; from then on, we can no longer add more. This does not mean that Remdesivir will work optimally with any virus; there will be some that respond better than others to treatment. It seems that the SARS-CoV-2 trials are promising. However, I recently read on the NIH website that this drug reduces the time patients are admitted from 15 days to 11 days on average, which may be beneficial to the health system because it allows ICU beds to be released sooner, but in individual terms, it doesn't seem to be much of an improvement either.
Another way to get antivirals is to redesign existing drugs and apply them to this coronavirus.
Many of the existing antiviral drugs are being redesigned. 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 SARS-CoV in 2002, you can redesign them on the computer, chemically synthesize them - which is relatively easy or fast - and apply them to SARS-CoV-2. Test them in cell cultures as a first phase, then in animals, and then in patients. That, in principle, is faster than a vaccine, already parts of a molecular structure that you know works against something that looks like SARS-CoV-2.
